Jennie Smith

Patients with severe diabetes but only mild obesity see a dramatic benefit after gastric bypass surgery, a new study has found, with 88% experiencing durable disease remission within 6 months, along with major reductions in 10-year cardiovascular risk.

No mortality, major surgical complications, excessive weight loss, or malnutrition was seen among the 66 patients in the study, all of whom underwent laparoscopic Roux-en-Y gastric bypass (RYGB) surgery, according to the findings published in the July issue of Diabetes Care (2012;35:1420-8) and presented at the annual scientific sessions of the American Diabetes Association in Philadelphia.

Bariatric surgery is currently recommended by the National Institutes of Health only for people with a body mass index (BMI) of 40 kg/m² or higher, or above 35 for people with comorbidities such as severe diabetes. Very obese patients with diabetes have seen dramatic reductions in disease activity after RYGB surgery, with an estimated 80%-85% experiencing durable remission. There is increasing evidence that the procedure triggers hormonal and metabolic antidiabetes responses independent of weight loss (Annu. Rev. Med. 2010;61:393-411; Int. J. Obes. 2009;33:S33-S40; Endocrinology 2009;150:2518-25).

People with mild obesity and diabetes constitute a larger group than the very obese, yet they do not currently qualify for bariatric surgery.

Dr. Ricardo V. Cohen of Oswaldo Cruz Hospital and Marcia Maria Braido Hospital, both in São Paulo, Brazil, and his colleagues sought to investigate whether people with a lower BMI and poorly controlled diabetes also would see significant benefit. More than one-fourth of people in the United States with diabetes have class I obesity, or a BMI of 30-35 (Int. J. Clin. Pract. 2007;61:737-47).

For their research, Dr. Cohen and his colleagues recruited 40 men and 26 women. All were white and ranged in age from 31 to 63 years, and had a BMI of 30.0-34.9 and diabetes lasting 7 years or more at the time of surgery. The mean HbA_1c level was 9.7% at the time of surgery, despite the use of insulin and/or oral diabetes medications (n = 7 on insulin). Follow-up on the cohort was 100%, for a median 5 years.

Within 26 weeks after surgery, 88% of patients were able to discontinue their diabetes medications and maintain an HbA_1c level of less than 6.5% without resuming diabetes medications in the follow-up period.

Improvement without remission was seen in 11% of patients, who were able to withdraw insulin and/or reduce dosages of oral medications between 3 and 14 weeks after surgery. One patient showed no improvement in glycemic control, but was able to withdraw insulin and achieve diabetes control with oral medications 7 months post surgery.

Mean HbA_1c for the entire cohort fell progressively throughout the study, from 9.7% to 5.9% (P less than .001). Fasting plasma glucose (FPG) fell from 156 mg/dL to 97 mg/dL (P less than .001). Most of these changes occurred within the first 6 months.

All patients saw progressive reductions in waist circumference and total body weight, although the magnitude of weight loss was not seen as corresponding with decreases in either FPG or HbA_1c until after 5 years post surgery, when the investigators saw significant correlations between weight loss and decrease in FPG. No correlations were seen between weight loss and decrease in HbA_1c. Also, while the ratio of change in C-peptide to change in glucose increased significantly in the postoperative period, there was no correlation seen between the magnitude of the increase and weight lost. All these findings suggest that the surgery induces mechanisms of antidiabetes action independent of weight loss.

The predicted 10-year risk of cardiovascular disease fell after surgery in the cohort, with a 71% decrease in coronary heart disease (CHD, P = .001), 84% decrease in fatal CHD (P = .001), 50% decrease in stroke (P = .01), and 57% decrease in fatal stroke (P = .009). Hypertension and dyslipidemia were also seen to have improved, with hypertension resolving in 15 of the 26 (58%) patients who had it at baseline, hypercholesterolemia resolving in 21 of 33 (64%) patients, and hypertriglyceridemia resolving in 18 of 31 (58%), in the follow-up period.

Importantly, none of the subjects lost excessive weight or showed evidence of malnutrition. The lowest BMI observed in the follow-up period was 23.6.

The findings, Dr. Cohen and his colleagues wrote in their analysis, have broad implications for health policy, as they "indicate that RYGB is a safe, effective procedure to ameliorate type 2 diabetes and associated comorbidities, thereby reducing predicted cardiovascular disease risk, in patients with a BMI of 30–35 kg/m²."

While randomized controlled trial data are required to confirm that the procedure can be recommended in these patients, the investigators wrote, "our favorable findings from a relatively large, long-term study help justify such trials to clarify whether standard indications for RYGB should be broadened and whether this operation might be viewed primarily as ‘metabolic,’ rather than ‘bariatric,’ surgery."

Dr. Cohen and colleagues’ study was funded by the Municipal Health Authority and Marcia Maria Braido Hospital in São Paulo, Brazil. Dr. Cohen disclosed that he received previous study funding from Covidien, and one of his coauthors, Dr. David E. Cummings of the University of Washington, Seattle, disclosed receiving past funding from Ethicon Endo-Surgery. The other authors said they had no relevant financial disclosures.

Patients with severe diabetes but only mild obesity see a dramatic benefit after gastric bypass surgery, a new study has found, with 88% experiencing durable disease remission within 6 months, along with major reductions in 10-year cardiovascular risk.

No mortality, major surgical complications, excessive weight loss, or malnutrition was seen among the 66 patients in the study, all of whom underwent laparoscopic Roux-en-Y gastric bypass (RYGB) surgery, according to the findings published in the July issue of Diabetes Care (2012;35:1420-8) and presented at the annual scientific sessions of the American Diabetes Association in Philadelphia.

Bariatric surgery is currently recommended by the National Institutes of Health only for people with a body mass index (BMI) of 40 kg/m² or higher, or above 35 for people with comorbidities such as severe diabetes. Very obese patients with diabetes have seen dramatic reductions in disease activity after RYGB surgery, with an estimated 80%-85% experiencing durable remission. There is increasing evidence that the procedure triggers hormonal and metabolic antidiabetes responses independent of weight loss (Annu. Rev. Med. 2010;61:393-411; Int. J. Obes. 2009;33:S33-S40; Endocrinology 2009;150:2518-25).

People with mild obesity and diabetes constitute a larger group than the very obese, yet they do not currently qualify for bariatric surgery.

Dr. Ricardo V. Cohen of Oswaldo Cruz Hospital and Marcia Maria Braido Hospital, both in São Paulo, Brazil, and his colleagues sought to investigate whether people with a lower BMI and poorly controlled diabetes also would see significant benefit. More than one-fourth of people in the United States with diabetes have class I obesity, or a BMI of 30-35 (Int. J. Clin. Pract. 2007;61:737-47).

For their research, Dr. Cohen and his colleagues recruited 40 men and 26 women. All were white and ranged in age from 31 to 63 years, and had a BMI of 30.0-34.9 and diabetes lasting 7 years or more at the time of surgery. The mean HbA_1c level was 9.7% at the time of surgery, despite the use of insulin and/or oral diabetes medications (n = 7 on insulin). Follow-up on the cohort was 100%, for a median 5 years.

Within 26 weeks after surgery, 88% of patients were able to discontinue their diabetes medications and maintain an HbA_1c level of less than 6.5% without resuming diabetes medications in the follow-up period.

Improvement without remission was seen in 11% of patients, who were able to withdraw insulin and/or reduce dosages of oral medications between 3 and 14 weeks after surgery. One patient showed no improvement in glycemic control, but was able to withdraw insulin and achieve diabetes control with oral medications 7 months post surgery.

Mean HbA_1c for the entire cohort fell progressively throughout the study, from 9.7% to 5.9% (P less than .001). Fasting plasma glucose (FPG) fell from 156 mg/dL to 97 mg/dL (P less than .001). Most of these changes occurred within the first 6 months.

All patients saw progressive reductions in waist circumference and total body weight, although the magnitude of weight loss was not seen as corresponding with decreases in either FPG or HbA_1c until after 5 years post surgery, when the investigators saw significant correlations between weight loss and decrease in FPG. No correlations were seen between weight loss and decrease in HbA_1c. Also, while the ratio of change in C-peptide to change in glucose increased significantly in the postoperative period, there was no correlation seen between the magnitude of the increase and weight lost. All these findings suggest that the surgery induces mechanisms of antidiabetes action independent of weight loss.

The predicted 10-year risk of cardiovascular disease fell after surgery in the cohort, with a 71% decrease in coronary heart disease (CHD, P = .001), 84% decrease in fatal CHD (P = .001), 50% decrease in stroke (P = .01), and 57% decrease in fatal stroke (P = .009). Hypertension and dyslipidemia were also seen to have improved, with hypertension resolving in 15 of the 26 (58%) patients who had it at baseline, hypercholesterolemia resolving in 21 of 33 (64%) patients, and hypertriglyceridemia resolving in 18 of 31 (58%), in the follow-up period.

