Somatic Disorders

A large, retrospective cohort study is the latest to look at the association between isotretinoin and attempted suicide. Concerns about a link between isotretinoin and suicidal behavior have abounded for years, although previous studies have failed to show a conclusive link.

By studying when (before, during, or up to 15 years after treatment) suicidal behavior is most likely to occur in relation to treatment, researchers found that although the risk is increased during and up to 1 year after treatment, such risk is more likely related to the psychological effects associated with the disease – severe acne – than with the isotretinoin, and may be affected by treatment failure.

Pharmacoepidemiologist Anders Sundström of the Karolinska Institute in Stockholm and colleagues examined named records for 5,756 Swedish patients (aged 15–49 years) who were prescribed isotretinoin in 1980–1989. The men had a mean age of 22.3 years (women, 27.1 years) at first prescription, and were taking mean daily doses of 44.5 mg and 39.2 mg isotretinoin, respectively, for severe acne. Mean length of treatment was 4 months for men and 3.9 months for women. The patients' clinical records were compared with hospital-discharge and cause-of-death registers for the 1980–2001 period.

In all, 128 patients in the cohort were hospitalized for attempted suicide on 210 occasions during the study period; there were 24 completed suicides during this time. When the study cohort was compared with the general population, the standardized incidence ratios for suicide attempts rose from 0.89 (95% confidence interval, 0.54–1.37) at 3 years before treatment to 1.36 (95% CI, 0.65–2.50) in the year before treatment for first attempts, and from 0.99 (95% CI, 0.65–1.44) at 3 years before treatment to 1.57 (95% CI, 0.86–2.63) in the year before treatment for all attempts.

The risks were shown to be highest within 6 months after the start of treatment: 1.93 (95% CI, 1.08–3.18) for first attempts and 1.78 (95% CI, 1.04–2.85) for all attempts. The investigators also found that women who made suicide attempts received two or three treatments more often than did women who did not attempt suicide, suggesting treatment failure as a possible contributor.

After treatment, the standardized incidence ratio declined to 0.97 (95% CI, 0.64–1.40) for first attempts and 1.04 (95% CI, 0.74–1.43) for all attempts within 3 years. After 3 years and for the duration of follow-up, the rate remained on par with the background rate for the population.

The investigators concluded that “an increased risk of attempted suicide was apparent up to six months after the end of treatment with isotretinoin.” However, they wrote, “the risk of attempted suicide was already rising before treatment, so an additional risk due to the isotretinoin treatment cannot be established.” Patients with a history of suicide attempts need not be denied treatment with isotretinoin, they wrote, but “close monitoring of patients for suicidal behavior for up to a year after treatment has ended” would be advisable (BMJ 2010 Nov. 12 [doi:10/1136/bmj.c5812]).

The investigators acknowledged some limitations of their study, including a lack of data on potential confounding factors other than age, sex, and calendar year. Low statistical precision was also a limitation: Although standardized incidence ratios were clearly rising before treatment, they wrote, “we found no statistical significance until six months after treatment. In the internal cohort crossover analysis – that is, analyzing outcomes before and after treatment in the same population – the differences in incidence did not reach statistical significance, making the estimated number needed to harm uncertain.”

Also, they wrote, “we had no information on the effect of treatment. A bias would exist if the patients who made suicide attempts had a poorer effect of treatment than did those who did not make such attempts. In that case, the suicidal behavior should be attributed to the treatment resistant acne and not to the treatment. However, such bias would only strengthen the assumed association between severe acne and suicidal behavior.”

In an editorial comment, Dr. Parker Magin of the University of Newcastle in Callaghan, New South Wales, Australia, and Dr. John Sullivan of the University of New South Wales in Sydney, said that clinicians could draw important practical conclusions from the study – namely, that during and after treatment with isotretinoin (and especially when treatment is unsuccessful), “patients should be carefully monitored for depression and suicidal thoughts. Patients probably have an increased risk before treatment, however, so all patients with acne of a severity for which isotretinoin is indicated should have psychosocial factors and suicidal intent monitored.”

As for who should perform the monitoring, Dr. Magin said that although dermatologists generally take on that role, general practitioners “have more appropriate training and experience in psychological medicine … and could add invaluable expertise in the psychological aspects of management in a shared care model with dermatologists.” Families of patients, Dr. Magin added, may also help with monitoring. (BMJ 2010 Nov. 12 [doi:10.1136/bmj.c5866])

The study was funded by the Swedish Research Council. Mr. Sundström and his coauthors declared that they had no conflicts of interest. Dr. Magin and Dr. Sullivan have been members of All About Acne, an organization supported by unrestricted educational grants from drug companies. Neither Dr. Magin nor Dr. Sullivan received payment from the organization, and the drug companies that provide support do not manufacture isotretinoin.

A large, retrospective cohort study is the latest to look at the association between isotretinoin and attempted suicide. Concerns about a link between isotretinoin and suicidal behavior have abounded for years, although previous studies have failed to show a conclusive link.

By studying when (before, during, or up to 15 years after treatment) suicidal behavior is most likely to occur in relation to treatment, researchers found that although the risk is increased during and up to 1 year after treatment, such risk is more likely related to the psychological effects associated with the disease – severe acne – than with the isotretinoin, and may be affected by treatment failure.

Pharmacoepidemiologist Anders Sundström of the Karolinska Institute in Stockholm and colleagues examined named records for 5,756 Swedish patients (aged 15–49 years) who were prescribed isotretinoin in 1980–1989. The men had a mean age of 22.3 years (women, 27.1 years) at first prescription, and were taking mean daily doses of 44.5 mg and 39.2 mg isotretinoin, respectively, for severe acne. Mean length of treatment was 4 months for men and 3.9 months for women. The patients' clinical records were compared with hospital-discharge and cause-of-death registers for the 1980–2001 period.

In all, 128 patients in the cohort were hospitalized for attempted suicide on 210 occasions during the study period; there were 24 completed suicides during this time. When the study cohort was compared with the general population, the standardized incidence ratios for suicide attempts rose from 0.89 (95% confidence interval, 0.54–1.37) at 3 years before treatment to 1.36 (95% CI, 0.65–2.50) in the year before treatment for first attempts, and from 0.99 (95% CI, 0.65–1.44) at 3 years before treatment to 1.57 (95% CI, 0.86–2.63) in the year before treatment for all attempts.

The risks were shown to be highest within 6 months after the start of treatment: 1.93 (95% CI, 1.08–3.18) for first attempts and 1.78 (95% CI, 1.04–2.85) for all attempts. The investigators also found that women who made suicide attempts received two or three treatments more often than did women who did not attempt suicide, suggesting treatment failure as a possible contributor.

After treatment, the standardized incidence ratio declined to 0.97 (95% CI, 0.64–1.40) for first attempts and 1.04 (95% CI, 0.74–1.43) for all attempts within 3 years. After 3 years and for the duration of follow-up, the rate remained on par with the background rate for the population.

The investigators concluded that “an increased risk of attempted suicide was apparent up to six months after the end of treatment with isotretinoin.” However, they wrote, “the risk of attempted suicide was already rising before treatment, so an additional risk due to the isotretinoin treatment cannot be established.” Patients with a history of suicide attempts need not be denied treatment with isotretinoin, they wrote, but “close monitoring of patients for suicidal behavior for up to a year after treatment has ended” would be advisable (BMJ 2010 Nov. 12 [doi:10/1136/bmj.c5812]).

The investigators acknowledged some limitations of their study, including a lack of data on potential confounding factors other than age, sex, and calendar year. Low statistical precision was also a limitation: Although standardized incidence ratios were clearly rising before treatment, they wrote, “we found no statistical significance until six months after treatment. In the internal cohort crossover analysis – that is, analyzing outcomes before and after treatment in the same population – the differences in incidence did not reach statistical significance, making the estimated number needed to harm uncertain.”

Also, they wrote, “we had no information on the effect of treatment. A bias would exist if the patients who made suicide attempts had a poorer effect of treatment than did those who did not make such attempts. In that case, the suicidal behavior should be attributed to the treatment resistant acne and not to the treatment. However, such bias would only strengthen the assumed association between severe acne and suicidal behavior.”

In an editorial comment, Dr. Parker Magin of the University of Newcastle in Callaghan, New South Wales, Australia, and Dr. John Sullivan of the University of New South Wales in Sydney, said that clinicians could draw important practical conclusions from the study – namely, that during and after treatment with isotretinoin (and especially when treatment is unsuccessful), “patients should be carefully monitored for depression and suicidal thoughts. Patients probably have an increased risk before treatment, however, so all patients with acne of a severity for which isotretinoin is indicated should have psychosocial factors and suicidal intent monitored.”

As for who should perform the monitoring, Dr. Magin said that although dermatologists generally take on that role, general practitioners “have more appropriate training and experience in psychological medicine … and could add invaluable expertise in the psychological aspects of management in a shared care model with dermatologists.” Families of patients, Dr. Magin added, may also help with monitoring. (BMJ 2010 Nov. 12 [doi:10.1136/bmj.c5866])

The study was funded by the Swedish Research Council. Mr. Sundström and his coauthors declared that they had no conflicts of interest. Dr. Magin and Dr. Sullivan have been members of All About Acne, an organization supported by unrestricted educational grants from drug companies. Neither Dr. Magin nor Dr. Sullivan received payment from the organization, and the drug companies that provide support do not manufacture isotretinoin.

A large, retrospective cohort study is the latest to look at the association between isotretinoin and attempted suicide. Concerns about a link between isotretinoin and suicidal behavior have abounded for years, although previous studies have failed to show a conclusive link.

By studying when (before, during, or up to 15 years after treatment) suicidal behavior is most likely to occur in relation to treatment, researchers found that although the risk is increased during and up to 1 year after treatment, such risk is more likely related to the psychological effects associated with the disease – severe acne – than with the isotretinoin, and may be affected by treatment failure.

Pharmacoepidemiologist Anders Sundström of the Karolinska Institute in Stockholm and colleagues examined named records for 5,756 Swedish patients (aged 15–49 years) who were prescribed isotretinoin in 1980–1989. The men had a mean age of 22.3 years (women, 27.1 years) at first prescription, and were taking mean daily doses of 44.5 mg and 39.2 mg isotretinoin, respectively, for severe acne. Mean length of treatment was 4 months for men and 3.9 months for women. The patients' clinical records were compared with hospital-discharge and cause-of-death registers for the 1980–2001 period.

In all, 128 patients in the cohort were hospitalized for attempted suicide on 210 occasions during the study period; there were 24 completed suicides during this time. When the study cohort was compared with the general population, the standardized incidence ratios for suicide attempts rose from 0.89 (95% confidence interval, 0.54–1.37) at 3 years before treatment to 1.36 (95% CI, 0.65–2.50) in the year before treatment for first attempts, and from 0.99 (95% CI, 0.65–1.44) at 3 years before treatment to 1.57 (95% CI, 0.86–2.63) in the year before treatment for all attempts.

The risks were shown to be highest within 6 months after the start of treatment: 1.93 (95% CI, 1.08–3.18) for first attempts and 1.78 (95% CI, 1.04–2.85) for all attempts. The investigators also found that women who made suicide attempts received two or three treatments more often than did women who did not attempt suicide, suggesting treatment failure as a possible contributor.

After treatment, the standardized incidence ratio declined to 0.97 (95% CI, 0.64–1.40) for first attempts and 1.04 (95% CI, 0.74–1.43) for all attempts within 3 years. After 3 years and for the duration of follow-up, the rate remained on par with the background rate for the population.

The investigators concluded that “an increased risk of attempted suicide was apparent up to six months after the end of treatment with isotretinoin.” However, they wrote, “the risk of attempted suicide was already rising before treatment, so an additional risk due to the isotretinoin treatment cannot be established.” Patients with a history of suicide attempts need not be denied treatment with isotretinoin, they wrote, but “close monitoring of patients for suicidal behavior for up to a year after treatment has ended” would be advisable (BMJ 2010 Nov. 12 [doi:10/1136/bmj.c5812]).

The investigators acknowledged some limitations of their study, including a lack of data on potential confounding factors other than age, sex, and calendar year. Low statistical precision was also a limitation: Although standardized incidence ratios were clearly rising before treatment, they wrote, “we found no statistical significance until six months after treatment. In the internal cohort crossover analysis – that is, analyzing outcomes before and after treatment in the same population – the differences in incidence did not reach statistical significance, making the estimated number needed to harm uncertain.”

Also, they wrote, “we had no information on the effect of treatment. A bias would exist if the patients who made suicide attempts had a poorer effect of treatment than did those who did not make such attempts. In that case, the suicidal behavior should be attributed to the treatment resistant acne and not to the treatment. However, such bias would only strengthen the assumed association between severe acne and suicidal behavior.”

In an editorial comment, Dr. Parker Magin of the University of Newcastle in Callaghan, New South Wales, Australia, and Dr. John Sullivan of the University of New South Wales in Sydney, said that clinicians could draw important practical conclusions from the study – namely, that during and after treatment with isotretinoin (and especially when treatment is unsuccessful), “patients should be carefully monitored for depression and suicidal thoughts. Patients probably have an increased risk before treatment, however, so all patients with acne of a severity for which isotretinoin is indicated should have psychosocial factors and suicidal intent monitored.”

As for who should perform the monitoring, Dr. Magin said that although dermatologists generally take on that role, general practitioners “have more appropriate training and experience in psychological medicine … and could add invaluable expertise in the psychological aspects of management in a shared care model with dermatologists.” Families of patients, Dr. Magin added, may also help with monitoring. (BMJ 2010 Nov. 12 [doi:10.1136/bmj.c5866])

The study was funded by the Swedish Research Council. Mr. Sundström and his coauthors declared that they had no conflicts of interest. Dr. Magin and Dr. Sullivan have been members of All About Acne, an organization supported by unrestricted educational grants from drug companies. Neither Dr. Magin nor Dr. Sullivan received payment from the organization, and the drug companies that provide support do not manufacture isotretinoin.

SAN ANTONIO – Poor medication adherence is significantly more common in heart failure patients who have excessive daytime sleepiness, a study shows.

The implication of this finding is that interventions aimed at improving excessive daytime sleepiness may pay dividends in terms of better medication adherence. This would be particularly advantageous in a condition such as heart failure, in which patients take numerous drugs that are important in controlling the neuroendocrine response to the disease, Barbara Riegel, D.N.Sc., observed.