Importantly, none of the subjects lost excessive weight or showed evidence of malnutrition. The lowest BMI observed in the follow-up period was 23.6.

The findings, Dr. Cohen and his colleagues wrote in their analysis, have broad implications for health policy, as they "indicate that RYGB is a safe, effective procedure to ameliorate type 2 diabetes and associated comorbidities, thereby reducing predicted cardiovascular disease risk, in patients with a BMI of 30–35 kg/m²."

While randomized controlled trial data are required to confirm that the procedure can be recommended in these patients, the investigators wrote, "our favorable findings from a relatively large, long-term study help justify such trials to clarify whether standard indications for RYGB should be broadened and whether this operation might be viewed primarily as ‘metabolic,’ rather than ‘bariatric,’ surgery."

Dr. Cohen and colleagues’ study was funded by the Municipal Health Authority and Marcia Maria Braido Hospital in São Paulo, Brazil. Dr. Cohen disclosed that he received previous study funding from Covidien, and one of his coauthors, Dr. David E. Cummings of the University of Washington, Seattle, disclosed receiving past funding from Ethicon Endo-Surgery. The other authors said they had no relevant financial disclosures.

Patients with severe diabetes but only mild obesity see a dramatic benefit after gastric bypass surgery, a new study has found, with 88% experiencing durable disease remission within 6 months, along with major reductions in 10-year cardiovascular risk.

No mortality, major surgical complications, excessive weight loss, or malnutrition was seen among the 66 patients in the study, all of whom underwent laparoscopic Roux-en-Y gastric bypass (RYGB) surgery, according to the findings published in the July issue of Diabetes Care (2012;35:1420-8) and presented at the annual scientific sessions of the American Diabetes Association in Philadelphia.

Bariatric surgery is currently recommended by the National Institutes of Health only for people with a body mass index (BMI) of 40 kg/m² or higher, or above 35 for people with comorbidities such as severe diabetes. Very obese patients with diabetes have seen dramatic reductions in disease activity after RYGB surgery, with an estimated 80%-85% experiencing durable remission. There is increasing evidence that the procedure triggers hormonal and metabolic antidiabetes responses independent of weight loss (Annu. Rev. Med. 2010;61:393-411; Int. J. Obes. 2009;33:S33-S40; Endocrinology 2009;150:2518-25).

People with mild obesity and diabetes constitute a larger group than the very obese, yet they do not currently qualify for bariatric surgery.

Dr. Ricardo V. Cohen of Oswaldo Cruz Hospital and Marcia Maria Braido Hospital, both in São Paulo, Brazil, and his colleagues sought to investigate whether people with a lower BMI and poorly controlled diabetes also would see significant benefit. More than one-fourth of people in the United States with diabetes have class I obesity, or a BMI of 30-35 (Int. J. Clin. Pract. 2007;61:737-47).

For their research, Dr. Cohen and his colleagues recruited 40 men and 26 women. All were white and ranged in age from 31 to 63 years, and had a BMI of 30.0-34.9 and diabetes lasting 7 years or more at the time of surgery. The mean HbA_1c level was 9.7% at the time of surgery, despite the use of insulin and/or oral diabetes medications (n = 7 on insulin). Follow-up on the cohort was 100%, for a median 5 years.

Within 26 weeks after surgery, 88% of patients were able to discontinue their diabetes medications and maintain an HbA_1c level of less than 6.5% without resuming diabetes medications in the follow-up period.

Improvement without remission was seen in 11% of patients, who were able to withdraw insulin and/or reduce dosages of oral medications between 3 and 14 weeks after surgery. One patient showed no improvement in glycemic control, but was able to withdraw insulin and achieve diabetes control with oral medications 7 months post surgery.

Mean HbA_1c for the entire cohort fell progressively throughout the study, from 9.7% to 5.9% (P less than .001). Fasting plasma glucose (FPG) fell from 156 mg/dL to 97 mg/dL (P less than .001). Most of these changes occurred within the first 6 months.

All patients saw progressive reductions in waist circumference and total body weight, although the magnitude of weight loss was not seen as corresponding with decreases in either FPG or HbA_1c until after 5 years post surgery, when the investigators saw significant correlations between weight loss and decrease in FPG. No correlations were seen between weight loss and decrease in HbA_1c. Also, while the ratio of change in C-peptide to change in glucose increased significantly in the postoperative period, there was no correlation seen between the magnitude of the increase and weight lost. All these findings suggest that the surgery induces mechanisms of antidiabetes action independent of weight loss.

The predicted 10-year risk of cardiovascular disease fell after surgery in the cohort, with a 71% decrease in coronary heart disease (CHD, P = .001), 84% decrease in fatal CHD (P = .001), 50% decrease in stroke (P = .01), and 57% decrease in fatal stroke (P = .009). Hypertension and dyslipidemia were also seen to have improved, with hypertension resolving in 15 of the 26 (58%) patients who had it at baseline, hypercholesterolemia resolving in 21 of 33 (64%) patients, and hypertriglyceridemia resolving in 18 of 31 (58%), in the follow-up period.

Importantly, none of the subjects lost excessive weight or showed evidence of malnutrition. The lowest BMI observed in the follow-up period was 23.6.

The findings, Dr. Cohen and his colleagues wrote in their analysis, have broad implications for health policy, as they "indicate that RYGB is a safe, effective procedure to ameliorate type 2 diabetes and associated comorbidities, thereby reducing predicted cardiovascular disease risk, in patients with a BMI of 30–35 kg/m²."

While randomized controlled trial data are required to confirm that the procedure can be recommended in these patients, the investigators wrote, "our favorable findings from a relatively large, long-term study help justify such trials to clarify whether standard indications for RYGB should be broadened and whether this operation might be viewed primarily as ‘metabolic,’ rather than ‘bariatric,’ surgery."

Dr. Cohen and colleagues’ study was funded by the Municipal Health Authority and Marcia Maria Braido Hospital in São Paulo, Brazil. Dr. Cohen disclosed that he received previous study funding from Covidien, and one of his coauthors, Dr. David E. Cummings of the University of Washington, Seattle, disclosed receiving past funding from Ethicon Endo-Surgery. The other authors said they had no relevant financial disclosures.

Up to 13% of one cohort of adults with cystic fibrosis were affected by musculoskeletal complications, judging from data presented at the annual European Congress of Rheumatology by Dr. Ali Jawad of the Royal London Hospital and London Chest Hospital.

Because people with cystic fibrosis (CF) are living into adulthood these days, it has become clear that the same bone and joint manifestations of CF that are well known to the physicians who take care of them continue to be an issue for these patients in adulthood. But these bone manifestations have received very little attention in adults, Dr. Jawad said in an interview. Unless these problems are diagnosed early, they are likely to become disabling and interfere with CF treatment, he added.

"From our perspective, it’s a new type of disease involvement. We don’t seem to see the episodic or the hypertrophic osteoarthropathy. Is this because there is now better treatment for these patients? Most of the series reported were over the last decade. To summarize: Unlike other cases, we had no cases of large-joint episodic arthritis or hypertrophic osteoarthropathy; instead, our patients showed a polyarthritis with an age of onset of 25 in females and 38 in men. In addition to NSAIDs, a lot of these patients require DMARDs [disease-modifying antirheumatic drugs], and the important thing is that these patients need recognition because they depend on their mobility and exercise for chest clearance every day as the central component of the treatment of cystic fibrosis."

The study involved 143 adults with cystic fibrosis who attended the quarterly musculoskeletal clinic at the hospital’s CF unit.

With his coinvestigators, Dr. Jawad found that more than 13% of CF patients (aged 16 and older) in the cohort were affected by musculoskeletal complications. The age of onset was lower for female patients than males.

In the cohort, 7% of all patients were seen to have CF-related arthropathy (CFA), which manifests itself in recurrent episodes of swelling and stiffness in the large joints. In all cases, CFA took the form of polyarthralgia. Reports of previous research by other investigators have shown that CFA is a relatively infrequent complication, occurring in 2%-8.5% of the CF population.

Other musculoskeletal diseases seen in the cohort included spondyloarthritis, chondromalacia patellae, vitamin D deficiency, back pain, and rotator cuff tendinopathy. One patient had erosive disease on ultrasound examination, but that condition could not be confirmed by x-ray. None was seen to have hypertrophic osteoarthropathy, which is characterized by abnormal proliferation of the skin and bone tissue at the distal parts of the extremities.