She presented a study of a convenience sample of 278 adult outpatients with chronic stage C heart failure who participated in structured in-home interviews by trained research assistants who assessed medication adherence during the previous month.

Participants were also evaluated for excessive daytime sleepiness according to the Epworth Sleepiness Scale. Excessive daytime sleepiness (defined as an Epworth score of 6 or greater) was present in 56.5% of patients. Among the subset of heart failure patients with excessive daytime sleepiness who had undergone testing in a sleep laboratory, the majority was found to have sleep-disordered breathing, with an apnea-hypopnea index of at least 15 events per hour, reported Dr. Riegel of the University of Pennsylvania School of Nursing, Philadelphia.

The most problematic medication adherence issue for the study participants was forgetting to take their medications on schedule. In all, 56% of heart failure patients with excessive daytime sleepiness reported often taking their medications more than 2 hours late, compared with 38% of nonsleepy subjects. In addition, 10% of subjects with excessive daytime sleepiness reported skipping consecutive medication doses, compared with 3% of nonsleepy patients.

This study was funded by the National Heart, Lung, and Blood Institute. Dr. Riegel reported having no financial conflicts.

SAN ANTONIO – Poor medication adherence is significantly more common in heart failure patients who have excessive daytime sleepiness, a study shows.

The implication of this finding is that interventions aimed at improving excessive daytime sleepiness may pay dividends in terms of better medication adherence. This would be particularly advantageous in a condition such as heart failure, in which patients take numerous drugs that are important in controlling the neuroendocrine response to the disease, Barbara Riegel, D.N.Sc., observed.

She presented a study of a convenience sample of 278 adult outpatients with chronic stage C heart failure who participated in structured in-home interviews by trained research assistants who assessed medication adherence during the previous month.

Participants were also evaluated for excessive daytime sleepiness according to the Epworth Sleepiness Scale. Excessive daytime sleepiness (defined as an Epworth score of 6 or greater) was present in 56.5% of patients. Among the subset of heart failure patients with excessive daytime sleepiness who had undergone testing in a sleep laboratory, the majority was found to have sleep-disordered breathing, with an apnea-hypopnea index of at least 15 events per hour, reported Dr. Riegel of the University of Pennsylvania School of Nursing, Philadelphia.

The most problematic medication adherence issue for the study participants was forgetting to take their medications on schedule. In all, 56% of heart failure patients with excessive daytime sleepiness reported often taking their medications more than 2 hours late, compared with 38% of nonsleepy subjects. In addition, 10% of subjects with excessive daytime sleepiness reported skipping consecutive medication doses, compared with 3% of nonsleepy patients.

This study was funded by the National Heart, Lung, and Blood Institute. Dr. Riegel reported having no financial conflicts.

SAN ANTONIO – Poor medication adherence is significantly more common in heart failure patients who have excessive daytime sleepiness, a study shows.

The implication of this finding is that interventions aimed at improving excessive daytime sleepiness may pay dividends in terms of better medication adherence. This would be particularly advantageous in a condition such as heart failure, in which patients take numerous drugs that are important in controlling the neuroendocrine response to the disease, Barbara Riegel, D.N.Sc., observed.

She presented a study of a convenience sample of 278 adult outpatients with chronic stage C heart failure who participated in structured in-home interviews by trained research assistants who assessed medication adherence during the previous month.

Participants were also evaluated for excessive daytime sleepiness according to the Epworth Sleepiness Scale. Excessive daytime sleepiness (defined as an Epworth score of 6 or greater) was present in 56.5% of patients. Among the subset of heart failure patients with excessive daytime sleepiness who had undergone testing in a sleep laboratory, the majority was found to have sleep-disordered breathing, with an apnea-hypopnea index of at least 15 events per hour, reported Dr. Riegel of the University of Pennsylvania School of Nursing, Philadelphia.

The most problematic medication adherence issue for the study participants was forgetting to take their medications on schedule. In all, 56% of heart failure patients with excessive daytime sleepiness reported often taking their medications more than 2 hours late, compared with 38% of nonsleepy subjects. In addition, 10% of subjects with excessive daytime sleepiness reported skipping consecutive medication doses, compared with 3% of nonsleepy patients.

This study was funded by the National Heart, Lung, and Blood Institute. Dr. Riegel reported having no financial conflicts.

MONTREAL – Sleep problems are common among individuals exposed to terrorist attacks, and new evidence suggests that sleep deficits are contributing to obesity in this traumatized population, researchers reported at the meeting.

Disturbed sleep and traumatic nightmares are hallmarks of posttraumatic stress disorder (PTSD), said Brian Hall, a doctoral candidate at Kent (Ohio) State University and a clinical psychology intern at the Medical University of South Carolina, Charleston. “Sleep is a treatment-refractory target in PTSD. In folks who respond well to treatments for PTSD, sleep problems tend to be a residual issue.”

In a study of 501 Israeli Jews living along the Gaza strip, Mr. Hall and his colleagues found that 47% had had at least one direct terrorist exposure involving the death of a relative, personal injury, injury of a relative or close friend, or witnessing a rocket or terrorist attack with injuries or fatalities.

PTSD was present in 5.5% of this highly exposed cohort, and depression in an additional 3.8%. Clinical sleep disturbance, assessed using the 18-item Pittsburgh Sleep Quality Index (PSQI), was present in 37.4% of the cohort, but reached 82% among those identified with PTSD, and 79% among those who were depressed. Overweight, assessed by body mass index, was present in 45% of the entire cohort, with 11% of the overweight group meeting criteria for obesity, he said at the meeting, cosponsored by Boston University.

Statistical analysis showed that although there was no direct effect of PTSD on BMI, sleep mediated this effect.

In a separate analysis of the same data, Stevan Hobfoll, Ph.D., of Rush University Medical Center, Chicago, reported that females were more prone than were males to sleep problems (odds ratio, 1.45), as were individuals aged 50–64 years (OR, 2.07) and those older than age 65 years (OR, 4.45). Sleep problems can worsen PTSD symptoms and might exacerbate health problems such as cardiovascular disease, stroke, and diabetes, Mr. Hall said in an interview. “Interventions targeting sleep problems are important in PTSD.”

Asked to comment on the findings, Jeffrey Knight, Ph.D., raised questions about them. “These things are all related, but to what degree and in what order? What do you do with the person in front of you?” said Dr. Knight, a clinical neuropsychologist at the National Center for PTSD, VA Boston Healthcare System, and Boston University. “What you have is a ball of symptoms traveling together as a unit – it's like a soccer ball – and at any particular time it rolls over and you see certain facets, but the other parts are still operative. Sleep is a piece of the protocol, but whether it's driven by anxiety or depression or nightmares, you need to address it differently.

None of the presenters reported having conflicts of interest.

MONTREAL – Sleep problems are common among individuals exposed to terrorist attacks, and new evidence suggests that sleep deficits are contributing to obesity in this traumatized population, researchers reported at the meeting.

Disturbed sleep and traumatic nightmares are hallmarks of posttraumatic stress disorder (PTSD), said Brian Hall, a doctoral candidate at Kent (Ohio) State University and a clinical psychology intern at the Medical University of South Carolina, Charleston. “Sleep is a treatment-refractory target in PTSD. In folks who respond well to treatments for PTSD, sleep problems tend to be a residual issue.”

In a study of 501 Israeli Jews living along the Gaza strip, Mr. Hall and his colleagues found that 47% had had at least one direct terrorist exposure involving the death of a relative, personal injury, injury of a relative or close friend, or witnessing a rocket or terrorist attack with injuries or fatalities.

PTSD was present in 5.5% of this highly exposed cohort, and depression in an additional 3.8%. Clinical sleep disturbance, assessed using the 18-item Pittsburgh Sleep Quality Index (PSQI), was present in 37.4% of the cohort, but reached 82% among those identified with PTSD, and 79% among those who were depressed. Overweight, assessed by body mass index, was present in 45% of the entire cohort, with 11% of the overweight group meeting criteria for obesity, he said at the meeting, cosponsored by Boston University.

Statistical analysis showed that although there was no direct effect of PTSD on BMI, sleep mediated this effect.

In a separate analysis of the same data, Stevan Hobfoll, Ph.D., of Rush University Medical Center, Chicago, reported that females were more prone than were males to sleep problems (odds ratio, 1.45), as were individuals aged 50–64 years (OR, 2.07) and those older than age 65 years (OR, 4.45). Sleep problems can worsen PTSD symptoms and might exacerbate health problems such as cardiovascular disease, stroke, and diabetes, Mr. Hall said in an interview. “Interventions targeting sleep problems are important in PTSD.”

Asked to comment on the findings, Jeffrey Knight, Ph.D., raised questions about them. “These things are all related, but to what degree and in what order? What do you do with the person in front of you?” said Dr. Knight, a clinical neuropsychologist at the National Center for PTSD, VA Boston Healthcare System, and Boston University. “What you have is a ball of symptoms traveling together as a unit – it's like a soccer ball – and at any particular time it rolls over and you see certain facets, but the other parts are still operative. Sleep is a piece of the protocol, but whether it's driven by anxiety or depression or nightmares, you need to address it differently.

None of the presenters reported having conflicts of interest.

MONTREAL – Sleep problems are common among individuals exposed to terrorist attacks, and new evidence suggests that sleep deficits are contributing to obesity in this traumatized population, researchers reported at the meeting.

Disturbed sleep and traumatic nightmares are hallmarks of posttraumatic stress disorder (PTSD), said Brian Hall, a doctoral candidate at Kent (Ohio) State University and a clinical psychology intern at the Medical University of South Carolina, Charleston. “Sleep is a treatment-refractory target in PTSD. In folks who respond well to treatments for PTSD, sleep problems tend to be a residual issue.”

In a study of 501 Israeli Jews living along the Gaza strip, Mr. Hall and his colleagues found that 47% had had at least one direct terrorist exposure involving the death of a relative, personal injury, injury of a relative or close friend, or witnessing a rocket or terrorist attack with injuries or fatalities.

PTSD was present in 5.5% of this highly exposed cohort, and depression in an additional 3.8%. Clinical sleep disturbance, assessed using the 18-item Pittsburgh Sleep Quality Index (PSQI), was present in 37.4% of the cohort, but reached 82% among those identified with PTSD, and 79% among those who were depressed. Overweight, assessed by body mass index, was present in 45% of the entire cohort, with 11% of the overweight group meeting criteria for obesity, he said at the meeting, cosponsored by Boston University.

Statistical analysis showed that although there was no direct effect of PTSD on BMI, sleep mediated this effect.

In a separate analysis of the same data, Stevan Hobfoll, Ph.D., of Rush University Medical Center, Chicago, reported that females were more prone than were males to sleep problems (odds ratio, 1.45), as were individuals aged 50–64 years (OR, 2.07) and those older than age 65 years (OR, 4.45). Sleep problems can worsen PTSD symptoms and might exacerbate health problems such as cardiovascular disease, stroke, and diabetes, Mr. Hall said in an interview. “Interventions targeting sleep problems are important in PTSD.”

Asked to comment on the findings, Jeffrey Knight, Ph.D., raised questions about them. “These things are all related, but to what degree and in what order? What do you do with the person in front of you?” said Dr. Knight, a clinical neuropsychologist at the National Center for PTSD, VA Boston Healthcare System, and Boston University. “What you have is a ball of symptoms traveling together as a unit – it's like a soccer ball – and at any particular time it rolls over and you see certain facets, but the other parts are still operative. Sleep is a piece of the protocol, but whether it's driven by anxiety or depression or nightmares, you need to address it differently.

None of the presenters reported having conflicts of interest.

MONTREAL – The physical burden of psychological trauma remains largely underrecognized from both a public health and clinical perspective, a panel of experts explained at the meeting. The interplay of mental and physical health should be a central consideration in prevention and treatment programs, they said.“

“I think we are just beginning to peel apart the onion” of the extent to which physical illness and mental illness are comorbid, said Dr. Sandro Galea, a physician and epidemiologist affiliated with the school of public health at Columbia University, New York. Mental illness “is a key component in the onset, progression, and severity of a full range of physical illnesses, which, if factored in properly, would illustrate a dramatically greater burden of mental illness than we have currently accepted,” he said.

In several ongoing studies across a wide variety of populations, Dr. Galea and his colleagues have documented “an extraordinary relationship” between posttraumatic stress disorder (PTSD) and health disorders such as vascular problems, respiratory and lung problems (including chronic obstructive pulmonary disease, tuberculosis, and emphysema), and other major illnesses such as arthritis, cancer, and diabetes, he reported.

“With few exceptions, it is pretty consistent across the board” that there is a clear association of physical health, functioning, and disability according to the presence or absence of current or lifetime PTSD, he said. For example, the Detroit Neighborhood Health Study shows evidence of epigenetic and immune system dysfunction among individuals with depression and/or PTSD, compared with unaffected individuals (Proc. Natl. Acad. Sci. 2010;10720:9470–5).

“As providers, we need to be aware of this association and should think about screening for trauma in many of our patients, particularly those with chronic illness,” said Dr. Beth E. Cohen of the University of California, San Francisco, and an internal medicine specialist at the San Francisco VA Medical Center. “There's a lot of data showing [that] people do not actually get diagnosed and treated for things like PTSD for years or even decades after they start to experience these symptoms. If we were able to treat people more aggressively up front, perhaps we could prevent a lot of this.”

As coinvestigator on the Heart and Soul Study, Dr. Cohen and her colleagues have documented an increased rate of cardiovascular disease (CVD) events among heart disease patients with a history of psychological trauma vs. those without (Arch. Gen. Psychiatry 2010;67:750–8). Over a mean of 6 years' follow-up, there was a 44% rate of CVD events in subjects in the highest quartile of psychological trauma, compared with 36% among those in the lowest quartile, she said.

“Psychological trauma was common in this cohort of patients with heart disease,” she said. In addition, greater lifetime trauma was prospectively associated with an increased risk of cardiac events, independent of psychiatric comorbidities, health behaviors, and conventional cardiac risk factors, she added.

“Cumulative psychological trauma is a very real risk factor for cardiac disease, and patients do not have to either develop a psychiatric disorder or engage in a negative health behavior for this cardiac risk to emerge,” Dr. Cohen said.

Dr. Cohen and Dr. Galea noted the importance of communication between mental and medical health care providers.