"Our CF service is multidisciplinary, and includes practitioners from other disciplines such as hepatology, endocrinology, and rheumatology, along with specialist nurses, physiotherapists, and a nutritionist," Dr. Jawad said. Because most of the patients in the service receive nutritional advice, he added, vitamin D deficiency was rare.

Patients are customarily started on NSAIDs and, if these prove insufficient, are moved on to DMARDs. "Patients’ [responses] to DMARDs vary," Dr. Jawad said. "We initially start with sulfasalazine and/or hydroxychloroquine. If there is no response, we add or replace one of these with methotrexate. We have one patient on methotrexate for whom we are now considering a tumor necrosis factor inhibitor such as etanercept."

For patients with CF-related arthropathy and other complications, "early diagnosis is essential," Dr. Jawad said, because joint pain, swelling, and limitation of movement may become disabling and interfere with exercise and chest clearance, all of which are essential components of the treatment schedule for CF.

Although NSAIDs usually control symptoms, half of the patients needed DMARDs as well.

Early diagnosis and appropriate management are especially important for CF patients, because joint pain, swelling, and limitation of movement may become disabling and interfere with mobility, exercise, and clearing the airway of thick mucus, all essential components of CF daily treatment.

Up to 13% of one cohort of adults with cystic fibrosis were affected by musculoskeletal complications, judging from data presented at the annual European Congress of Rheumatology by Dr. Ali Jawad of the Royal London Hospital and London Chest Hospital.

Because people with cystic fibrosis (CF) are living into adulthood these days, it has become clear that the same bone and joint manifestations of CF that are well known to the physicians who take care of them continue to be an issue for these patients in adulthood. But these bone manifestations have received very little attention in adults, Dr. Jawad said in an interview. Unless these problems are diagnosed early, they are likely to become disabling and interfere with CF treatment, he added.

"From our perspective, it’s a new type of disease involvement. We don’t seem to see the episodic or the hypertrophic osteoarthropathy. Is this because there is now better treatment for these patients? Most of the series reported were over the last decade. To summarize: Unlike other cases, we had no cases of large-joint episodic arthritis or hypertrophic osteoarthropathy; instead, our patients showed a polyarthritis with an age of onset of 25 in females and 38 in men. In addition to NSAIDs, a lot of these patients require DMARDs [disease-modifying antirheumatic drugs], and the important thing is that these patients need recognition because they depend on their mobility and exercise for chest clearance every day as the central component of the treatment of cystic fibrosis."

The study involved 143 adults with cystic fibrosis who attended the quarterly musculoskeletal clinic at the hospital’s CF unit.

With his coinvestigators, Dr. Jawad found that more than 13% of CF patients (aged 16 and older) in the cohort were affected by musculoskeletal complications. The age of onset was lower for female patients than males.

In the cohort, 7% of all patients were seen to have CF-related arthropathy (CFA), which manifests itself in recurrent episodes of swelling and stiffness in the large joints. In all cases, CFA took the form of polyarthralgia. Reports of previous research by other investigators have shown that CFA is a relatively infrequent complication, occurring in 2%-8.5% of the CF population.

Other musculoskeletal diseases seen in the cohort included spondyloarthritis, chondromalacia patellae, vitamin D deficiency, back pain, and rotator cuff tendinopathy. One patient had erosive disease on ultrasound examination, but that condition could not be confirmed by x-ray. None was seen to have hypertrophic osteoarthropathy, which is characterized by abnormal proliferation of the skin and bone tissue at the distal parts of the extremities.

"Our CF service is multidisciplinary, and includes practitioners from other disciplines such as hepatology, endocrinology, and rheumatology, along with specialist nurses, physiotherapists, and a nutritionist," Dr. Jawad said. Because most of the patients in the service receive nutritional advice, he added, vitamin D deficiency was rare.

Patients are customarily started on NSAIDs and, if these prove insufficient, are moved on to DMARDs. "Patients’ [responses] to DMARDs vary," Dr. Jawad said. "We initially start with sulfasalazine and/or hydroxychloroquine. If there is no response, we add or replace one of these with methotrexate. We have one patient on methotrexate for whom we are now considering a tumor necrosis factor inhibitor such as etanercept."

For patients with CF-related arthropathy and other complications, "early diagnosis is essential," Dr. Jawad said, because joint pain, swelling, and limitation of movement may become disabling and interfere with exercise and chest clearance, all of which are essential components of the treatment schedule for CF.

Although NSAIDs usually control symptoms, half of the patients needed DMARDs as well.

Early diagnosis and appropriate management are especially important for CF patients, because joint pain, swelling, and limitation of movement may become disabling and interfere with mobility, exercise, and clearing the airway of thick mucus, all essential components of CF daily treatment.

Up to 13% of one cohort of adults with cystic fibrosis were affected by musculoskeletal complications, judging from data presented at the annual European Congress of Rheumatology by Dr. Ali Jawad of the Royal London Hospital and London Chest Hospital.

Because people with cystic fibrosis (CF) are living into adulthood these days, it has become clear that the same bone and joint manifestations of CF that are well known to the physicians who take care of them continue to be an issue for these patients in adulthood. But these bone manifestations have received very little attention in adults, Dr. Jawad said in an interview. Unless these problems are diagnosed early, they are likely to become disabling and interfere with CF treatment, he added.

"From our perspective, it’s a new type of disease involvement. We don’t seem to see the episodic or the hypertrophic osteoarthropathy. Is this because there is now better treatment for these patients? Most of the series reported were over the last decade. To summarize: Unlike other cases, we had no cases of large-joint episodic arthritis or hypertrophic osteoarthropathy; instead, our patients showed a polyarthritis with an age of onset of 25 in females and 38 in men. In addition to NSAIDs, a lot of these patients require DMARDs [disease-modifying antirheumatic drugs], and the important thing is that these patients need recognition because they depend on their mobility and exercise for chest clearance every day as the central component of the treatment of cystic fibrosis."

The study involved 143 adults with cystic fibrosis who attended the quarterly musculoskeletal clinic at the hospital’s CF unit.

With his coinvestigators, Dr. Jawad found that more than 13% of CF patients (aged 16 and older) in the cohort were affected by musculoskeletal complications. The age of onset was lower for female patients than males.

In the cohort, 7% of all patients were seen to have CF-related arthropathy (CFA), which manifests itself in recurrent episodes of swelling and stiffness in the large joints. In all cases, CFA took the form of polyarthralgia. Reports of previous research by other investigators have shown that CFA is a relatively infrequent complication, occurring in 2%-8.5% of the CF population.

Other musculoskeletal diseases seen in the cohort included spondyloarthritis, chondromalacia patellae, vitamin D deficiency, back pain, and rotator cuff tendinopathy. One patient had erosive disease on ultrasound examination, but that condition could not be confirmed by x-ray. None was seen to have hypertrophic osteoarthropathy, which is characterized by abnormal proliferation of the skin and bone tissue at the distal parts of the extremities.

"Our CF service is multidisciplinary, and includes practitioners from other disciplines such as hepatology, endocrinology, and rheumatology, along with specialist nurses, physiotherapists, and a nutritionist," Dr. Jawad said. Because most of the patients in the service receive nutritional advice, he added, vitamin D deficiency was rare.

Patients are customarily started on NSAIDs and, if these prove insufficient, are moved on to DMARDs. "Patients’ [responses] to DMARDs vary," Dr. Jawad said. "We initially start with sulfasalazine and/or hydroxychloroquine. If there is no response, we add or replace one of these with methotrexate. We have one patient on methotrexate for whom we are now considering a tumor necrosis factor inhibitor such as etanercept."

For patients with CF-related arthropathy and other complications, "early diagnosis is essential," Dr. Jawad said, because joint pain, swelling, and limitation of movement may become disabling and interfere with exercise and chest clearance, all of which are essential components of the treatment schedule for CF.

Although NSAIDs usually control symptoms, half of the patients needed DMARDs as well.

Early diagnosis and appropriate management are especially important for CF patients, because joint pain, swelling, and limitation of movement may become disabling and interfere with mobility, exercise, and clearing the airway of thick mucus, all essential components of CF daily treatment.

The estrogen hypothesis of schizophrenia holds that estrogen has a protective, mitigating effect on schizophrenia in women, and that this helps explain why women tend to present with first episodes later in life, present less frequently than men, and, some studies have found, have better prognosis and treatment response.

A growing scientific and clinical literature on estrogen and the brain has added heft to what was once a contentious theory. Estrogen has been found to modulate dopamine and serotonin transmission. Estrogen levels in women with schizophrenia have been shown to be lower than those seen in healthy women, with illness onset or relapses most often occurring during the phase of the menstrual cycle when estrogen drops. Women also see a higher rate of late life–onset schizophrenia than do men, which might be related to estrogen decreases at menopause (Schizophr. Res. Treatment 2012 [doi:10.1155/2012/916198]).

A handful of studies has explored whether estrogen replacement therapy, in the form of oral or transdermal estrogen, is helpful in patients with schizophrenia. Recent research has begun to investigate whether agents with estrogenlike effects, such as the selective estrogen receptor modulator (SERM) raloxifene, also could be helpful when added to conventional treatment with antipsychotics. Raloxifene, manufactured by Eli Lilly & Co. as Evista, is licensed as a preventive therapy for osteoporosis, and – unlike estrogens – does not affect breast or uterine tissue.

At the fourth International Congress of Medicine and Women’s Mental Health, held in April in Medellin, Colombia, schizophrenia researcher Dr. Judith Usall of Parc Sanitari Sant Joan de Déu, in Barcelona, presented her ongoing work exploring the estrogen hypothesis and raloxifene. Dr. Usall is one of a small group of researchers working with raloxifene in schizophrenia patients; another leader in the field, Dr. Jayashri Kulkarni of Australia’s Alfred Hospital in Melbourne and Monash University in Clayton, Victoria, previously had tested raloxifene in a pilot study – a small, randomized, controlled trial enrolling postmenopausal women with schizophrenia (n = 26) – and found it to be effective (Psychoneuroendocrinology 2010;335:1142-7).

Last year, in a randomized, placebo-controlled trial enrolling 33 postmenopausal women with schizophrenia, Dr. Usall and colleagues found that adding 60 mg daily of raloxifene – the standard dosage indicated for osteoporosis prevention – to regular antipsychotic treatment improved psychotic symptoms at 12 weeks, compared with antipsychotics alone, with reduction in negative (P = .044), positive (P = .031), and general psychopathological (P = .045) symptoms, and without significant adverse effects (J. Clin. Psychiatry 2011;72:1552-7).

A new trial of similar design, also led by Dr. Usall, began enrolling in January, and will recruit a cohort of 80 postmenopausal women with schizophrenia to determine whether they see a benefit after 6 months of adjunctive treatment with 60 mg of raloxifene.

"My main objective is to improve the treatment of patients with schizophrenia, as well as to improve our knowledge of the etiology of schizophrenia," Dr. Udall said in an interview. "If our trial and others confirm and expand upon our positive results, I think that the use of raloxifene could be recommended in postmenopausal patients."

The Australian researchers are taking a somewhat bolder approach, using higher doses of raloxifene and recruiting younger women and men as well as postmenopausal women to their randomized, controlled trials. Dr. Kulkarni and colleagues are close to wrapping up a larger trial in postmenopausal women with schizophrenia (n = 180) using 120 mg daily of raloxifene in the intervention arm. Their pilot study of raloxifene in postmenopausal women had used the lower dose, but "while the 60-mg [dose] gave some cognitive improvement, it didn’t really touch the psychotic symptoms," Dr. Kulkarni said in an interview.

Dr. Usall said she thought that raloxifene also might be useful in premenopausal women with schizophrenia, particularly those with symptom exacerbations coinciding with their menstrual cycles, but noted that safety information was lacking for both the higher dose and for younger women. "My trial addresses the possible efficacy of raloxifene only in postmenopausal women with schizophrenia," Dr. Usall said.

The Barcelona researchers also are focusing on the negative symptoms of schizophrenia, setting their primary clinical end point at a 20% or more improvement in negative symptoms. Their reasoning, Dr. Usall said, is that "antipsychotics are not as effective in negative symptoms as in positive ones, and because there are different neurobiological and clinical data that point to the possible efficacy of estrogen in negative symptoms."

Dr. Kulkarni said that although no formal analysis has yet been conducted for her team’s raloxifene trial in younger women (n = 120), "it’s already looking even better than in the older women. We’re getting positive symptom response plus cognitive improvement."

Dr. Kulkarni also said that she has seen "dramatic turnarounds" in some postmenopausal patients and among women with whose psychosis onset was post partum, in the intervention arms of her studies. But there have also been slow responders and nonresponders, she said. Predictors of response "will hopefully get clearer as our sample sizes increase. We think there may be an inherited sensitivity to the hormonal milieu."

The Australian team also is conducting a small trial of raloxifene in men with schizophrenia, designed to enroll 30. Dr. Kulkarni previously had worked with estradiol in men with schizophrenia (Schizophr. Res. 2011;125:278-83), but found that its feminizing effects necessitated that the trial be stopped. The investigators hope that raloxifene, which is more selective, will deliver improvement without the feminizing effects.

Raloxifene is a long way from being a standard of care for schizophrenia in patients of any age or sex, but it is increasingly being used as an adjunct treatment for postmenopausal women with schizophrenia in Australia, Dr. Kulkarni said. Some researchers have begun to recommend it as a supplementary treatment for younger women, too.

In a recent literature review on treating hormone-linked disease exacerbations among women with schizophrenia, Dr. Mary V. Seeman of the University of Toronto concluded that raloxifene could be considered among treatment options for premenstrual symptom aggravation (Acta. Psychiatr. Scand. 2012;125:363-71).

Dr. Seeman said in an e-mail interview that although SERMs for schizophrenic symptoms have been used mainly in research studies and not in general practice, "individual clinicians may prescribe them for individual patients."

Dr. Kulkarni said that awareness is growing of the potential to add estrogens or SERMs when standard treatment is not enough.

"We’re in a transition phase at the moment, because we’ve gone from [SERMs’] being used purely in research to their being a product that’s out there to be tried; it’s a question of getting the information to practicing clinicians." A 2012 paper by the Stanley Research Foundation, which has helped fund Dr. Kulkarni’s and Dr. Usall’s clinical trials, recommended several adjunct treatments for schizophrenia, among which were estrogen and raloxifene.

Still, "psychiatry tends to operate in a silo," Dr. Kulkarni said. "Most psychiatrists are happy to prescribe antidepressants or antipsychotics but may not want to prescribe a hormone because it opens up a whole new clinical area. I think that’s to the profession’s detriment." Dr. Kulkarni added that as the results of more ongoing trials come in, "we can begin to think about creating clinical guidelines" for adjunctive treatment with SERMs.

Dr. Usall commented that "unfortunately, the issue of gender-sensitive mental health is not sufficiently introduced into clinical practice." However, she said, clinicians can nonetheless incorporate aspects of the estrogen hypothesis into the management of female schizophrenia patients even without prescribing SERMs.

Exacerbations of disease activity often will coincide with menstrual changes, Dr. Usall said, and symptoms should "always be evaluated with regard to the menstrual cycle." Clinicians might choose to add estrogen/progesterone combinations, or increase dosage of antipsychotic drugs during the luteal phase, she said.

Dr. Kulkarni said she felt that raloxifene represented "a whole new avenue" of adjunctive treatment, with many drugs like it currently in the pipeline. Dr. Seeman, meanwhile, cautioned that SERMs might represent only the first stage of a new treatment paradigm.

"While SERMs like raloxifene are thought to be safe for breast and uterus, they still have difficulty in crossing the blood-brain barrier," she said. "I suspect that, with time, safe estrogenlike compounds that enter the brain more efficiently will be developed – maybe they already exist – and will be useful for neuropsychiatric disease, including schizophrenia. It’s still early days but very promising."

Dr. Usall, Dr. Seeman, and Dr. Kulkarni declared no conflicts of interest related to their research. Dr. Seeman is medical adviser to Clera Inc.

The estrogen hypothesis of schizophrenia holds that estrogen has a protective, mitigating effect on schizophrenia in women, and that this helps explain why women tend to present with first episodes later in life, present less frequently than men, and, some studies have found, have better prognosis and treatment response.

A growing scientific and clinical literature on estrogen and the brain has added heft to what was once a contentious theory. Estrogen has been found to modulate dopamine and serotonin transmission. Estrogen levels in women with schizophrenia have been shown to be lower than those seen in healthy women, with illness onset or relapses most often occurring during the phase of the menstrual cycle when estrogen drops. Women also see a higher rate of late life–onset schizophrenia than do men, which might be related to estrogen decreases at menopause (Schizophr. Res. Treatment 2012 [doi:10.1155/2012/916198]).

A handful of studies has explored whether estrogen replacement therapy, in the form of oral or transdermal estrogen, is helpful in patients with schizophrenia. Recent research has begun to investigate whether agents with estrogenlike effects, such as the selective estrogen receptor modulator (SERM) raloxifene, also could be helpful when added to conventional treatment with antipsychotics. Raloxifene, manufactured by Eli Lilly & Co. as Evista, is licensed as a preventive therapy for osteoporosis, and – unlike estrogens – does not affect breast or uterine tissue.