Psychiatrists should know that the psychological trauma they treat is “part of a much greater constellation of symptoms,” Dr. Galea said in an interview. “One of the big challenges of medicine is that we are trained in silos. The rheumatologist doesn't think about PTSD, and the psychiatrist doesn't think about arthritis. We need to be profoundly aware that mental illness does not exist in isolation and, in fact, is linked to an inextricable part of physical function. We need to make sure that the physicians in charge of the physical symptoms realize the centrality of mental illness in that presentation.”

Conversely, mental health practitioners need to be aware of their patients' increased risk for physical illness, Dr. Cohen said. “We need to think of efforts to reduce cardiac risk in patients with psychological trauma, but given that this doesn't seem to be driven simply by things like cholesterol or blood pressure, we really need to think outside the box,” she said in an interview.

Neither Dr. Cohen nor Dr. Galea reported any conflicts of interest.

'We are just beginning to peel apart the onion' of the extent to which physical and mental illnesses are comorbid.

Source DR. GALEA

MONTREAL – The physical burden of psychological trauma remains largely underrecognized from both a public health and clinical perspective, a panel of experts explained at the meeting. The interplay of mental and physical health should be a central consideration in prevention and treatment programs, they said.“

“I think we are just beginning to peel apart the onion” of the extent to which physical illness and mental illness are comorbid, said Dr. Sandro Galea, a physician and epidemiologist affiliated with the school of public health at Columbia University, New York. Mental illness “is a key component in the onset, progression, and severity of a full range of physical illnesses, which, if factored in properly, would illustrate a dramatically greater burden of mental illness than we have currently accepted,” he said.

In several ongoing studies across a wide variety of populations, Dr. Galea and his colleagues have documented “an extraordinary relationship” between posttraumatic stress disorder (PTSD) and health disorders such as vascular problems, respiratory and lung problems (including chronic obstructive pulmonary disease, tuberculosis, and emphysema), and other major illnesses such as arthritis, cancer, and diabetes, he reported.

“With few exceptions, it is pretty consistent across the board” that there is a clear association of physical health, functioning, and disability according to the presence or absence of current or lifetime PTSD, he said. For example, the Detroit Neighborhood Health Study shows evidence of epigenetic and immune system dysfunction among individuals with depression and/or PTSD, compared with unaffected individuals (Proc. Natl. Acad. Sci. 2010;10720:9470–5).

“As providers, we need to be aware of this association and should think about screening for trauma in many of our patients, particularly those with chronic illness,” said Dr. Beth E. Cohen of the University of California, San Francisco, and an internal medicine specialist at the San Francisco VA Medical Center. “There's a lot of data showing [that] people do not actually get diagnosed and treated for things like PTSD for years or even decades after they start to experience these symptoms. If we were able to treat people more aggressively up front, perhaps we could prevent a lot of this.”

As coinvestigator on the Heart and Soul Study, Dr. Cohen and her colleagues have documented an increased rate of cardiovascular disease (CVD) events among heart disease patients with a history of psychological trauma vs. those without (Arch. Gen. Psychiatry 2010;67:750–8). Over a mean of 6 years' follow-up, there was a 44% rate of CVD events in subjects in the highest quartile of psychological trauma, compared with 36% among those in the lowest quartile, she said.

“Psychological trauma was common in this cohort of patients with heart disease,” she said. In addition, greater lifetime trauma was prospectively associated with an increased risk of cardiac events, independent of psychiatric comorbidities, health behaviors, and conventional cardiac risk factors, she added.

“Cumulative psychological trauma is a very real risk factor for cardiac disease, and patients do not have to either develop a psychiatric disorder or engage in a negative health behavior for this cardiac risk to emerge,” Dr. Cohen said.

Dr. Cohen and Dr. Galea noted the importance of communication between mental and medical health care providers.

Psychiatrists should know that the psychological trauma they treat is “part of a much greater constellation of symptoms,” Dr. Galea said in an interview. “One of the big challenges of medicine is that we are trained in silos. The rheumatologist doesn't think about PTSD, and the psychiatrist doesn't think about arthritis. We need to be profoundly aware that mental illness does not exist in isolation and, in fact, is linked to an inextricable part of physical function. We need to make sure that the physicians in charge of the physical symptoms realize the centrality of mental illness in that presentation.”

Conversely, mental health practitioners need to be aware of their patients' increased risk for physical illness, Dr. Cohen said. “We need to think of efforts to reduce cardiac risk in patients with psychological trauma, but given that this doesn't seem to be driven simply by things like cholesterol or blood pressure, we really need to think outside the box,” she said in an interview.

Neither Dr. Cohen nor Dr. Galea reported any conflicts of interest.

'We are just beginning to peel apart the onion' of the extent to which physical and mental illnesses are comorbid.

Source DR. GALEA

MONTREAL – The physical burden of psychological trauma remains largely underrecognized from both a public health and clinical perspective, a panel of experts explained at the meeting. The interplay of mental and physical health should be a central consideration in prevention and treatment programs, they said.“

“I think we are just beginning to peel apart the onion” of the extent to which physical illness and mental illness are comorbid, said Dr. Sandro Galea, a physician and epidemiologist affiliated with the school of public health at Columbia University, New York. Mental illness “is a key component in the onset, progression, and severity of a full range of physical illnesses, which, if factored in properly, would illustrate a dramatically greater burden of mental illness than we have currently accepted,” he said.

In several ongoing studies across a wide variety of populations, Dr. Galea and his colleagues have documented “an extraordinary relationship” between posttraumatic stress disorder (PTSD) and health disorders such as vascular problems, respiratory and lung problems (including chronic obstructive pulmonary disease, tuberculosis, and emphysema), and other major illnesses such as arthritis, cancer, and diabetes, he reported.

“With few exceptions, it is pretty consistent across the board” that there is a clear association of physical health, functioning, and disability according to the presence or absence of current or lifetime PTSD, he said. For example, the Detroit Neighborhood Health Study shows evidence of epigenetic and immune system dysfunction among individuals with depression and/or PTSD, compared with unaffected individuals (Proc. Natl. Acad. Sci. 2010;10720:9470–5).

“As providers, we need to be aware of this association and should think about screening for trauma in many of our patients, particularly those with chronic illness,” said Dr. Beth E. Cohen of the University of California, San Francisco, and an internal medicine specialist at the San Francisco VA Medical Center. “There's a lot of data showing [that] people do not actually get diagnosed and treated for things like PTSD for years or even decades after they start to experience these symptoms. If we were able to treat people more aggressively up front, perhaps we could prevent a lot of this.”

As coinvestigator on the Heart and Soul Study, Dr. Cohen and her colleagues have documented an increased rate of cardiovascular disease (CVD) events among heart disease patients with a history of psychological trauma vs. those without (Arch. Gen. Psychiatry 2010;67:750–8). Over a mean of 6 years' follow-up, there was a 44% rate of CVD events in subjects in the highest quartile of psychological trauma, compared with 36% among those in the lowest quartile, she said.

“Psychological trauma was common in this cohort of patients with heart disease,” she said. In addition, greater lifetime trauma was prospectively associated with an increased risk of cardiac events, independent of psychiatric comorbidities, health behaviors, and conventional cardiac risk factors, she added.

“Cumulative psychological trauma is a very real risk factor for cardiac disease, and patients do not have to either develop a psychiatric disorder or engage in a negative health behavior for this cardiac risk to emerge,” Dr. Cohen said.

Dr. Cohen and Dr. Galea noted the importance of communication between mental and medical health care providers.

Psychiatrists should know that the psychological trauma they treat is “part of a much greater constellation of symptoms,” Dr. Galea said in an interview. “One of the big challenges of medicine is that we are trained in silos. The rheumatologist doesn't think about PTSD, and the psychiatrist doesn't think about arthritis. We need to be profoundly aware that mental illness does not exist in isolation and, in fact, is linked to an inextricable part of physical function. We need to make sure that the physicians in charge of the physical symptoms realize the centrality of mental illness in that presentation.”

Conversely, mental health practitioners need to be aware of their patients' increased risk for physical illness, Dr. Cohen said. “We need to think of efforts to reduce cardiac risk in patients with psychological trauma, but given that this doesn't seem to be driven simply by things like cholesterol or blood pressure, we really need to think outside the box,” she said in an interview.

Neither Dr. Cohen nor Dr. Galea reported any conflicts of interest.

'We are just beginning to peel apart the onion' of the extent to which physical and mental illnesses are comorbid.

Source DR. GALEA

Consider this rare disorder in patients with rapid-onset neurologic symptoms

Ms. J, age 63, is admitted to Neurology with progressive dizziness and cognitive impairment. She had developed word-finding difficulties, weakness, memory problems, and an episode of arm shaking, which prompted referral for inpatient workup. Ms. J has a history of hypertension, palpitations, and diabetes mellitus.

Her neurologic examination is variable; some examiners find pronounced aphasia and right-sided weakness, whereas others document a nearly normal examination. Lumbar puncture (LP) shows normal cell count, glucose, protein, and negative Gram’s stain; MRI of the brain is normal. Enterovirus polymerase chain reaction, cryptococcal antigen, and Lyme antibody are negative. Electroencephalography (EEG) demonstrates diffuse slowing. The primary team requests psychiatric consultation to assess for conversion disorder.

Ms. J is cooperative with psychiatric evaluation. She denies current or past psychiatric symptomatology and does not meet criteria for major depression, dysthymia, adjustment disorder, anxiety disorder, psychosis, or mania. She denies personal or family history of suicidal or homicidal ideation, intent, or plan. Her youngest son died 5 years earlier; she is financially secure and her 40-year marriage is stable. Ms. J denies having a history of substance use, physical or sexual abuse, or trauma.

In the Cardiology clinic 2 months ago, Ms. J denied having neurologic symptoms and was noted to be doing well. Her neurologic symptoms began shortly after that visit and steadily progressed. She is unable to identify an inciting event or stressor. Ms. J worked until 2 weeks before this admission. Neurologic examination at the time of psychiatric consultation is notable for waxing and waning expressive aphasia, right homonymous hemianopsia, and mildly decreased strength in the left biceps and forearm.

Ms. J presented to her cardiologist reporting dizziness and blurred vision 6 weeks ago, and she was observed in the hospital 3 weeks earlier for further evaluation. Laboratory testing during that hospitalization included blood counts, basic metabolic panel, thyroid function studies, erythrocyte sedimentation rate, thiamine, folic acid and vitamin B12, rapid plasma reagin and human immunodeficiency virus antibody, and LP, all reported as within normal limits.

Thorough review of Ms. J’s medical records reveals abnormalities that would be difficult to ascribe to conversion disorder. Specifically, 6 weeks ago, MRI of the brain demonstrated restricted diffusion in the left occipital lobe, and cerebrospinal fluid (CSF) neuron-specific enolase was moderately elevated at 34 ng/mL. The psychiatric consultant discusses these findings and concern for possible rapidly progressive dementia or Creutzfeldt-Jakob disease (CJD) with the primary team, Ms. J, and her family.

Ms. J is discharged with testing for CSF protein 14-3-3 pending and medical follow-up in 10 days. At follow-up 1 week later, her symptoms are worse; she is completely aphasic and wheelchair-bound. Antithyroglobulin and antimicrosomal thyroid antibodies and paraneoplastic antibody panel return normal. CSF protein 14-3-3 ultimately returns positive, supporting a clinical diagnosis of CJD. Ms. J dies shortly after hospital follow-up, less than 4 months after her first complaint of neurologic symptoms. No autopsy is performed.

Patients with conversion disorder may present with neurologic symptoms such as blindness, seizures, paralysis, or sensory loss with no identifiable anatomical or medical explanation.¹ Conversion seizures—also known as pseudoseizures or nonepileptic seizures—may be clinically indistinguishable from generalized tonic-clonic seizures, but no EEG correlate can be identified.^1,2 Conversion disorder is conceptualized as an unconscious manifestation of psychological conflict or stress—patients are not aware they are producing symptoms—and has been associated with emotional, sexual, and physical trauma.^3,4

Conversion disorder is a diagnosis of exclusion and requires thorough evaluation to rule out neurologic or medical etiologies. The differential diagnosis for conversion disorder includes the broad medical differential diagnosis for the symptom, whether it be paralysis, seizures, sensory loss, or other presenting symptoms. Therefore, when evaluating patients for conversion disorder, be vigilant to the possibility of not only underlying psychological stress or trauma but also undiscovered medical or neurologic illness.

In Ms. J’s case, the primary team began to suspect there was no organic cause of her neurologic symptoms. However, psychiatric evaluation revealed that Ms. J had no history of stress or trauma that typically would be associated with conversion disorder, nor did she manifest other psychiatric symptoms, except waxing and waning mental status, which raised concerns for possible delirium or encephalopathy. Additionally, slowing on EEG was a nonspecific but abnormal finding that made conversion disorder unlikely. The consulting psychiatrist discussed this slowing, in conjunction with the abnormal MRI and elevated CSF neuron-specific enolase, with members of the referring Neurology service, who ordered additional testing of CSF for protein 14-3-3.