At the fourth International Congress of Medicine and Women’s Mental Health, held in April in Medellin, Colombia, schizophrenia researcher Dr. Judith Usall of Parc Sanitari Sant Joan de Déu, in Barcelona, presented her ongoing work exploring the estrogen hypothesis and raloxifene. Dr. Usall is one of a small group of researchers working with raloxifene in schizophrenia patients; another leader in the field, Dr. Jayashri Kulkarni of Australia’s Alfred Hospital in Melbourne and Monash University in Clayton, Victoria, previously had tested raloxifene in a pilot study – a small, randomized, controlled trial enrolling postmenopausal women with schizophrenia (n = 26) – and found it to be effective (Psychoneuroendocrinology 2010;335:1142-7).

Last year, in a randomized, placebo-controlled trial enrolling 33 postmenopausal women with schizophrenia, Dr. Usall and colleagues found that adding 60 mg daily of raloxifene – the standard dosage indicated for osteoporosis prevention – to regular antipsychotic treatment improved psychotic symptoms at 12 weeks, compared with antipsychotics alone, with reduction in negative (P = .044), positive (P = .031), and general psychopathological (P = .045) symptoms, and without significant adverse effects (J. Clin. Psychiatry 2011;72:1552-7).

A new trial of similar design, also led by Dr. Usall, began enrolling in January, and will recruit a cohort of 80 postmenopausal women with schizophrenia to determine whether they see a benefit after 6 months of adjunctive treatment with 60 mg of raloxifene.

"My main objective is to improve the treatment of patients with schizophrenia, as well as to improve our knowledge of the etiology of schizophrenia," Dr. Udall said in an interview. "If our trial and others confirm and expand upon our positive results, I think that the use of raloxifene could be recommended in postmenopausal patients."

The Australian researchers are taking a somewhat bolder approach, using higher doses of raloxifene and recruiting younger women and men as well as postmenopausal women to their randomized, controlled trials. Dr. Kulkarni and colleagues are close to wrapping up a larger trial in postmenopausal women with schizophrenia (n = 180) using 120 mg daily of raloxifene in the intervention arm. Their pilot study of raloxifene in postmenopausal women had used the lower dose, but "while the 60-mg [dose] gave some cognitive improvement, it didn’t really touch the psychotic symptoms," Dr. Kulkarni said in an interview.

Dr. Usall said she thought that raloxifene also might be useful in premenopausal women with schizophrenia, particularly those with symptom exacerbations coinciding with their menstrual cycles, but noted that safety information was lacking for both the higher dose and for younger women. "My trial addresses the possible efficacy of raloxifene only in postmenopausal women with schizophrenia," Dr. Usall said.

The Barcelona researchers also are focusing on the negative symptoms of schizophrenia, setting their primary clinical end point at a 20% or more improvement in negative symptoms. Their reasoning, Dr. Usall said, is that "antipsychotics are not as effective in negative symptoms as in positive ones, and because there are different neurobiological and clinical data that point to the possible efficacy of estrogen in negative symptoms."

Dr. Kulkarni said that although no formal analysis has yet been conducted for her team’s raloxifene trial in younger women (n = 120), "it’s already looking even better than in the older women. We’re getting positive symptom response plus cognitive improvement."

Dr. Kulkarni also said that she has seen "dramatic turnarounds" in some postmenopausal patients and among women with whose psychosis onset was post partum, in the intervention arms of her studies. But there have also been slow responders and nonresponders, she said. Predictors of response "will hopefully get clearer as our sample sizes increase. We think there may be an inherited sensitivity to the hormonal milieu."

The Australian team also is conducting a small trial of raloxifene in men with schizophrenia, designed to enroll 30. Dr. Kulkarni previously had worked with estradiol in men with schizophrenia (Schizophr. Res. 2011;125:278-83), but found that its feminizing effects necessitated that the trial be stopped. The investigators hope that raloxifene, which is more selective, will deliver improvement without the feminizing effects.

Raloxifene is a long way from being a standard of care for schizophrenia in patients of any age or sex, but it is increasingly being used as an adjunct treatment for postmenopausal women with schizophrenia in Australia, Dr. Kulkarni said. Some researchers have begun to recommend it as a supplementary treatment for younger women, too.

In a recent literature review on treating hormone-linked disease exacerbations among women with schizophrenia, Dr. Mary V. Seeman of the University of Toronto concluded that raloxifene could be considered among treatment options for premenstrual symptom aggravation (Acta. Psychiatr. Scand. 2012;125:363-71).

Dr. Seeman said in an e-mail interview that although SERMs for schizophrenic symptoms have been used mainly in research studies and not in general practice, "individual clinicians may prescribe them for individual patients."

Dr. Kulkarni said that awareness is growing of the potential to add estrogens or SERMs when standard treatment is not enough.

"We’re in a transition phase at the moment, because we’ve gone from [SERMs’] being used purely in research to their being a product that’s out there to be tried; it’s a question of getting the information to practicing clinicians." A 2012 paper by the Stanley Research Foundation, which has helped fund Dr. Kulkarni’s and Dr. Usall’s clinical trials, recommended several adjunct treatments for schizophrenia, among which were estrogen and raloxifene.

Still, "psychiatry tends to operate in a silo," Dr. Kulkarni said. "Most psychiatrists are happy to prescribe antidepressants or antipsychotics but may not want to prescribe a hormone because it opens up a whole new clinical area. I think that’s to the profession’s detriment." Dr. Kulkarni added that as the results of more ongoing trials come in, "we can begin to think about creating clinical guidelines" for adjunctive treatment with SERMs.

Dr. Usall commented that "unfortunately, the issue of gender-sensitive mental health is not sufficiently introduced into clinical practice." However, she said, clinicians can nonetheless incorporate aspects of the estrogen hypothesis into the management of female schizophrenia patients even without prescribing SERMs.

Exacerbations of disease activity often will coincide with menstrual changes, Dr. Usall said, and symptoms should "always be evaluated with regard to the menstrual cycle." Clinicians might choose to add estrogen/progesterone combinations, or increase dosage of antipsychotic drugs during the luteal phase, she said.

Dr. Kulkarni said she felt that raloxifene represented "a whole new avenue" of adjunctive treatment, with many drugs like it currently in the pipeline. Dr. Seeman, meanwhile, cautioned that SERMs might represent only the first stage of a new treatment paradigm.

"While SERMs like raloxifene are thought to be safe for breast and uterus, they still have difficulty in crossing the blood-brain barrier," she said. "I suspect that, with time, safe estrogenlike compounds that enter the brain more efficiently will be developed – maybe they already exist – and will be useful for neuropsychiatric disease, including schizophrenia. It’s still early days but very promising."

Dr. Usall, Dr. Seeman, and Dr. Kulkarni declared no conflicts of interest related to their research. Dr. Seeman is medical adviser to Clera Inc.

The estrogen hypothesis of schizophrenia holds that estrogen has a protective, mitigating effect on schizophrenia in women, and that this helps explain why women tend to present with first episodes later in life, present less frequently than men, and, some studies have found, have better prognosis and treatment response.

A growing scientific and clinical literature on estrogen and the brain has added heft to what was once a contentious theory. Estrogen has been found to modulate dopamine and serotonin transmission. Estrogen levels in women with schizophrenia have been shown to be lower than those seen in healthy women, with illness onset or relapses most often occurring during the phase of the menstrual cycle when estrogen drops. Women also see a higher rate of late life–onset schizophrenia than do men, which might be related to estrogen decreases at menopause (Schizophr. Res. Treatment 2012 [doi:10.1155/2012/916198]).

A handful of studies has explored whether estrogen replacement therapy, in the form of oral or transdermal estrogen, is helpful in patients with schizophrenia. Recent research has begun to investigate whether agents with estrogenlike effects, such as the selective estrogen receptor modulator (SERM) raloxifene, also could be helpful when added to conventional treatment with antipsychotics. Raloxifene, manufactured by Eli Lilly & Co. as Evista, is licensed as a preventive therapy for osteoporosis, and – unlike estrogens – does not affect breast or uterine tissue.

At the fourth International Congress of Medicine and Women’s Mental Health, held in April in Medellin, Colombia, schizophrenia researcher Dr. Judith Usall of Parc Sanitari Sant Joan de Déu, in Barcelona, presented her ongoing work exploring the estrogen hypothesis and raloxifene. Dr. Usall is one of a small group of researchers working with raloxifene in schizophrenia patients; another leader in the field, Dr. Jayashri Kulkarni of Australia’s Alfred Hospital in Melbourne and Monash University in Clayton, Victoria, previously had tested raloxifene in a pilot study – a small, randomized, controlled trial enrolling postmenopausal women with schizophrenia (n = 26) – and found it to be effective (Psychoneuroendocrinology 2010;335:1142-7).