Creutzfeldt-Jakob disease

CJD is a rapidly progressive neurodegenerative disorder characterized by cognitive changes, behavioral changes, gait disturbances, akinetic mutism, and myoclonus.⁵ CJD results from the transition of prion proteins, which are present in the normal human brain, to disease-associated forms that aggregate and propagate and result in neurotoxicity with spongiform changes in neurons.⁶ The transition of normal prions to disease-associated prions may be hereditary, iatrogenic, infectious, or sporadic. Because the pathologic prion protein can be transmitted and normal sterilization procedures do not prevent the spread of CJD, special precautions should be taken to avoid contact with blood or CSF from patients suspected of having CJD.⁵

CJD most commonly occurs in the sporadic form, for which there are no identifiable risk factors, with an average age of onset between age 50 and 70. The disease affects women and men equally at a rate of 1 to 2 persons per million per year worldwide.^6,7 Most patients with CJD die within 12 months of diagnosis⁸; median survival is 4 to 5 months.^7,9 Although there is no approved or standard effective treatment for this uniformly fatal disease, research into the possibility of genetic or post-translational treatments is ongoing. One group reported inhibition of prion propagation by quinacrine and chlorpromazine in vitro.¹⁰ Clinical studies of quinacrine have demonstrated tolerability but no impact on the course of CJD.⁶

Clues to diagnosis. Although there is no treatment for CJD, early diagnosis can help patients and families understand the relentless progression of symptoms and also permits end-of-life planning and palliative care.¹¹ Diagnosing CJD requires a high level of suspicion and traditionally has required brain biopsy or autopsy for conclusive diagnosis, although in some cases rare EEG findings of periodic sharp wave complexes or generalized periodic epileptiform discharges (GPEDs) have suggested the diagnosis.^7,8,12 Recently, specific MRI findings have been described with fluid attenuated inversion recovery (FLAIR) and diffusion sequences.^9,13,14

Routine LP for CSF examination (including cell count, protein, and glucose) frequently is normal.⁸ Specific testing to assess for CJD is required. Elevated levels of CSF neuron-specific enolase (normal <30 ng/mL) and protein 14-3-3 (normal <8 ng/mL) are fairly sensitive and specific for CJD when assessed in patients with the proper clinical history, although normal levels of these proteins have been detected in patients later confirmed to have CJD.^7,15 A large multinational collaborative study of confirmed CJD cases that evaluated diagnostic test characteristics recommended that because each test has limitations and can be falsely negative—even in a case of later-confirmed CJD—a rational approach to diagnosis includes brain MRI with diffusion-weighted imaging, CSF analysis for protein 14-3-3, and EEG to assess for periodic sharp wave complexes or GPEDs.¹⁶

Because CJD presentation varies widely, most clinicians will not consider the diagnosis until the disease has progressed or the patient has died. Patients who present with psychological symptoms or predominant language disturbances and dysphagia may be referred to a psychiatrist or an ear, nose, and throat specialist before seeing a neurologist.⁹ Patients may be extensively evaluated and treated for conversion disorder when the correct diagnosis is CJD.¹⁷

Sporadic CJD traditionally is associated with neurologic presentations, whereas variant CJD is believed to present with psychiatric symptomatology. However, in a 25-year retrospective review of 126 patients with sporadic CJD, 80% of cases demonstrated psychiatric symptoms within the first 100 days of the disease course.¹⁸ Of these, nearly 25% showed psychiatric symptoms at presentation, including sleep disturbances, psychotic symptoms, agitation, and anxiety.

Psychiatrists should be aware of distinguishing features of rapidly progressive dementias and CJD, especially in the setting of psychiatric consultation, to rule out somatic etiologies of unexplained neurologic symptoms. It is important to obtain a history of baseline functioning, duration of decline, and psychiatric symptomatology to differentiate between organic and somatic causes. Differential diagnosis for rapidly progressive cognitive impairment is broad and includes delirium from diverse medical causes; rapidly progressive dementia such as accelerated Alzheimer’s disease, Lewy body disease, or frontotemporal dementia; and psychogenic causes, including conversion disorder (Table 1).^7,8,12Table 2 provides distinguishing features of CJD, Alzheimer’s disease, Lewy body disease, and frontotemporal dementia with motor neuron disease.^7,8,19

Table 1

Differential diagnosis of rapidly progressive dementia

Table 2

Distinguishing features of Creutzfeldt-Jakob disease

Related Resources

National Institute of Neurological Disorders and Stroke. Creutzfeldt-Jakob disease fact sheet. www.ninds.nih.gov/disorders/cjd/detail_cjd.htm.

Centers for Disease Control and Prevention. About CJD. www.cdc.gov/ncidod/dvrd/cjd.

Drug Brand Names

Chlorpromazine • Thorazine, Largactil

Quinacine • Atabrine

Disclosure

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

Consider this rare disorder in patients with rapid-onset neurologic symptoms

Ms. J, age 63, is admitted to Neurology with progressive dizziness and cognitive impairment. She had developed word-finding difficulties, weakness, memory problems, and an episode of arm shaking, which prompted referral for inpatient workup. Ms. J has a history of hypertension, palpitations, and diabetes mellitus.

Her neurologic examination is variable; some examiners find pronounced aphasia and right-sided weakness, whereas others document a nearly normal examination. Lumbar puncture (LP) shows normal cell count, glucose, protein, and negative Gram’s stain; MRI of the brain is normal. Enterovirus polymerase chain reaction, cryptococcal antigen, and Lyme antibody are negative. Electroencephalography (EEG) demonstrates diffuse slowing. The primary team requests psychiatric consultation to assess for conversion disorder.

Ms. J is cooperative with psychiatric evaluation. She denies current or past psychiatric symptomatology and does not meet criteria for major depression, dysthymia, adjustment disorder, anxiety disorder, psychosis, or mania. She denies personal or family history of suicidal or homicidal ideation, intent, or plan. Her youngest son died 5 years earlier; she is financially secure and her 40-year marriage is stable. Ms. J denies having a history of substance use, physical or sexual abuse, or trauma.

In the Cardiology clinic 2 months ago, Ms. J denied having neurologic symptoms and was noted to be doing well. Her neurologic symptoms began shortly after that visit and steadily progressed. She is unable to identify an inciting event or stressor. Ms. J worked until 2 weeks before this admission. Neurologic examination at the time of psychiatric consultation is notable for waxing and waning expressive aphasia, right homonymous hemianopsia, and mildly decreased strength in the left biceps and forearm.

Ms. J presented to her cardiologist reporting dizziness and blurred vision 6 weeks ago, and she was observed in the hospital 3 weeks earlier for further evaluation. Laboratory testing during that hospitalization included blood counts, basic metabolic panel, thyroid function studies, erythrocyte sedimentation rate, thiamine, folic acid and vitamin B12, rapid plasma reagin and human immunodeficiency virus antibody, and LP, all reported as within normal limits.

Thorough review of Ms. J’s medical records reveals abnormalities that would be difficult to ascribe to conversion disorder. Specifically, 6 weeks ago, MRI of the brain demonstrated restricted diffusion in the left occipital lobe, and cerebrospinal fluid (CSF) neuron-specific enolase was moderately elevated at 34 ng/mL. The psychiatric consultant discusses these findings and concern for possible rapidly progressive dementia or Creutzfeldt-Jakob disease (CJD) with the primary team, Ms. J, and her family.

Ms. J is discharged with testing for CSF protein 14-3-3 pending and medical follow-up in 10 days. At follow-up 1 week later, her symptoms are worse; she is completely aphasic and wheelchair-bound. Antithyroglobulin and antimicrosomal thyroid antibodies and paraneoplastic antibody panel return normal. CSF protein 14-3-3 ultimately returns positive, supporting a clinical diagnosis of CJD. Ms. J dies shortly after hospital follow-up, less than 4 months after her first complaint of neurologic symptoms. No autopsy is performed.

Patients with conversion disorder may present with neurologic symptoms such as blindness, seizures, paralysis, or sensory loss with no identifiable anatomical or medical explanation.¹ Conversion seizures—also known as pseudoseizures or nonepileptic seizures—may be clinically indistinguishable from generalized tonic-clonic seizures, but no EEG correlate can be identified.^1,2 Conversion disorder is conceptualized as an unconscious manifestation of psychological conflict or stress—patients are not aware they are producing symptoms—and has been associated with emotional, sexual, and physical trauma.^3,4

Conversion disorder is a diagnosis of exclusion and requires thorough evaluation to rule out neurologic or medical etiologies. The differential diagnosis for conversion disorder includes the broad medical differential diagnosis for the symptom, whether it be paralysis, seizures, sensory loss, or other presenting symptoms. Therefore, when evaluating patients for conversion disorder, be vigilant to the possibility of not only underlying psychological stress or trauma but also undiscovered medical or neurologic illness.

In Ms. J’s case, the primary team began to suspect there was no organic cause of her neurologic symptoms. However, psychiatric evaluation revealed that Ms. J had no history of stress or trauma that typically would be associated with conversion disorder, nor did she manifest other psychiatric symptoms, except waxing and waning mental status, which raised concerns for possible delirium or encephalopathy. Additionally, slowing on EEG was a nonspecific but abnormal finding that made conversion disorder unlikely. The consulting psychiatrist discussed this slowing, in conjunction with the abnormal MRI and elevated CSF neuron-specific enolase, with members of the referring Neurology service, who ordered additional testing of CSF for protein 14-3-3.

Creutzfeldt-Jakob disease

CJD is a rapidly progressive neurodegenerative disorder characterized by cognitive changes, behavioral changes, gait disturbances, akinetic mutism, and myoclonus.⁵ CJD results from the transition of prion proteins, which are present in the normal human brain, to disease-associated forms that aggregate and propagate and result in neurotoxicity with spongiform changes in neurons.⁶ The transition of normal prions to disease-associated prions may be hereditary, iatrogenic, infectious, or sporadic. Because the pathologic prion protein can be transmitted and normal sterilization procedures do not prevent the spread of CJD, special precautions should be taken to avoid contact with blood or CSF from patients suspected of having CJD.⁵

CJD most commonly occurs in the sporadic form, for which there are no identifiable risk factors, with an average age of onset between age 50 and 70. The disease affects women and men equally at a rate of 1 to 2 persons per million per year worldwide.^6,7 Most patients with CJD die within 12 months of diagnosis⁸; median survival is 4 to 5 months.^7,9 Although there is no approved or standard effective treatment for this uniformly fatal disease, research into the possibility of genetic or post-translational treatments is ongoing. One group reported inhibition of prion propagation by quinacrine and chlorpromazine in vitro.¹⁰ Clinical studies of quinacrine have demonstrated tolerability but no impact on the course of CJD.⁶

Clues to diagnosis. Although there is no treatment for CJD, early diagnosis can help patients and families understand the relentless progression of symptoms and also permits end-of-life planning and palliative care.¹¹ Diagnosing CJD requires a high level of suspicion and traditionally has required brain biopsy or autopsy for conclusive diagnosis, although in some cases rare EEG findings of periodic sharp wave complexes or generalized periodic epileptiform discharges (GPEDs) have suggested the diagnosis.^7,8,12 Recently, specific MRI findings have been described with fluid attenuated inversion recovery (FLAIR) and diffusion sequences.^9,13,14

Routine LP for CSF examination (including cell count, protein, and glucose) frequently is normal.⁸ Specific testing to assess for CJD is required. Elevated levels of CSF neuron-specific enolase (normal <30 ng/mL) and protein 14-3-3 (normal <8 ng/mL) are fairly sensitive and specific for CJD when assessed in patients with the proper clinical history, although normal levels of these proteins have been detected in patients later confirmed to have CJD.^7,15 A large multinational collaborative study of confirmed CJD cases that evaluated diagnostic test characteristics recommended that because each test has limitations and can be falsely negative—even in a case of later-confirmed CJD—a rational approach to diagnosis includes brain MRI with diffusion-weighted imaging, CSF analysis for protein 14-3-3, and EEG to assess for periodic sharp wave complexes or GPEDs.¹⁶

Because CJD presentation varies widely, most clinicians will not consider the diagnosis until the disease has progressed or the patient has died. Patients who present with psychological symptoms or predominant language disturbances and dysphagia may be referred to a psychiatrist or an ear, nose, and throat specialist before seeing a neurologist.⁹ Patients may be extensively evaluated and treated for conversion disorder when the correct diagnosis is CJD.¹⁷

Sporadic CJD traditionally is associated with neurologic presentations, whereas variant CJD is believed to present with psychiatric symptomatology. However, in a 25-year retrospective review of 126 patients with sporadic CJD, 80% of cases demonstrated psychiatric symptoms within the first 100 days of the disease course.¹⁸ Of these, nearly 25% showed psychiatric symptoms at presentation, including sleep disturbances, psychotic symptoms, agitation, and anxiety.

Psychiatrists should be aware of distinguishing features of rapidly progressive dementias and CJD, especially in the setting of psychiatric consultation, to rule out somatic etiologies of unexplained neurologic symptoms. It is important to obtain a history of baseline functioning, duration of decline, and psychiatric symptomatology to differentiate between organic and somatic causes. Differential diagnosis for rapidly progressive cognitive impairment is broad and includes delirium from diverse medical causes; rapidly progressive dementia such as accelerated Alzheimer’s disease, Lewy body disease, or frontotemporal dementia; and psychogenic causes, including conversion disorder (Table 1).^7,8,12Table 2 provides distinguishing features of CJD, Alzheimer’s disease, Lewy body disease, and frontotemporal dementia with motor neuron disease.^7,8,19

Table 1

Differential diagnosis of rapidly progressive dementia

Table 2

Distinguishing features of Creutzfeldt-Jakob disease

Related Resources

National Institute of Neurological Disorders and Stroke. Creutzfeldt-Jakob disease fact sheet. www.ninds.nih.gov/disorders/cjd/detail_cjd.htm.

Centers for Disease Control and Prevention. About CJD. www.cdc.gov/ncidod/dvrd/cjd.

Drug Brand Names

Chlorpromazine • Thorazine, Largactil

Quinacine • Atabrine

Disclosure

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

Consider this rare disorder in patients with rapid-onset neurologic symptoms

Ms. J, age 63, is admitted to Neurology with progressive dizziness and cognitive impairment. She had developed word-finding difficulties, weakness, memory problems, and an episode of arm shaking, which prompted referral for inpatient workup. Ms. J has a history of hypertension, palpitations, and diabetes mellitus.

Her neurologic examination is variable; some examiners find pronounced aphasia and right-sided weakness, whereas others document a nearly normal examination. Lumbar puncture (LP) shows normal cell count, glucose, protein, and negative Gram’s stain; MRI of the brain is normal. Enterovirus polymerase chain reaction, cryptococcal antigen, and Lyme antibody are negative. Electroencephalography (EEG) demonstrates diffuse slowing. The primary team requests psychiatric consultation to assess for conversion disorder.

Ms. J is cooperative with psychiatric evaluation. She denies current or past psychiatric symptomatology and does not meet criteria for major depression, dysthymia, adjustment disorder, anxiety disorder, psychosis, or mania. She denies personal or family history of suicidal or homicidal ideation, intent, or plan. Her youngest son died 5 years earlier; she is financially secure and her 40-year marriage is stable. Ms. J denies having a history of substance use, physical or sexual abuse, or trauma.

In the Cardiology clinic 2 months ago, Ms. J denied having neurologic symptoms and was noted to be doing well. Her neurologic symptoms began shortly after that visit and steadily progressed. She is unable to identify an inciting event or stressor. Ms. J worked until 2 weeks before this admission. Neurologic examination at the time of psychiatric consultation is notable for waxing and waning expressive aphasia, right homonymous hemianopsia, and mildly decreased strength in the left biceps and forearm.

Ms. J presented to her cardiologist reporting dizziness and blurred vision 6 weeks ago, and she was observed in the hospital 3 weeks earlier for further evaluation. Laboratory testing during that hospitalization included blood counts, basic metabolic panel, thyroid function studies, erythrocyte sedimentation rate, thiamine, folic acid and vitamin B12, rapid plasma reagin and human immunodeficiency virus antibody, and LP, all reported as within normal limits.

Thorough review of Ms. J’s medical records reveals abnormalities that would be difficult to ascribe to conversion disorder. Specifically, 6 weeks ago, MRI of the brain demonstrated restricted diffusion in the left occipital lobe, and cerebrospinal fluid (CSF) neuron-specific enolase was moderately elevated at 34 ng/mL. The psychiatric consultant discusses these findings and concern for possible rapidly progressive dementia or Creutzfeldt-Jakob disease (CJD) with the primary team, Ms. J, and her family.

Ms. J is discharged with testing for CSF protein 14-3-3 pending and medical follow-up in 10 days. At follow-up 1 week later, her symptoms are worse; she is completely aphasic and wheelchair-bound. Antithyroglobulin and antimicrosomal thyroid antibodies and paraneoplastic antibody panel return normal. CSF protein 14-3-3 ultimately returns positive, supporting a clinical diagnosis of CJD. Ms. J dies shortly after hospital follow-up, less than 4 months after her first complaint of neurologic symptoms. No autopsy is performed.

Patients with conversion disorder may present with neurologic symptoms such as blindness, seizures, paralysis, or sensory loss with no identifiable anatomical or medical explanation.¹ Conversion seizures—also known as pseudoseizures or nonepileptic seizures—may be clinically indistinguishable from generalized tonic-clonic seizures, but no EEG correlate can be identified.^1,2 Conversion disorder is conceptualized as an unconscious manifestation of psychological conflict or stress—patients are not aware they are producing symptoms—and has been associated with emotional, sexual, and physical trauma.^3,4

Conversion disorder is a diagnosis of exclusion and requires thorough evaluation to rule out neurologic or medical etiologies. The differential diagnosis for conversion disorder includes the broad medical differential diagnosis for the symptom, whether it be paralysis, seizures, sensory loss, or other presenting symptoms. Therefore, when evaluating patients for conversion disorder, be vigilant to the possibility of not only underlying psychological stress or trauma but also undiscovered medical or neurologic illness.

In Ms. J’s case, the primary team began to suspect there was no organic cause of her neurologic symptoms. However, psychiatric evaluation revealed that Ms. J had no history of stress or trauma that typically would be associated with conversion disorder, nor did she manifest other psychiatric symptoms, except waxing and waning mental status, which raised concerns for possible delirium or encephalopathy. Additionally, slowing on EEG was a nonspecific but abnormal finding that made conversion disorder unlikely. The consulting psychiatrist discussed this slowing, in conjunction with the abnormal MRI and elevated CSF neuron-specific enolase, with members of the referring Neurology service, who ordered additional testing of CSF for protein 14-3-3.

Creutzfeldt-Jakob disease

CJD is a rapidly progressive neurodegenerative disorder characterized by cognitive changes, behavioral changes, gait disturbances, akinetic mutism, and myoclonus.⁵ CJD results from the transition of prion proteins, which are present in the normal human brain, to disease-associated forms that aggregate and propagate and result in neurotoxicity with spongiform changes in neurons.⁶ The transition of normal prions to disease-associated prions may be hereditary, iatrogenic, infectious, or sporadic. Because the pathologic prion protein can be transmitted and normal sterilization procedures do not prevent the spread of CJD, special precautions should be taken to avoid contact with blood or CSF from patients suspected of having CJD.⁵

CJD most commonly occurs in the sporadic form, for which there are no identifiable risk factors, with an average age of onset between age 50 and 70. The disease affects women and men equally at a rate of 1 to 2 persons per million per year worldwide.^6,7 Most patients with CJD die within 12 months of diagnosis⁸; median survival is 4 to 5 months.^7,9 Although there is no approved or standard effective treatment for this uniformly fatal disease, research into the possibility of genetic or post-translational treatments is ongoing. One group reported inhibition of prion propagation by quinacrine and chlorpromazine in vitro.¹⁰ Clinical studies of quinacrine have demonstrated tolerability but no impact on the course of CJD.⁶

Clues to diagnosis. Although there is no treatment for CJD, early diagnosis can help patients and families understand the relentless progression of symptoms and also permits end-of-life planning and palliative care.¹¹ Diagnosing CJD requires a high level of suspicion and traditionally has required brain biopsy or autopsy for conclusive diagnosis, although in some cases rare EEG findings of periodic sharp wave complexes or generalized periodic epileptiform discharges (GPEDs) have suggested the diagnosis.^7,8,12 Recently, specific MRI findings have been described with fluid attenuated inversion recovery (FLAIR) and diffusion sequences.^9,13,14

Routine LP for CSF examination (including cell count, protein, and glucose) frequently is normal.⁸ Specific testing to assess for CJD is required. Elevated levels of CSF neuron-specific enolase (normal <30 ng/mL) and protein 14-3-3 (normal <8 ng/mL) are fairly sensitive and specific for CJD when assessed in patients with the proper clinical history, although normal levels of these proteins have been detected in patients later confirmed to have CJD.^7,15 A large multinational collaborative study of confirmed CJD cases that evaluated diagnostic test characteristics recommended that because each test has limitations and can be falsely negative—even in a case of later-confirmed CJD—a rational approach to diagnosis includes brain MRI with diffusion-weighted imaging, CSF analysis for protein 14-3-3, and EEG to assess for periodic sharp wave complexes or GPEDs.¹⁶

Because CJD presentation varies widely, most clinicians will not consider the diagnosis until the disease has progressed or the patient has died. Patients who present with psychological symptoms or predominant language disturbances and dysphagia may be referred to a psychiatrist or an ear, nose, and throat specialist before seeing a neurologist.⁹ Patients may be extensively evaluated and treated for conversion disorder when the correct diagnosis is CJD.¹⁷

Sporadic CJD traditionally is associated with neurologic presentations, whereas variant CJD is believed to present with psychiatric symptomatology. However, in a 25-year retrospective review of 126 patients with sporadic CJD, 80% of cases demonstrated psychiatric symptoms within the first 100 days of the disease course.¹⁸ Of these, nearly 25% showed psychiatric symptoms at presentation, including sleep disturbances, psychotic symptoms, agitation, and anxiety.

Psychiatrists should be aware of distinguishing features of rapidly progressive dementias and CJD, especially in the setting of psychiatric consultation, to rule out somatic etiologies of unexplained neurologic symptoms. It is important to obtain a history of baseline functioning, duration of decline, and psychiatric symptomatology to differentiate between organic and somatic causes. Differential diagnosis for rapidly progressive cognitive impairment is broad and includes delirium from diverse medical causes; rapidly progressive dementia such as accelerated Alzheimer’s disease, Lewy body disease, or frontotemporal dementia; and psychogenic causes, including conversion disorder (Table 1).^7,8,12Table 2 provides distinguishing features of CJD, Alzheimer’s disease, Lewy body disease, and frontotemporal dementia with motor neuron disease.^7,8,19

Table 1

Differential diagnosis of rapidly progressive dementia

Table 2

Distinguishing features of Creutzfeldt-Jakob disease

Related Resources

National Institute of Neurological Disorders and Stroke. Creutzfeldt-Jakob disease fact sheet. www.ninds.nih.gov/disorders/cjd/detail_cjd.htm.

Centers for Disease Control and Prevention. About CJD. www.cdc.gov/ncidod/dvrd/cjd.

Drug Brand Names

Chlorpromazine • Thorazine, Largactil

Quinacine • Atabrine

Disclosure

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

Discuss this article at http://currentpsychiatry.blogspot.com/2010/11/depression-treatment-for-women-with.html#comments

Psychological distress among patients with breast cancer is common and is linked to worse clinical outcomes. Depressive and anxiety symptoms affect up to 40% of breast cancer patients,¹ and depression is associated with a higher relative risk of mortality in individuals with breast cancer.² Psychotropic medications and psychotherapy used to treat depression in patients without carcinoma also are appropriate and effective for breast cancer patients. However, some patients present distinct challenges to standard treatment. For example, growing evidence suggests that some selective serotonin reuptake inhibitors (SSRIs) may reduce the effectiveness of tamoxifen, a chemotherapeutic agent. This article discusses challenges in diagnosing and treating depression in breast cancer patients and reviews evidence supporting appropriate psychiatric care.

Increased vulnerability

In 10% to 30% of women, a breast cancer diagnosis may lead to increased vulnerability to depressive disorders, including adjustment disorders with depressed mood, major depressive disorder (MDD), and mood disorders related to general medical conditions.^3,4 The risk of developing a depressive disorder is highest in the year after receiving the breast cancer diagnosis.⁴

A woman’s risk of developing a depressive disorder may depend on the type of cancer treatment she receives. For example, breast asymmetry is common after breast conserving surgery. Waljee et al⁵ found that women with breast asymmetry had increased fears of cancer recurrence and more feelings of self-consciousness. More pronounced asymmetry led to a higher incidence of depressive symptoms. However, among 90 patients undergoing bilateral prophylactic mastectomy, the rate of depression had not changed 1 year after the procedure.⁶ Chemotherapy, particularly at high doses, is a risk factor for depression.^4,7,8

Self-blame for developing breast cancer can affect mood. In 2007, Friedman et al⁹ determined that higher levels of self-blame correlated with higher levels of depression and decreased quality of life. Women often blamed themselves for various reasons, including:

• poor coping skills
• anxiety about their health and treatments
• inability to express emotions
• delays in medical consultation.

Exacerbated symptoms and side effects. Women with depression often experience increased side effects from cancer treatments, and the subjective experience of these effects—including hot flashes, cognitive impairment, pain, and sexual dysfunction—likely is intensified.⁴ Somatic symptoms of depression may be exacerbated by cancer treatment side effects or mistaken for effects of the treatment. When somatic symptoms of depression are mistaken for treatment side effects, depression—and the opportunity to treat it—can be overlooked.¹⁰

Depression may be a risk factor for poor adherence to cancer treatment. In a quantitative review of studies correlating depression and medical treatment noncompliance, DiMatteo et al¹¹ determined that compared with nondepressed patients, those with depression were 3 times more likely to not adhere to treatment recommendations; this review was not limited to cancer patients. Depressive symptoms—notably poor concentration and amotivation—can create the impression that a patient is poorly adherent. Women with comorbid depression and breast cancer may have difficulty understanding treatment recommendations or remembering daily treatment goals.⁴

Appropriate screening tools

Factors that may increase a breast cancer patient’s risk for developing a psychiatric disorder are listed in Table 1.¹⁰ Many depression screening tools are available; below we describe 3 commonly used for patients with breast cancer.

The National Comprehensive Cancer Center Distress Thermometer allows patients to rate their overall distress level over the past week on a scale from 0 to 10, using a visual analogue.¹² The Distress Thermometer has been validated for several cancer populations and in different parts of the world. A score of 7 has both good sensitivity and specificity for detecting depression in breast cancer patients. Consider a complete psychiatric evaluation for patients with scores ≥7.¹³

The Profile of Mood States questionnaire¹⁴ is a reliable, valid 65-item questionnaire often used in studies of mood dysregulation and breast cancer. Subscales include depression-dejection, tension-anxiety, anger-hostility, confusion-bewilderment, vigor-activity, and fatigue-inertia. Using a 5-point Likert scale, patients rate their symptoms over the past week. Subscale scores are then added to a total mood disturbance score.^14,15

The Hospital Anxiety and Depression Scale (HADS) is a sensitive, reliable 14-item scale that is commonly used to study depression and anxiety in patients with breast cancer.¹⁶ HADS includes two 7-item subscales—anxiety and depression—and answers are scored on a 4-point Likert scale. Patients are asked to respond quickly and avoid thinking too long about their answers.

Table 1

Risk factors for psychiatric distress related to breast cancer

Psychotherapeutic options

Behavioral therapies can diminish symptoms of depression, according to a review of studies and practice guidelines on managing depression in cancer patients.¹⁷ Group interventions, in particular, can be valuable. Anderson et al¹⁸ found that group cohesion, member connectedness, and more sessions correlated with decreased psychological distress.

Psychoeducation aims to provide medical information and discuss cancer’s causes, prognosis, and treatment strategies. Group settings can help improve communication and problem-solving skills. In a randomized controlled trial (RCT) of 203 women with breast cancer, psychoeducational group treatment reduced depression, anger, and fatigue.¹⁹

Cognitive-behavioral therapy (CBT) helps patients identify and restructure negative thoughts and increase positive, adaptive behaviors. Hunter et al²⁰ noted significant improvement in depressed mood, anxiety, and sleep in 17 women experiencing menopausal symptoms who received group CBT after completing breast cancer treatment. In 1 study, 124 patients with metastatic breast cancer who received 8 weekly sessions of group CBT reported reduced depression and mood disturbance and improved self-esteem compared with a no-therapy control group.²¹

Supportive-expressive therapy (SET) is a manual-based therapy that focuses on increasing social support, improving symptom control, and enhancing communication between the patient and treatment team. Affective expression helps lead the therapist to issues that should be addressed. Evidence on the effectiveness of SET for patients with breast cancer is mixed. A study of 357 women with breast cancer who were randomly assigned to 12-week group SET or an educational control condition found no evidence that SET reduced distress.²² However, a trial of 485 women with advanced breast cancer who were randomly assigned to group SET plus relaxation therapy or relaxation therapy alone showed that SET improved quality of life, including protection against depression.²³

Mindfulness-based stress reduction (MBSR) is a standardized form of meditation and yoga. Clinicians teach patients visualization, breathing exercises, and meditation to help them become aware of the body’s reaction to stress and how to regulate it. In an RCT of 84 female breast cancer survivors, a 6-week MBSR program diminished depressive symptoms, improved physical functioning, and reduced fear of cancer recurrence.²⁴

Evidence for antidepressants

SSRIs. Expert consensus guidelines on treating depression in women recommend an SSRI as a first-line agent.²⁵ In RCTs, fluoxetine, paroxetine, and sertraline were more effective than placebo in treating depression and related symptoms specifically in women with breast cancer (Table 2).^26-28

The interaction between SSRIs and chemotherapy agents is a concern. Tamoxifen decreases the rate of death from breast cancer in hormone receptor positive breast cancers.²⁹ Endoxifen, a potent anti-estrogen, is an active metabolite of tamoxifen via cytochrome P450 (CYP) 2D6. Goetz et al³⁰ demonstrated that women with decreased or inhibited metabolism via CYP2D6 had significantly shorter times to breast cancer recurrence, compared with women with extensive CYP2D6 metabolism.