Last year, in a randomized, placebo-controlled trial enrolling 33 postmenopausal women with schizophrenia, Dr. Usall and colleagues found that adding 60 mg daily of raloxifene – the standard dosage indicated for osteoporosis prevention – to regular antipsychotic treatment improved psychotic symptoms at 12 weeks, compared with antipsychotics alone, with reduction in negative (P = .044), positive (P = .031), and general psychopathological (P = .045) symptoms, and without significant adverse effects (J. Clin. Psychiatry 2011;72:1552-7).

A new trial of similar design, also led by Dr. Usall, began enrolling in January, and will recruit a cohort of 80 postmenopausal women with schizophrenia to determine whether they see a benefit after 6 months of adjunctive treatment with 60 mg of raloxifene.

"My main objective is to improve the treatment of patients with schizophrenia, as well as to improve our knowledge of the etiology of schizophrenia," Dr. Udall said in an interview. "If our trial and others confirm and expand upon our positive results, I think that the use of raloxifene could be recommended in postmenopausal patients."

The Australian researchers are taking a somewhat bolder approach, using higher doses of raloxifene and recruiting younger women and men as well as postmenopausal women to their randomized, controlled trials. Dr. Kulkarni and colleagues are close to wrapping up a larger trial in postmenopausal women with schizophrenia (n = 180) using 120 mg daily of raloxifene in the intervention arm. Their pilot study of raloxifene in postmenopausal women had used the lower dose, but "while the 60-mg [dose] gave some cognitive improvement, it didn’t really touch the psychotic symptoms," Dr. Kulkarni said in an interview.

Dr. Usall said she thought that raloxifene also might be useful in premenopausal women with schizophrenia, particularly those with symptom exacerbations coinciding with their menstrual cycles, but noted that safety information was lacking for both the higher dose and for younger women. "My trial addresses the possible efficacy of raloxifene only in postmenopausal women with schizophrenia," Dr. Usall said.

The Barcelona researchers also are focusing on the negative symptoms of schizophrenia, setting their primary clinical end point at a 20% or more improvement in negative symptoms. Their reasoning, Dr. Usall said, is that "antipsychotics are not as effective in negative symptoms as in positive ones, and because there are different neurobiological and clinical data that point to the possible efficacy of estrogen in negative symptoms."

Dr. Kulkarni said that although no formal analysis has yet been conducted for her team’s raloxifene trial in younger women (n = 120), "it’s already looking even better than in the older women. We’re getting positive symptom response plus cognitive improvement."

Dr. Kulkarni also said that she has seen "dramatic turnarounds" in some postmenopausal patients and among women with whose psychosis onset was post partum, in the intervention arms of her studies. But there have also been slow responders and nonresponders, she said. Predictors of response "will hopefully get clearer as our sample sizes increase. We think there may be an inherited sensitivity to the hormonal milieu."

The Australian team also is conducting a small trial of raloxifene in men with schizophrenia, designed to enroll 30. Dr. Kulkarni previously had worked with estradiol in men with schizophrenia (Schizophr. Res. 2011;125:278-83), but found that its feminizing effects necessitated that the trial be stopped. The investigators hope that raloxifene, which is more selective, will deliver improvement without the feminizing effects.

Raloxifene is a long way from being a standard of care for schizophrenia in patients of any age or sex, but it is increasingly being used as an adjunct treatment for postmenopausal women with schizophrenia in Australia, Dr. Kulkarni said. Some researchers have begun to recommend it as a supplementary treatment for younger women, too.

In a recent literature review on treating hormone-linked disease exacerbations among women with schizophrenia, Dr. Mary V. Seeman of the University of Toronto concluded that raloxifene could be considered among treatment options for premenstrual symptom aggravation (Acta. Psychiatr. Scand. 2012;125:363-71).

Dr. Seeman said in an e-mail interview that although SERMs for schizophrenic symptoms have been used mainly in research studies and not in general practice, "individual clinicians may prescribe them for individual patients."

Dr. Kulkarni said that awareness is growing of the potential to add estrogens or SERMs when standard treatment is not enough.

"We’re in a transition phase at the moment, because we’ve gone from [SERMs’] being used purely in research to their being a product that’s out there to be tried; it’s a question of getting the information to practicing clinicians." A 2012 paper by the Stanley Research Foundation, which has helped fund Dr. Kulkarni’s and Dr. Usall’s clinical trials, recommended several adjunct treatments for schizophrenia, among which were estrogen and raloxifene.

Still, "psychiatry tends to operate in a silo," Dr. Kulkarni said. "Most psychiatrists are happy to prescribe antidepressants or antipsychotics but may not want to prescribe a hormone because it opens up a whole new clinical area. I think that’s to the profession’s detriment." Dr. Kulkarni added that as the results of more ongoing trials come in, "we can begin to think about creating clinical guidelines" for adjunctive treatment with SERMs.

Dr. Usall commented that "unfortunately, the issue of gender-sensitive mental health is not sufficiently introduced into clinical practice." However, she said, clinicians can nonetheless incorporate aspects of the estrogen hypothesis into the management of female schizophrenia patients even without prescribing SERMs.

Exacerbations of disease activity often will coincide with menstrual changes, Dr. Usall said, and symptoms should "always be evaluated with regard to the menstrual cycle." Clinicians might choose to add estrogen/progesterone combinations, or increase dosage of antipsychotic drugs during the luteal phase, she said.

Dr. Kulkarni said she felt that raloxifene represented "a whole new avenue" of adjunctive treatment, with many drugs like it currently in the pipeline. Dr. Seeman, meanwhile, cautioned that SERMs might represent only the first stage of a new treatment paradigm.

"While SERMs like raloxifene are thought to be safe for breast and uterus, they still have difficulty in crossing the blood-brain barrier," she said. "I suspect that, with time, safe estrogenlike compounds that enter the brain more efficiently will be developed – maybe they already exist – and will be useful for neuropsychiatric disease, including schizophrenia. It’s still early days but very promising."

Dr. Usall, Dr. Seeman, and Dr. Kulkarni declared no conflicts of interest related to their research. Dr. Seeman is medical adviser to Clera Inc.

Recurrent depression from midlife through late life increases the risk of vascular dementia, suggesting a progressive etiologic association with vascular disease, a large, long-term retrospective cohort study has shown.

When depression begins only in late life, it might be part of the Alzheimer’s disease prodrome, the researchers found.

Whether treatment of depression could help prevent or delay the onset of either type of dementia was not established in the study.

A growing body of evidence has shown depression to be associated with a higher risk of developing dementia; however, it is has not yet been established how the disorders relate to each other.

For their research, published in the May 2012 issue of Archives of General Psychiatry (2012;69:493-8), Deborah E. Barnes, Ph.D., of the University of California, San Francisco, and the San Francisco Veterans Affairs Medical Center, and her colleagues examined sets of records for 13,535 subjects (57.9% female, 24.2% nonwhite). All were between the ages of 40 and 55 and were members of the Kaiser Permanente health system in the years 1964 through 1973, when they participated in a voluntary health exam in San Francisco and Oakland as part of their membership.

The 1964-1973 exam asked subjects whether they often felt "unhappy or depressed," and positive answers were considered by Dr. Barnes and her colleagues to be indicative of depression symptoms at midlife. The same patient records were screened for depression diagnoses and hospitalizations between 1990 and 2000, and then for dementia diagnoses between 2003 and 2009. None of the included study subjects had dementia at baseline or in 2003, at the onset of follow-up.

Dr. Barnes and her colleagues found that 14.1% of subjects had depressive symptoms in midlife only, 9.2% in late life only, and 4.2% in both. After the investigators adjusted for comorbidities and demographic factors, the hazard of any form of dementia increased by about 20% for people with midlife depressive symptoms only (HR, 1.19 [95% CI, 1.07-1.32]); by 70% for late-life symptoms only (1.72 [1.54-1.92]); and by 80% for people with both (1.77 [1.52-2.06]).

When vascular dementia and Alzheimer’s disease were analyzed separately, subjects with midlife depressive symptoms only did not have a significantly increased risk of Alzheimer’s disease (HR, 1.06 [95% CI, 0.85- 1.33]) or vascular dementia (HR, 1.24 [0.90-1.72]). Those with late-life depressive symptoms saw a twofold increase in Alzheimer’s risk (HR, 2.06 [95% CI, 1.67-2.55]). Those with both midlife and late-life symptoms, meanwhile, had more than a threefold increase in vascular dementia risk (HR, 3.51 [2.44-5.05]).

"There has been an ongoing debate in the field as to whether the association between depression and dementia reflects an etiologic relationship or whether depression is a prodromal symptom of dementia. Our results suggest that the answer may differ depending on the dementia subtype," Dr. Barnes and her colleagues wrote.