SSRIs can varyingly inhibit CYP2D6. In a prospective trial of 158 breast cancer patients receiving tamoxifen, paroxetine and fluoxetine were found to be strong inhibitors of CYP2D6 and led to low levels of endoxifen.³¹ In contrast, weaker inhibitors, including sertraline and citalopram, led to intermediate levels of endoxifen. In a retrospective cohort study, Kelly et al³² demonstrated that women treated with paroxetine, in combination with tamoxifen, had an increased risk of death compared with women treated with other SSRIs or venlafaxine and tamoxifen. They estimated that paroxetine use in women treated with tamoxifen would lead to 1 additional breast cancer death per 20 women within 5 years of discontinuing tamoxifen.

According to American Psychiatric Association practice guidelines for treatment of MDD, depressed breast cancer patients who receive tamoxifen generally should be treated with an antidepressant that has minimal effect on CYP2D6 metabolism, such as citalopram, escitalopram, venlafaxine, or desvenlafaxine.³³

Serotonin-norepinephrine reuptake inhibitors (SNRIs) may be used to treat depressive disorders. In addition, venlafaxine may be helpful in treating post-mastectomy pain syndrome. Approximately one-half of patients who undergo mastectomy or breast reconstruction may experience a postoperative pain syndrome.³⁴ The most common symptom is a burning, stabbing pain in the axilla, arm, and chest wall of the affected side. This pain is worsened by movement and is poorly responsive to opioids.³⁵

In a 10-week RCT of 13 patients with neuropathic pain after breast cancer treatment, venlafaxine significantly improved pain relief compared with placebo, although the drug did not affect depression or anxiety.³⁶ In a study of 100 patients given venlafaxine or placebo for 2 weeks starting the night before undergoing partial or radical mastectomy with axillary dissection, those receiving venlafaxine had a significantly lower incidence of pain in the chest wall, arm, and axillary region, and scores of pain with movement were decreased.³⁷ There was no difference in opioid usage between groups.

Tricyclic antidepressants have been demonstrated to be effective in breast cancer patients. Side effects—notably anticholinergic effects—limit their use as antidepressants, especially when compared with SSRI treatment. In a study that randomly assigned 179 women with breast cancer to paroxetine, 20 to 40 mg/d, or amitriptyline, 75 to 150 mg/d, anticholinergic effects were almost twice as frequent in the amitriptyline group (19%) compared with paroxetine (11%).³⁸ In a 4-week double-blind, placebo-controlled crossover trial of 15 breast cancer patients, amitriptyline significantly relieved neuropathic pain, but its adverse effects made most patients unwilling to use the medication regularly.³⁹

Table 2

Evidence supporting SSRI use in patients with breast cancer*

Related Resources

• American Cancer Society. www.cancer.org.
• National Comprehensive Cancer network. www.nccn.org.

Drug Brand Names

• Amitripyline • Elavil
• Citalopram • Celexa
• Desvenlafaxine • Pristiq
• Escitalopram • Lexapro
• Fluoxetine • Prozac
• Paroxetine • Paxil
• Sertraline • Zoloft
• Tamoxifen • Nolvadex
• Venlafaxine • Effexor

Disclosure

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

Discuss this article at http://currentpsychiatry.blogspot.com/2010/11/depression-treatment-for-women-with.html#comments

Psychological distress among patients with breast cancer is common and is linked to worse clinical outcomes. Depressive and anxiety symptoms affect up to 40% of breast cancer patients,¹ and depression is associated with a higher relative risk of mortality in individuals with breast cancer.² Psychotropic medications and psychotherapy used to treat depression in patients without carcinoma also are appropriate and effective for breast cancer patients. However, some patients present distinct challenges to standard treatment. For example, growing evidence suggests that some selective serotonin reuptake inhibitors (SSRIs) may reduce the effectiveness of tamoxifen, a chemotherapeutic agent. This article discusses challenges in diagnosing and treating depression in breast cancer patients and reviews evidence supporting appropriate psychiatric care.

Increased vulnerability

In 10% to 30% of women, a breast cancer diagnosis may lead to increased vulnerability to depressive disorders, including adjustment disorders with depressed mood, major depressive disorder (MDD), and mood disorders related to general medical conditions.^3,4 The risk of developing a depressive disorder is highest in the year after receiving the breast cancer diagnosis.⁴

A woman’s risk of developing a depressive disorder may depend on the type of cancer treatment she receives. For example, breast asymmetry is common after breast conserving surgery. Waljee et al⁵ found that women with breast asymmetry had increased fears of cancer recurrence and more feelings of self-consciousness. More pronounced asymmetry led to a higher incidence of depressive symptoms. However, among 90 patients undergoing bilateral prophylactic mastectomy, the rate of depression had not changed 1 year after the procedure.⁶ Chemotherapy, particularly at high doses, is a risk factor for depression.^4,7,8

Self-blame for developing breast cancer can affect mood. In 2007, Friedman et al⁹ determined that higher levels of self-blame correlated with higher levels of depression and decreased quality of life. Women often blamed themselves for various reasons, including:

• poor coping skills
• anxiety about their health and treatments
• inability to express emotions
• delays in medical consultation.

Exacerbated symptoms and side effects. Women with depression often experience increased side effects from cancer treatments, and the subjective experience of these effects—including hot flashes, cognitive impairment, pain, and sexual dysfunction—likely is intensified.⁴ Somatic symptoms of depression may be exacerbated by cancer treatment side effects or mistaken for effects of the treatment. When somatic symptoms of depression are mistaken for treatment side effects, depression—and the opportunity to treat it—can be overlooked.¹⁰

Depression may be a risk factor for poor adherence to cancer treatment. In a quantitative review of studies correlating depression and medical treatment noncompliance, DiMatteo et al¹¹ determined that compared with nondepressed patients, those with depression were 3 times more likely to not adhere to treatment recommendations; this review was not limited to cancer patients. Depressive symptoms—notably poor concentration and amotivation—can create the impression that a patient is poorly adherent. Women with comorbid depression and breast cancer may have difficulty understanding treatment recommendations or remembering daily treatment goals.⁴

Appropriate screening tools

Factors that may increase a breast cancer patient’s risk for developing a psychiatric disorder are listed in Table 1.¹⁰ Many depression screening tools are available; below we describe 3 commonly used for patients with breast cancer.

The National Comprehensive Cancer Center Distress Thermometer allows patients to rate their overall distress level over the past week on a scale from 0 to 10, using a visual analogue.¹² The Distress Thermometer has been validated for several cancer populations and in different parts of the world. A score of 7 has both good sensitivity and specificity for detecting depression in breast cancer patients. Consider a complete psychiatric evaluation for patients with scores ≥7.¹³

The Profile of Mood States questionnaire¹⁴ is a reliable, valid 65-item questionnaire often used in studies of mood dysregulation and breast cancer. Subscales include depression-dejection, tension-anxiety, anger-hostility, confusion-bewilderment, vigor-activity, and fatigue-inertia. Using a 5-point Likert scale, patients rate their symptoms over the past week. Subscale scores are then added to a total mood disturbance score.^14,15

The Hospital Anxiety and Depression Scale (HADS) is a sensitive, reliable 14-item scale that is commonly used to study depression and anxiety in patients with breast cancer.¹⁶ HADS includes two 7-item subscales—anxiety and depression—and answers are scored on a 4-point Likert scale. Patients are asked to respond quickly and avoid thinking too long about their answers.

Table 1

Risk factors for psychiatric distress related to breast cancer

Psychotherapeutic options

Behavioral therapies can diminish symptoms of depression, according to a review of studies and practice guidelines on managing depression in cancer patients.¹⁷ Group interventions, in particular, can be valuable. Anderson et al¹⁸ found that group cohesion, member connectedness, and more sessions correlated with decreased psychological distress.

Psychoeducation aims to provide medical information and discuss cancer’s causes, prognosis, and treatment strategies. Group settings can help improve communication and problem-solving skills. In a randomized controlled trial (RCT) of 203 women with breast cancer, psychoeducational group treatment reduced depression, anger, and fatigue.¹⁹

Cognitive-behavioral therapy (CBT) helps patients identify and restructure negative thoughts and increase positive, adaptive behaviors. Hunter et al²⁰ noted significant improvement in depressed mood, anxiety, and sleep in 17 women experiencing menopausal symptoms who received group CBT after completing breast cancer treatment. In 1 study, 124 patients with metastatic breast cancer who received 8 weekly sessions of group CBT reported reduced depression and mood disturbance and improved self-esteem compared with a no-therapy control group.²¹

Supportive-expressive therapy (SET) is a manual-based therapy that focuses on increasing social support, improving symptom control, and enhancing communication between the patient and treatment team. Affective expression helps lead the therapist to issues that should be addressed. Evidence on the effectiveness of SET for patients with breast cancer is mixed. A study of 357 women with breast cancer who were randomly assigned to 12-week group SET or an educational control condition found no evidence that SET reduced distress.²² However, a trial of 485 women with advanced breast cancer who were randomly assigned to group SET plus relaxation therapy or relaxation therapy alone showed that SET improved quality of life, including protection against depression.²³

Mindfulness-based stress reduction (MBSR) is a standardized form of meditation and yoga. Clinicians teach patients visualization, breathing exercises, and meditation to help them become aware of the body’s reaction to stress and how to regulate it. In an RCT of 84 female breast cancer survivors, a 6-week MBSR program diminished depressive symptoms, improved physical functioning, and reduced fear of cancer recurrence.²⁴

Evidence for antidepressants

SSRIs. Expert consensus guidelines on treating depression in women recommend an SSRI as a first-line agent.²⁵ In RCTs, fluoxetine, paroxetine, and sertraline were more effective than placebo in treating depression and related symptoms specifically in women with breast cancer (Table 2).^26-28

The interaction between SSRIs and chemotherapy agents is a concern. Tamoxifen decreases the rate of death from breast cancer in hormone receptor positive breast cancers.²⁹ Endoxifen, a potent anti-estrogen, is an active metabolite of tamoxifen via cytochrome P450 (CYP) 2D6. Goetz et al³⁰ demonstrated that women with decreased or inhibited metabolism via CYP2D6 had significantly shorter times to breast cancer recurrence, compared with women with extensive CYP2D6 metabolism.

SSRIs can varyingly inhibit CYP2D6. In a prospective trial of 158 breast cancer patients receiving tamoxifen, paroxetine and fluoxetine were found to be strong inhibitors of CYP2D6 and led to low levels of endoxifen.³¹ In contrast, weaker inhibitors, including sertraline and citalopram, led to intermediate levels of endoxifen. In a retrospective cohort study, Kelly et al³² demonstrated that women treated with paroxetine, in combination with tamoxifen, had an increased risk of death compared with women treated with other SSRIs or venlafaxine and tamoxifen. They estimated that paroxetine use in women treated with tamoxifen would lead to 1 additional breast cancer death per 20 women within 5 years of discontinuing tamoxifen.

According to American Psychiatric Association practice guidelines for treatment of MDD, depressed breast cancer patients who receive tamoxifen generally should be treated with an antidepressant that has minimal effect on CYP2D6 metabolism, such as citalopram, escitalopram, venlafaxine, or desvenlafaxine.³³

Serotonin-norepinephrine reuptake inhibitors (SNRIs) may be used to treat depressive disorders. In addition, venlafaxine may be helpful in treating post-mastectomy pain syndrome. Approximately one-half of patients who undergo mastectomy or breast reconstruction may experience a postoperative pain syndrome.³⁴ The most common symptom is a burning, stabbing pain in the axilla, arm, and chest wall of the affected side. This pain is worsened by movement and is poorly responsive to opioids.³⁵

In a 10-week RCT of 13 patients with neuropathic pain after breast cancer treatment, venlafaxine significantly improved pain relief compared with placebo, although the drug did not affect depression or anxiety.³⁶ In a study of 100 patients given venlafaxine or placebo for 2 weeks starting the night before undergoing partial or radical mastectomy with axillary dissection, those receiving venlafaxine had a significantly lower incidence of pain in the chest wall, arm, and axillary region, and scores of pain with movement were decreased.³⁷ There was no difference in opioid usage between groups.

Tricyclic antidepressants have been demonstrated to be effective in breast cancer patients. Side effects—notably anticholinergic effects—limit their use as antidepressants, especially when compared with SSRI treatment. In a study that randomly assigned 179 women with breast cancer to paroxetine, 20 to 40 mg/d, or amitriptyline, 75 to 150 mg/d, anticholinergic effects were almost twice as frequent in the amitriptyline group (19%) compared with paroxetine (11%).³⁸ In a 4-week double-blind, placebo-controlled crossover trial of 15 breast cancer patients, amitriptyline significantly relieved neuropathic pain, but its adverse effects made most patients unwilling to use the medication regularly.³⁹

Table 2

Evidence supporting SSRI use in patients with breast cancer*

Related Resources

• American Cancer Society. www.cancer.org.
• National Comprehensive Cancer network. www.nccn.org.

Drug Brand Names

• Amitripyline • Elavil
• Citalopram • Celexa
• Desvenlafaxine • Pristiq
• Escitalopram • Lexapro
• Fluoxetine • Prozac
• Paroxetine • Paxil
• Sertraline • Zoloft
• Tamoxifen • Nolvadex
• Venlafaxine • Effexor

Disclosure

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

Discuss this article at http://currentpsychiatry.blogspot.com/2010/11/depression-treatment-for-women-with.html#comments

Psychological distress among patients with breast cancer is common and is linked to worse clinical outcomes. Depressive and anxiety symptoms affect up to 40% of breast cancer patients,¹ and depression is associated with a higher relative risk of mortality in individuals with breast cancer.² Psychotropic medications and psychotherapy used to treat depression in patients without carcinoma also are appropriate and effective for breast cancer patients. However, some patients present distinct challenges to standard treatment. For example, growing evidence suggests that some selective serotonin reuptake inhibitors (SSRIs) may reduce the effectiveness of tamoxifen, a chemotherapeutic agent. This article discusses challenges in diagnosing and treating depression in breast cancer patients and reviews evidence supporting appropriate psychiatric care.

Increased vulnerability

In 10% to 30% of women, a breast cancer diagnosis may lead to increased vulnerability to depressive disorders, including adjustment disorders with depressed mood, major depressive disorder (MDD), and mood disorders related to general medical conditions.^3,4 The risk of developing a depressive disorder is highest in the year after receiving the breast cancer diagnosis.⁴

A woman’s risk of developing a depressive disorder may depend on the type of cancer treatment she receives. For example, breast asymmetry is common after breast conserving surgery. Waljee et al⁵ found that women with breast asymmetry had increased fears of cancer recurrence and more feelings of self-consciousness. More pronounced asymmetry led to a higher incidence of depressive symptoms. However, among 90 patients undergoing bilateral prophylactic mastectomy, the rate of depression had not changed 1 year after the procedure.⁶ Chemotherapy, particularly at high doses, is a risk factor for depression.^4,7,8

Self-blame for developing breast cancer can affect mood. In 2007, Friedman et al⁹ determined that higher levels of self-blame correlated with higher levels of depression and decreased quality of life. Women often blamed themselves for various reasons, including:

• poor coping skills
• anxiety about their health and treatments
• inability to express emotions
• delays in medical consultation.

Exacerbated symptoms and side effects. Women with depression often experience increased side effects from cancer treatments, and the subjective experience of these effects—including hot flashes, cognitive impairment, pain, and sexual dysfunction—likely is intensified.⁴ Somatic symptoms of depression may be exacerbated by cancer treatment side effects or mistaken for effects of the treatment. When somatic symptoms of depression are mistaken for treatment side effects, depression—and the opportunity to treat it—can be overlooked.¹⁰

Depression may be a risk factor for poor adherence to cancer treatment. In a quantitative review of studies correlating depression and medical treatment noncompliance, DiMatteo et al¹¹ determined that compared with nondepressed patients, those with depression were 3 times more likely to not adhere to treatment recommendations; this review was not limited to cancer patients. Depressive symptoms—notably poor concentration and amotivation—can create the impression that a patient is poorly adherent. Women with comorbid depression and breast cancer may have difficulty understanding treatment recommendations or remembering daily treatment goals.⁴

Appropriate screening tools

Factors that may increase a breast cancer patient’s risk for developing a psychiatric disorder are listed in Table 1.¹⁰ Many depression screening tools are available; below we describe 3 commonly used for patients with breast cancer.

The National Comprehensive Cancer Center Distress Thermometer allows patients to rate their overall distress level over the past week on a scale from 0 to 10, using a visual analogue.¹² The Distress Thermometer has been validated for several cancer populations and in different parts of the world. A score of 7 has both good sensitivity and specificity for detecting depression in breast cancer patients. Consider a complete psychiatric evaluation for patients with scores ≥7.¹³

The Profile of Mood States questionnaire¹⁴ is a reliable, valid 65-item questionnaire often used in studies of mood dysregulation and breast cancer. Subscales include depression-dejection, tension-anxiety, anger-hostility, confusion-bewilderment, vigor-activity, and fatigue-inertia. Using a 5-point Likert scale, patients rate their symptoms over the past week. Subscale scores are then added to a total mood disturbance score.^14,15

The Hospital Anxiety and Depression Scale (HADS) is a sensitive, reliable 14-item scale that is commonly used to study depression and anxiety in patients with breast cancer.¹⁶ HADS includes two 7-item subscales—anxiety and depression—and answers are scored on a 4-point Likert scale. Patients are asked to respond quickly and avoid thinking too long about their answers.

Table 1

Risk factors for psychiatric distress related to breast cancer

Psychotherapeutic options

Behavioral therapies can diminish symptoms of depression, according to a review of studies and practice guidelines on managing depression in cancer patients.¹⁷ Group interventions, in particular, can be valuable. Anderson et al¹⁸ found that group cohesion, member connectedness, and more sessions correlated with decreased psychological distress.

Psychoeducation aims to provide medical information and discuss cancer’s causes, prognosis, and treatment strategies. Group settings can help improve communication and problem-solving skills. In a randomized controlled trial (RCT) of 203 women with breast cancer, psychoeducational group treatment reduced depression, anger, and fatigue.¹⁹

Cognitive-behavioral therapy (CBT) helps patients identify and restructure negative thoughts and increase positive, adaptive behaviors. Hunter et al²⁰ noted significant improvement in depressed mood, anxiety, and sleep in 17 women experiencing menopausal symptoms who received group CBT after completing breast cancer treatment. In 1 study, 124 patients with metastatic breast cancer who received 8 weekly sessions of group CBT reported reduced depression and mood disturbance and improved self-esteem compared with a no-therapy control group.²¹

Supportive-expressive therapy (SET) is a manual-based therapy that focuses on increasing social support, improving symptom control, and enhancing communication between the patient and treatment team. Affective expression helps lead the therapist to issues that should be addressed. Evidence on the effectiveness of SET for patients with breast cancer is mixed. A study of 357 women with breast cancer who were randomly assigned to 12-week group SET or an educational control condition found no evidence that SET reduced distress.²² However, a trial of 485 women with advanced breast cancer who were randomly assigned to group SET plus relaxation therapy or relaxation therapy alone showed that SET improved quality of life, including protection against depression.²³

Mindfulness-based stress reduction (MBSR) is a standardized form of meditation and yoga. Clinicians teach patients visualization, breathing exercises, and meditation to help them become aware of the body’s reaction to stress and how to regulate it. In an RCT of 84 female breast cancer survivors, a 6-week MBSR program diminished depressive symptoms, improved physical functioning, and reduced fear of cancer recurrence.²⁴

Evidence for antidepressants

SSRIs. Expert consensus guidelines on treating depression in women recommend an SSRI as a first-line agent.²⁵ In RCTs, fluoxetine, paroxetine, and sertraline were more effective than placebo in treating depression and related symptoms specifically in women with breast cancer (Table 2).^26-28

The interaction between SSRIs and chemotherapy agents is a concern. Tamoxifen decreases the rate of death from breast cancer in hormone receptor positive breast cancers.²⁹ Endoxifen, a potent anti-estrogen, is an active metabolite of tamoxifen via cytochrome P450 (CYP) 2D6. Goetz et al³⁰ demonstrated that women with decreased or inhibited metabolism via CYP2D6 had significantly shorter times to breast cancer recurrence, compared with women with extensive CYP2D6 metabolism.

SSRIs can varyingly inhibit CYP2D6. In a prospective trial of 158 breast cancer patients receiving tamoxifen, paroxetine and fluoxetine were found to be strong inhibitors of CYP2D6 and led to low levels of endoxifen.³¹ In contrast, weaker inhibitors, including sertraline and citalopram, led to intermediate levels of endoxifen. In a retrospective cohort study, Kelly et al³² demonstrated that women treated with paroxetine, in combination with tamoxifen, had an increased risk of death compared with women treated with other SSRIs or venlafaxine and tamoxifen. They estimated that paroxetine use in women treated with tamoxifen would lead to 1 additional breast cancer death per 20 women within 5 years of discontinuing tamoxifen.

According to American Psychiatric Association practice guidelines for treatment of MDD, depressed breast cancer patients who receive tamoxifen generally should be treated with an antidepressant that has minimal effect on CYP2D6 metabolism, such as citalopram, escitalopram, venlafaxine, or desvenlafaxine.³³

Serotonin-norepinephrine reuptake inhibitors (SNRIs) may be used to treat depressive disorders. In addition, venlafaxine may be helpful in treating post-mastectomy pain syndrome. Approximately one-half of patients who undergo mastectomy or breast reconstruction may experience a postoperative pain syndrome.³⁴ The most common symptom is a burning, stabbing pain in the axilla, arm, and chest wall of the affected side. This pain is worsened by movement and is poorly responsive to opioids.³⁵

In a 10-week RCT of 13 patients with neuropathic pain after breast cancer treatment, venlafaxine significantly improved pain relief compared with placebo, although the drug did not affect depression or anxiety.³⁶ In a study of 100 patients given venlafaxine or placebo for 2 weeks starting the night before undergoing partial or radical mastectomy with axillary dissection, those receiving venlafaxine had a significantly lower incidence of pain in the chest wall, arm, and axillary region, and scores of pain with movement were decreased.³⁷ There was no difference in opioid usage between groups.

Tricyclic antidepressants have been demonstrated to be effective in breast cancer patients. Side effects—notably anticholinergic effects—limit their use as antidepressants, especially when compared with SSRI treatment. In a study that randomly assigned 179 women with breast cancer to paroxetine, 20 to 40 mg/d, or amitriptyline, 75 to 150 mg/d, anticholinergic effects were almost twice as frequent in the amitriptyline group (19%) compared with paroxetine (11%).³⁸ In a 4-week double-blind, placebo-controlled crossover trial of 15 breast cancer patients, amitriptyline significantly relieved neuropathic pain, but its adverse effects made most patients unwilling to use the medication regularly.³⁹

Table 2

Evidence supporting SSRI use in patients with breast cancer*

Related Resources

• American Cancer Society. www.cancer.org.
• National Comprehensive Cancer network. www.nccn.org.

Drug Brand Names

• Amitripyline • Elavil
• Citalopram • Celexa
• Desvenlafaxine • Pristiq
• Escitalopram • Lexapro
• Fluoxetine • Prozac
• Paroxetine • Paxil
• Sertraline • Zoloft
• Tamoxifen • Nolvadex
• Venlafaxine • Effexor

Disclosure

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

ATLANTA – St. John's wort appears to convert clopidogrel hyporesponders into robust responders.

This raises the intriguing possibility that the herbal therapy might provide a “twofer”: enhanced platelet inhibition in clopidogrel (Plavix) hyporesponders, plus a well-studied antidepressant effect that could be of particular value in patients with coronary artery disease, Dr. Wei C. Lau said at the annual scientific session of the American College of Cardiology.

“Depression plays a big role in coronary artery disease, and addressing depression is a big part of our cardiac rehab program. The next step in our research is going to be St. John's wort versus placebo to see if we get a double whammy: a treatment that improves platelet inhibition in patients on clopidogrel while also improving the psyche,” added Dr. Lau, director of adult cardiovascular and thoracic anesthesiology at the University of Michigan Cardiovascular Center, Ann Arbor.

It's now well established that about 20% of clopidogrel-treated patients are low responders to the platelet-inhibiting drug, placing them at increased risk of major thrombotic events related to coronary stenting.

The recommended solutions at this point are to double the maintenance dose from 75 to 150 mg/day, switch to an alternative platelet inhibitor, or add another agent such as cilostazol (Pletal). But doubling the clopidogrel dose raises the associated bleeding risk, while cilostazol is a relatively expensive drug with compliance issues related to its twice-daily dosing.

“I think we can do this better with St. John's wort,” according to Dr. Lau. “It's a dollar a pill once daily.”

Clopidogrel is a prodrug activated by the cytochrome P450 isoenzyme. St. John's wort (Hypericum perforatum) is a potent inducer of increased metabolic activity of the CYP 3A4 enzyme, with resultant enhanced platelet-inhibiting effects.

Dr. Lau and his coinvestigators, including Dr. Paul A. Gurbel of Johns Hopkins University, Baltimore, measured platelet function in 62 heart patients on chronic maintenance clopidogrel at the standard 75 mg once daily. They identified 19 patients as clopidogrel hyporesponders with suboptimal platelet inhibition. They randomized these 19 patients in double-blind fashion to St. John's wort at 300 mg once daily or placebo for 14 days while continuing on clopidogrel, then repeated the platelet aggregation studies.

Platelet inhibition improved by 20% in the St. John's wort group while remaining unchanged in controls. In an earlier study involving 10 clopidogrel-hyporesponsive healthy volunteers, 2 weeks of St. John's wort at 300 mg thrice daily boosted platelet inhibition by 36%.

St. John's wort's effects on the cytochrome P450 isoenzyme could in theory affect the metabolism of certain other drugs commonly prescribed in patients with coronary disease. Dr. Lau said that he and his colleagues have demonstrated that, reassuringly, the herbal therapy does not affect LDL levels in patients on statins. However, further prospective randomized studies are clearly needed to firmly establish the safety and efficacy of St. John's wort in converting clopidogrel nonresponders to responders, he added.

In an interview, Dr. Lau said the lack of effective Food and Drug Administration oversight of herbal therapies makes him feel compelled to test every lot of St. John's wort with which he works. He has found, as have others, that concentrations of the active agent often are not as labeled and vary widely from batch to batch with some manufacturers. He has settled on the German Kira brand for its consistency.

Dr. Lau disclosed having no financial interests relevant to this study.

ATLANTA – St. John's wort appears to convert clopidogrel hyporesponders into robust responders.

This raises the intriguing possibility that the herbal therapy might provide a “twofer”: enhanced platelet inhibition in clopidogrel (Plavix) hyporesponders, plus a well-studied antidepressant effect that could be of particular value in patients with coronary artery disease, Dr. Wei C. Lau said at the annual scientific session of the American College of Cardiology.

“Depression plays a big role in coronary artery disease, and addressing depression is a big part of our cardiac rehab program. The next step in our research is going to be St. John's wort versus placebo to see if we get a double whammy: a treatment that improves platelet inhibition in patients on clopidogrel while also improving the psyche,” added Dr. Lau, director of adult cardiovascular and thoracic anesthesiology at the University of Michigan Cardiovascular Center, Ann Arbor.

It's now well established that about 20% of clopidogrel-treated patients are low responders to the platelet-inhibiting drug, placing them at increased risk of major thrombotic events related to coronary stenting.

The recommended solutions at this point are to double the maintenance dose from 75 to 150 mg/day, switch to an alternative platelet inhibitor, or add another agent such as cilostazol (Pletal). But doubling the clopidogrel dose raises the associated bleeding risk, while cilostazol is a relatively expensive drug with compliance issues related to its twice-daily dosing.

“I think we can do this better with St. John's wort,” according to Dr. Lau. “It's a dollar a pill once daily.”

Clopidogrel is a prodrug activated by the cytochrome P450 isoenzyme. St. John's wort (Hypericum perforatum) is a potent inducer of increased metabolic activity of the CYP 3A4 enzyme, with resultant enhanced platelet-inhibiting effects.

Dr. Lau and his coinvestigators, including Dr. Paul A. Gurbel of Johns Hopkins University, Baltimore, measured platelet function in 62 heart patients on chronic maintenance clopidogrel at the standard 75 mg once daily. They identified 19 patients as clopidogrel hyporesponders with suboptimal platelet inhibition. They randomized these 19 patients in double-blind fashion to St. John's wort at 300 mg once daily or placebo for 14 days while continuing on clopidogrel, then repeated the platelet aggregation studies.