The recurrence of depression in late life "may reflect a long-term process of subclinical cerebrovascular changes that may predispose toward development of [vascular dementia]," the investigators wrote; however, they acknowledged, other mechanisms could also increase vulnerability to dementia among individuals prone to depression. Future studies are needed to learn whether the treatment of depression "may help to maintain cognitive function and delay dementia onset," Dr. Barnes and her colleagues reported.

With regard to the late-life depression patients at higher risk for Alzheimer’s disease, they wrote, future studies might examine whether patients "might benefit from monitoring for cognitive deterioration and earlier treatment with memory-enhancing agents."

Dr. Barnes and her colleagues noted as strengths of their study its large size and 45-year time span, while acknowledging among its weaknesses its reliance on a nonspecific, self-reported measure of depression at baseline. The electronic medical record data used in the study probably were not sensitive enough to capture the true magnitude of late-life depression and dementia in the study population, they wrote.

The study was funded by the Brain and Behavior Research Foundation (formerly the National Alliance for Research on Schizophrenia and Depression), Kaiser Permanente, and the National Institutes of Health. None of its authors declared conflicts of interest.

Recurrent depression from midlife through late life increases the risk of vascular dementia, suggesting a progressive etiologic association with vascular disease, a large, long-term retrospective cohort study has shown.

When depression begins only in late life, it might be part of the Alzheimer’s disease prodrome, the researchers found.

Whether treatment of depression could help prevent or delay the onset of either type of dementia was not established in the study.

A growing body of evidence has shown depression to be associated with a higher risk of developing dementia; however, it is has not yet been established how the disorders relate to each other.

For their research, published in the May 2012 issue of Archives of General Psychiatry (2012;69:493-8), Deborah E. Barnes, Ph.D., of the University of California, San Francisco, and the San Francisco Veterans Affairs Medical Center, and her colleagues examined sets of records for 13,535 subjects (57.9% female, 24.2% nonwhite). All were between the ages of 40 and 55 and were members of the Kaiser Permanente health system in the years 1964 through 1973, when they participated in a voluntary health exam in San Francisco and Oakland as part of their membership.

The 1964-1973 exam asked subjects whether they often felt "unhappy or depressed," and positive answers were considered by Dr. Barnes and her colleagues to be indicative of depression symptoms at midlife. The same patient records were screened for depression diagnoses and hospitalizations between 1990 and 2000, and then for dementia diagnoses between 2003 and 2009. None of the included study subjects had dementia at baseline or in 2003, at the onset of follow-up.

Dr. Barnes and her colleagues found that 14.1% of subjects had depressive symptoms in midlife only, 9.2% in late life only, and 4.2% in both. After the investigators adjusted for comorbidities and demographic factors, the hazard of any form of dementia increased by about 20% for people with midlife depressive symptoms only (HR, 1.19 [95% CI, 1.07-1.32]); by 70% for late-life symptoms only (1.72 [1.54-1.92]); and by 80% for people with both (1.77 [1.52-2.06]).

When vascular dementia and Alzheimer’s disease were analyzed separately, subjects with midlife depressive symptoms only did not have a significantly increased risk of Alzheimer’s disease (HR, 1.06 [95% CI, 0.85- 1.33]) or vascular dementia (HR, 1.24 [0.90-1.72]). Those with late-life depressive symptoms saw a twofold increase in Alzheimer’s risk (HR, 2.06 [95% CI, 1.67-2.55]). Those with both midlife and late-life symptoms, meanwhile, had more than a threefold increase in vascular dementia risk (HR, 3.51 [2.44-5.05]).

"There has been an ongoing debate in the field as to whether the association between depression and dementia reflects an etiologic relationship or whether depression is a prodromal symptom of dementia. Our results suggest that the answer may differ depending on the dementia subtype," Dr. Barnes and her colleagues wrote.

The recurrence of depression in late life "may reflect a long-term process of subclinical cerebrovascular changes that may predispose toward development of [vascular dementia]," the investigators wrote; however, they acknowledged, other mechanisms could also increase vulnerability to dementia among individuals prone to depression. Future studies are needed to learn whether the treatment of depression "may help to maintain cognitive function and delay dementia onset," Dr. Barnes and her colleagues reported.

With regard to the late-life depression patients at higher risk for Alzheimer’s disease, they wrote, future studies might examine whether patients "might benefit from monitoring for cognitive deterioration and earlier treatment with memory-enhancing agents."

Dr. Barnes and her colleagues noted as strengths of their study its large size and 45-year time span, while acknowledging among its weaknesses its reliance on a nonspecific, self-reported measure of depression at baseline. The electronic medical record data used in the study probably were not sensitive enough to capture the true magnitude of late-life depression and dementia in the study population, they wrote.

The study was funded by the Brain and Behavior Research Foundation (formerly the National Alliance for Research on Schizophrenia and Depression), Kaiser Permanente, and the National Institutes of Health. None of its authors declared conflicts of interest.

Recurrent depression from midlife through late life increases the risk of vascular dementia, suggesting a progressive etiologic association with vascular disease, a large, long-term retrospective cohort study has shown.

When depression begins only in late life, it might be part of the Alzheimer’s disease prodrome, the researchers found.

Whether treatment of depression could help prevent or delay the onset of either type of dementia was not established in the study.

A growing body of evidence has shown depression to be associated with a higher risk of developing dementia; however, it is has not yet been established how the disorders relate to each other.

For their research, published in the May 2012 issue of Archives of General Psychiatry (2012;69:493-8), Deborah E. Barnes, Ph.D., of the University of California, San Francisco, and the San Francisco Veterans Affairs Medical Center, and her colleagues examined sets of records for 13,535 subjects (57.9% female, 24.2% nonwhite). All were between the ages of 40 and 55 and were members of the Kaiser Permanente health system in the years 1964 through 1973, when they participated in a voluntary health exam in San Francisco and Oakland as part of their membership.

The 1964-1973 exam asked subjects whether they often felt "unhappy or depressed," and positive answers were considered by Dr. Barnes and her colleagues to be indicative of depression symptoms at midlife. The same patient records were screened for depression diagnoses and hospitalizations between 1990 and 2000, and then for dementia diagnoses between 2003 and 2009. None of the included study subjects had dementia at baseline or in 2003, at the onset of follow-up.

Dr. Barnes and her colleagues found that 14.1% of subjects had depressive symptoms in midlife only, 9.2% in late life only, and 4.2% in both. After the investigators adjusted for comorbidities and demographic factors, the hazard of any form of dementia increased by about 20% for people with midlife depressive symptoms only (HR, 1.19 [95% CI, 1.07-1.32]); by 70% for late-life symptoms only (1.72 [1.54-1.92]); and by 80% for people with both (1.77 [1.52-2.06]).

When vascular dementia and Alzheimer’s disease were analyzed separately, subjects with midlife depressive symptoms only did not have a significantly increased risk of Alzheimer’s disease (HR, 1.06 [95% CI, 0.85- 1.33]) or vascular dementia (HR, 1.24 [0.90-1.72]). Those with late-life depressive symptoms saw a twofold increase in Alzheimer’s risk (HR, 2.06 [95% CI, 1.67-2.55]). Those with both midlife and late-life symptoms, meanwhile, had more than a threefold increase in vascular dementia risk (HR, 3.51 [2.44-5.05]).

"There has been an ongoing debate in the field as to whether the association between depression and dementia reflects an etiologic relationship or whether depression is a prodromal symptom of dementia. Our results suggest that the answer may differ depending on the dementia subtype," Dr. Barnes and her colleagues wrote.

The recurrence of depression in late life "may reflect a long-term process of subclinical cerebrovascular changes that may predispose toward development of [vascular dementia]," the investigators wrote; however, they acknowledged, other mechanisms could also increase vulnerability to dementia among individuals prone to depression. Future studies are needed to learn whether the treatment of depression "may help to maintain cognitive function and delay dementia onset," Dr. Barnes and her colleagues reported.

With regard to the late-life depression patients at higher risk for Alzheimer’s disease, they wrote, future studies might examine whether patients "might benefit from monitoring for cognitive deterioration and earlier treatment with memory-enhancing agents."

Dr. Barnes and her colleagues noted as strengths of their study its large size and 45-year time span, while acknowledging among its weaknesses its reliance on a nonspecific, self-reported measure of depression at baseline. The electronic medical record data used in the study probably were not sensitive enough to capture the true magnitude of late-life depression and dementia in the study population, they wrote.

The study was funded by the Brain and Behavior Research Foundation (formerly the National Alliance for Research on Schizophrenia and Depression), Kaiser Permanente, and the National Institutes of Health. None of its authors declared conflicts of interest.