Platelet inhibition improved by 20% in the St. John's wort group while remaining unchanged in controls. In an earlier study involving 10 clopidogrel-hyporesponsive healthy volunteers, 2 weeks of St. John's wort at 300 mg thrice daily boosted platelet inhibition by 36%.

St. John's wort's effects on the cytochrome P450 isoenzyme could in theory affect the metabolism of certain other drugs commonly prescribed in patients with coronary disease. Dr. Lau said that he and his colleagues have demonstrated that, reassuringly, the herbal therapy does not affect LDL levels in patients on statins. However, further prospective randomized studies are clearly needed to firmly establish the safety and efficacy of St. John's wort in converting clopidogrel nonresponders to responders, he added.

In an interview, Dr. Lau said the lack of effective Food and Drug Administration oversight of herbal therapies makes him feel compelled to test every lot of St. John's wort with which he works. He has found, as have others, that concentrations of the active agent often are not as labeled and vary widely from batch to batch with some manufacturers. He has settled on the German Kira brand for its consistency.

Dr. Lau disclosed having no financial interests relevant to this study.

ATLANTA – St. John's wort appears to convert clopidogrel hyporesponders into robust responders.

This raises the intriguing possibility that the herbal therapy might provide a “twofer”: enhanced platelet inhibition in clopidogrel (Plavix) hyporesponders, plus a well-studied antidepressant effect that could be of particular value in patients with coronary artery disease, Dr. Wei C. Lau said at the annual scientific session of the American College of Cardiology.

“Depression plays a big role in coronary artery disease, and addressing depression is a big part of our cardiac rehab program. The next step in our research is going to be St. John's wort versus placebo to see if we get a double whammy: a treatment that improves platelet inhibition in patients on clopidogrel while also improving the psyche,” added Dr. Lau, director of adult cardiovascular and thoracic anesthesiology at the University of Michigan Cardiovascular Center, Ann Arbor.

It's now well established that about 20% of clopidogrel-treated patients are low responders to the platelet-inhibiting drug, placing them at increased risk of major thrombotic events related to coronary stenting.

The recommended solutions at this point are to double the maintenance dose from 75 to 150 mg/day, switch to an alternative platelet inhibitor, or add another agent such as cilostazol (Pletal). But doubling the clopidogrel dose raises the associated bleeding risk, while cilostazol is a relatively expensive drug with compliance issues related to its twice-daily dosing.

“I think we can do this better with St. John's wort,” according to Dr. Lau. “It's a dollar a pill once daily.”

Clopidogrel is a prodrug activated by the cytochrome P450 isoenzyme. St. John's wort (Hypericum perforatum) is a potent inducer of increased metabolic activity of the CYP 3A4 enzyme, with resultant enhanced platelet-inhibiting effects.

Dr. Lau and his coinvestigators, including Dr. Paul A. Gurbel of Johns Hopkins University, Baltimore, measured platelet function in 62 heart patients on chronic maintenance clopidogrel at the standard 75 mg once daily. They identified 19 patients as clopidogrel hyporesponders with suboptimal platelet inhibition. They randomized these 19 patients in double-blind fashion to St. John's wort at 300 mg once daily or placebo for 14 days while continuing on clopidogrel, then repeated the platelet aggregation studies.

Platelet inhibition improved by 20% in the St. John's wort group while remaining unchanged in controls. In an earlier study involving 10 clopidogrel-hyporesponsive healthy volunteers, 2 weeks of St. John's wort at 300 mg thrice daily boosted platelet inhibition by 36%.

St. John's wort's effects on the cytochrome P450 isoenzyme could in theory affect the metabolism of certain other drugs commonly prescribed in patients with coronary disease. Dr. Lau said that he and his colleagues have demonstrated that, reassuringly, the herbal therapy does not affect LDL levels in patients on statins. However, further prospective randomized studies are clearly needed to firmly establish the safety and efficacy of St. John's wort in converting clopidogrel nonresponders to responders, he added.

In an interview, Dr. Lau said the lack of effective Food and Drug Administration oversight of herbal therapies makes him feel compelled to test every lot of St. John's wort with which he works. He has found, as have others, that concentrations of the active agent often are not as labeled and vary widely from batch to batch with some manufacturers. He has settled on the German Kira brand for its consistency.

Dr. Lau disclosed having no financial interests relevant to this study.

SAN DIEGO – Plasma levels of serotonin were significantly elevated in patients with decompensated systolic heart failure, compared with patients in the compensated state and with normal controls, according to a single-center study.

The finding suggests that serotonin has an active role in the progression of heart failure, researchers led by Dr. Ahmed M. Selim wrote in a poster at the meeting.

“More studies should be done to test the sensitivity, specificity, and prognostic value of serotonin as a marker for congestive heart failure and also to investigate the therapeutic benefits of the medications affecting this pathway,” noted the researchers of the cardiology department at Albert Einstein College of Medicine, New York.

Dr. Selim and his associates collected plasma serotonin levels from 29 patients who were admitted with decompensated heart failure, 61 patients with stable heart failure, and 22 normal controls. They excluded patients on medications affecting serotonin receptors and those with pulmonary hypertension. All heart failure patients were on stable doses ofheedications and had left-ventricular ejection fractions of 40% or less;, wntrols had a mean ejection fraction of 59%. Ppatients' mean age was 55 years;, a% were male.

The mean serotonin level in controls was 2.4 ng/mL, vs. 4.1 ng/mL in the compensated group and 11.8 ng/mL in the decompensated group,. ndependent of age, race, renal function, diabetes mend hypertension. “All results were highly significant,” the researchers wrote.

SAN DIEGO – Plasma levels of serotonin were significantly elevated in patients with decompensated systolic heart failure, compared with patients in the compensated state and with normal controls, according to a single-center study.

The finding suggests that serotonin has an active role in the progression of heart failure, researchers led by Dr. Ahmed M. Selim wrote in a poster at the meeting.

“More studies should be done to test the sensitivity, specificity, and prognostic value of serotonin as a marker for congestive heart failure and also to investigate the therapeutic benefits of the medications affecting this pathway,” noted the researchers of the cardiology department at Albert Einstein College of Medicine, New York.

Dr. Selim and his associates collected plasma serotonin levels from 29 patients who were admitted with decompensated heart failure, 61 patients with stable heart failure, and 22 normal controls. They excluded patients on medications affecting serotonin receptors and those with pulmonary hypertension. All heart failure patients were on stable doses ofheedications and had left-ventricular ejection fractions of 40% or less;, wntrols had a mean ejection fraction of 59%. Ppatients' mean age was 55 years;, a% were male.

The mean serotonin level in controls was 2.4 ng/mL, vs. 4.1 ng/mL in the compensated group and 11.8 ng/mL in the decompensated group,. ndependent of age, race, renal function, diabetes mend hypertension. “All results were highly significant,” the researchers wrote.

SAN DIEGO – Plasma levels of serotonin were significantly elevated in patients with decompensated systolic heart failure, compared with patients in the compensated state and with normal controls, according to a single-center study.

The finding suggests that serotonin has an active role in the progression of heart failure, researchers led by Dr. Ahmed M. Selim wrote in a poster at the meeting.

“More studies should be done to test the sensitivity, specificity, and prognostic value of serotonin as a marker for congestive heart failure and also to investigate the therapeutic benefits of the medications affecting this pathway,” noted the researchers of the cardiology department at Albert Einstein College of Medicine, New York.

Dr. Selim and his associates collected plasma serotonin levels from 29 patients who were admitted with decompensated heart failure, 61 patients with stable heart failure, and 22 normal controls. They excluded patients on medications affecting serotonin receptors and those with pulmonary hypertension. All heart failure patients were on stable doses ofheedications and had left-ventricular ejection fractions of 40% or less;, wntrols had a mean ejection fraction of 59%. Ppatients' mean age was 55 years;, a% were male.

The mean serotonin level in controls was 2.4 ng/mL, vs. 4.1 ng/mL in the compensated group and 11.8 ng/mL in the decompensated group,. ndependent of age, race, renal function, diabetes mend hypertension. “All results were highly significant,” the researchers wrote.

Insurance companies and surgical teams usually require patients to undergo a psychiatric evaluation before major surgeries such as organ transplants,¹ amputations, or bariatric procedures because these surgeries are expensive, require patients to change their lifestyle, and use limited resources. Psychiatrists perform pre-surgical evaluations by diagnostic interview, observation, and obtaining collateral information. Your evaluation should address key elements and give the surgical team input about a patient’s suitability for surgery. You also can comment on treatments that would make the patient a better candidate for surgery and plan for post-surgery psychiatric morbidities.

Key elements

Major mental illness. Without adequate treatment, major mood disorders can make a patient unable to undergo surgery. In addition, these types of surgeries are substantial life events that can trigger mood episodes. Educate patients about early signs of relapse and suggest a plan of action for treatment. A patient with an uncontrolled psychotic disorder and poor social support and/or case management is not a good candidate for surgery.

Substance use. Patients with active substance dependence are poor candidates for major surgeries unless they receive substance abuse treatment. During evaluation, motivational interviewing can help guide a patient toward treatment. Ensure that patients whose substance dependence is in remission have adequate support and treatment plans to prevent relapse.

Capacity to make decisions is based on the nature of the procedure and the patient’s ability to understand the process and risk vs benefits. The threshold for capacity can vary based on the procedure and the risks.²

Treatment adherence requires compliance with close medical follow-up, complicated medications, or lifestyle changes. A history of compliance with medical directives, medications, and appointments is important. Collateral information from the surgical team or caregivers can be helpful.

Coping style and strategies. Quiz the patient about internal and external resources they have used to cope with stress. A pattern of decompensation to using primitive defense mechanisms to handle stress suggests that the patient may have a personality disorder and might be a poor surgical candidate. Ability to use relatively mature defense strategies in stressful times suggests a good candidate.

Safety. Active suicidal or homicidal ideation is problematic in patients seeking major surgical interventions. Ensure that the stress of the surgery will not trigger dangerous behaviors. A history of frequent self-harm or impulsive suicidality suggests the that patient may have an unstable axis I or II disorder and might be a poor candidate for major surgery without further treatment.

Insurance companies and surgical teams usually require patients to undergo a psychiatric evaluation before major surgeries such as organ transplants,¹ amputations, or bariatric procedures because these surgeries are expensive, require patients to change their lifestyle, and use limited resources. Psychiatrists perform pre-surgical evaluations by diagnostic interview, observation, and obtaining collateral information. Your evaluation should address key elements and give the surgical team input about a patient’s suitability for surgery. You also can comment on treatments that would make the patient a better candidate for surgery and plan for post-surgery psychiatric morbidities.

Key elements

Major mental illness. Without adequate treatment, major mood disorders can make a patient unable to undergo surgery. In addition, these types of surgeries are substantial life events that can trigger mood episodes. Educate patients about early signs of relapse and suggest a plan of action for treatment. A patient with an uncontrolled psychotic disorder and poor social support and/or case management is not a good candidate for surgery.

Substance use. Patients with active substance dependence are poor candidates for major surgeries unless they receive substance abuse treatment. During evaluation, motivational interviewing can help guide a patient toward treatment. Ensure that patients whose substance dependence is in remission have adequate support and treatment plans to prevent relapse.

Capacity to make decisions is based on the nature of the procedure and the patient’s ability to understand the process and risk vs benefits. The threshold for capacity can vary based on the procedure and the risks.²

Treatment adherence requires compliance with close medical follow-up, complicated medications, or lifestyle changes. A history of compliance with medical directives, medications, and appointments is important. Collateral information from the surgical team or caregivers can be helpful.

Coping style and strategies. Quiz the patient about internal and external resources they have used to cope with stress. A pattern of decompensation to using primitive defense mechanisms to handle stress suggests that the patient may have a personality disorder and might be a poor surgical candidate. Ability to use relatively mature defense strategies in stressful times suggests a good candidate.

Safety. Active suicidal or homicidal ideation is problematic in patients seeking major surgical interventions. Ensure that the stress of the surgery will not trigger dangerous behaviors. A history of frequent self-harm or impulsive suicidality suggests the that patient may have an unstable axis I or II disorder and might be a poor candidate for major surgery without further treatment.

Insurance companies and surgical teams usually require patients to undergo a psychiatric evaluation before major surgeries such as organ transplants,¹ amputations, or bariatric procedures because these surgeries are expensive, require patients to change their lifestyle, and use limited resources. Psychiatrists perform pre-surgical evaluations by diagnostic interview, observation, and obtaining collateral information. Your evaluation should address key elements and give the surgical team input about a patient’s suitability for surgery. You also can comment on treatments that would make the patient a better candidate for surgery and plan for post-surgery psychiatric morbidities.

Key elements

Major mental illness. Without adequate treatment, major mood disorders can make a patient unable to undergo surgery. In addition, these types of surgeries are substantial life events that can trigger mood episodes. Educate patients about early signs of relapse and suggest a plan of action for treatment. A patient with an uncontrolled psychotic disorder and poor social support and/or case management is not a good candidate for surgery.

Substance use. Patients with active substance dependence are poor candidates for major surgeries unless they receive substance abuse treatment. During evaluation, motivational interviewing can help guide a patient toward treatment. Ensure that patients whose substance dependence is in remission have adequate support and treatment plans to prevent relapse.

Capacity to make decisions is based on the nature of the procedure and the patient’s ability to understand the process and risk vs benefits. The threshold for capacity can vary based on the procedure and the risks.²

Treatment adherence requires compliance with close medical follow-up, complicated medications, or lifestyle changes. A history of compliance with medical directives, medications, and appointments is important. Collateral information from the surgical team or caregivers can be helpful.

Coping style and strategies. Quiz the patient about internal and external resources they have used to cope with stress. A pattern of decompensation to using primitive defense mechanisms to handle stress suggests that the patient may have a personality disorder and might be a poor surgical candidate. Ability to use relatively mature defense strategies in stressful times suggests a good candidate.

Safety. Active suicidal or homicidal ideation is problematic in patients seeking major surgical interventions. Ensure that the stress of the surgery will not trigger dangerous behaviors. A history of frequent self-harm or impulsive suicidality suggests the that patient may have an unstable axis I or II disorder and might be a poor candidate for major surgery without further treatment.