After initially turning it down – and being pressured to reevaluate by the U.K. Department of Health – the clinical effectiveness agency for England and Wales has decided to recommend abiraterone, in combination with glucocorticoids, as a second-line treatment for metastatic prostate cancer.

The National Institute for Health and Clinical Excellence announced on May 16 that its new draft guidance recommending abiraterone (Zytiga, Janssen) for castration-resistant prostate cancer came in response to both a new manufacturer pricing agreement and additional information on how many patients were likely to be eligible for treatment.

In February, NICE had deemed abiraterone, which has been shown to prolong survival by a median 4.6 months, not cost-effective at an estimated £63,200 per quality-adjusted life year.

The following month, the U.K. Department of Health asked NICE to reevaluate its decision with regard to its estimates of the number of men eligible to be treated with abiraterone. NICE evaluates differently end-of-life treatments for patients with a life expectancy of less than 2 years, depending on the size of the population affected.

A revised pricing scheme in addition to revised estimates of the population eligible for abiraterone treatment lowered NICE’s estimates to £46,800 per QALY, just under its threshold for an end-of-life treatment in a small population.

Abiraterone works by blocking androgen synthesis in the adrenal glands, prostate tissue, and prostate tumors. It is indicated for men whose disease has progressed following docetaxel-containing chemotherapy regimens, and who have been deemed "castration resistant" because their tumors do not respond to androgen-deprivation treatments that may or may not include surgical castration.

The list price of abiraterone is £2,930 for a 30-day supply of 120 tablets; NICE did not disclose the new discounted price. It is taken as a single dose of 1,000 mg daily, in four tablets. In a manufacturer-sponsored randomized controlled trial (n = 1,195), subjects receiving abiraterone plus prednisone or prednisolone saw a median overall survival gain of 14.8 months compared with 10.9 months for those taking placebo plus either prednisone or prednisolone after 1 year follow-up (HR 0.65; 95% confidence interval, 0.54-0.77; P less than .001).

The trial (N. Engl. J. Med. 2011;364:1995-2005) was stopped due to significant evidence of benefit, but follow-up continued, and an updated analysis after 20.2 months showed that median survival continued to be significantly longer in the abiraterone group than the prednisolone group (15.8 months compared with 11.2 months; HR 0.74; 95% CI 0.64 to 0.86).

In its earlier draft guidance NICE had estimated the number of men eligible for second-line treatment with abiraterone to be at least 3,500 in 2011. The revised estimate suggests that only 2,500 would have been eligible – a small population, by NICE’s calculations, and therefore meeting its cost-effectiveness criteria for an end-of-life treatment.

After initially turning it down – and being pressured to reevaluate by the U.K. Department of Health – the clinical effectiveness agency for England and Wales has decided to recommend abiraterone, in combination with glucocorticoids, as a second-line treatment for metastatic prostate cancer.

The National Institute for Health and Clinical Excellence announced on May 16 that its new draft guidance recommending abiraterone (Zytiga, Janssen) for castration-resistant prostate cancer came in response to both a new manufacturer pricing agreement and additional information on how many patients were likely to be eligible for treatment.

In February, NICE had deemed abiraterone, which has been shown to prolong survival by a median 4.6 months, not cost-effective at an estimated £63,200 per quality-adjusted life year.

The following month, the U.K. Department of Health asked NICE to reevaluate its decision with regard to its estimates of the number of men eligible to be treated with abiraterone. NICE evaluates differently end-of-life treatments for patients with a life expectancy of less than 2 years, depending on the size of the population affected.

A revised pricing scheme in addition to revised estimates of the population eligible for abiraterone treatment lowered NICE’s estimates to £46,800 per QALY, just under its threshold for an end-of-life treatment in a small population.

Abiraterone works by blocking androgen synthesis in the adrenal glands, prostate tissue, and prostate tumors. It is indicated for men whose disease has progressed following docetaxel-containing chemotherapy regimens, and who have been deemed "castration resistant" because their tumors do not respond to androgen-deprivation treatments that may or may not include surgical castration.

The list price of abiraterone is £2,930 for a 30-day supply of 120 tablets; NICE did not disclose the new discounted price. It is taken as a single dose of 1,000 mg daily, in four tablets. In a manufacturer-sponsored randomized controlled trial (n = 1,195), subjects receiving abiraterone plus prednisone or prednisolone saw a median overall survival gain of 14.8 months compared with 10.9 months for those taking placebo plus either prednisone or prednisolone after 1 year follow-up (HR 0.65; 95% confidence interval, 0.54-0.77; P less than .001).

The trial (N. Engl. J. Med. 2011;364:1995-2005) was stopped due to significant evidence of benefit, but follow-up continued, and an updated analysis after 20.2 months showed that median survival continued to be significantly longer in the abiraterone group than the prednisolone group (15.8 months compared with 11.2 months; HR 0.74; 95% CI 0.64 to 0.86).

In its earlier draft guidance NICE had estimated the number of men eligible for second-line treatment with abiraterone to be at least 3,500 in 2011. The revised estimate suggests that only 2,500 would have been eligible – a small population, by NICE’s calculations, and therefore meeting its cost-effectiveness criteria for an end-of-life treatment.

After initially turning it down – and being pressured to reevaluate by the U.K. Department of Health – the clinical effectiveness agency for England and Wales has decided to recommend abiraterone, in combination with glucocorticoids, as a second-line treatment for metastatic prostate cancer.

The National Institute for Health and Clinical Excellence announced on May 16 that its new draft guidance recommending abiraterone (Zytiga, Janssen) for castration-resistant prostate cancer came in response to both a new manufacturer pricing agreement and additional information on how many patients were likely to be eligible for treatment.

In February, NICE had deemed abiraterone, which has been shown to prolong survival by a median 4.6 months, not cost-effective at an estimated £63,200 per quality-adjusted life year.

The following month, the U.K. Department of Health asked NICE to reevaluate its decision with regard to its estimates of the number of men eligible to be treated with abiraterone. NICE evaluates differently end-of-life treatments for patients with a life expectancy of less than 2 years, depending on the size of the population affected.

A revised pricing scheme in addition to revised estimates of the population eligible for abiraterone treatment lowered NICE’s estimates to £46,800 per QALY, just under its threshold for an end-of-life treatment in a small population.

Abiraterone works by blocking androgen synthesis in the adrenal glands, prostate tissue, and prostate tumors. It is indicated for men whose disease has progressed following docetaxel-containing chemotherapy regimens, and who have been deemed "castration resistant" because their tumors do not respond to androgen-deprivation treatments that may or may not include surgical castration.

The list price of abiraterone is £2,930 for a 30-day supply of 120 tablets; NICE did not disclose the new discounted price. It is taken as a single dose of 1,000 mg daily, in four tablets. In a manufacturer-sponsored randomized controlled trial (n = 1,195), subjects receiving abiraterone plus prednisone or prednisolone saw a median overall survival gain of 14.8 months compared with 10.9 months for those taking placebo plus either prednisone or prednisolone after 1 year follow-up (HR 0.65; 95% confidence interval, 0.54-0.77; P less than .001).

The trial (N. Engl. J. Med. 2011;364:1995-2005) was stopped due to significant evidence of benefit, but follow-up continued, and an updated analysis after 20.2 months showed that median survival continued to be significantly longer in the abiraterone group than the prednisolone group (15.8 months compared with 11.2 months; HR 0.74; 95% CI 0.64 to 0.86).

In its earlier draft guidance NICE had estimated the number of men eligible for second-line treatment with abiraterone to be at least 3,500 in 2011. The revised estimate suggests that only 2,500 would have been eligible – a small population, by NICE’s calculations, and therefore meeting its cost-effectiveness criteria for an end-of-life treatment.

Schizophrenia patients who underwent 80 hours of computerized training showed significant and sustained improvements in the ability to distinguish between internal experience and outside reality, a group of researchers has shown.

Improvements in reality monitoring – in which patients can distinguish a self-generated image, sound, or written phrase from one presented to them – corresponded to improvements in activation of the medial prefrontal cortex (mPFC), as confirmed by functional magnetic resonance imaging (fMRI).

The findings suggest that it is possible to improve brain function even among people who have lived decades with their disease.

The researchers, led by Karuna Subramaniam, Ph.D., of the San Francisco VA Medical Center, also recorded improved mPFC activity corresponding with behavioral improvements 6 months after the intervention had ended, suggesting a broader benefit to the training (Neuron 2012;73:842-53).

For their research, Dr. Subramaniam and colleagues recruited 31 clinically stable, persistently ill, volunteer schizophrenia patients, five of whom were women. The mean age of all subjects was 40 years, and mean illness duration was 19.4 years. A separate group of 16 healthy controls was recruited.

All underwent a baseline reality monitoring experiment in which brain activation patterns were recorded. The 16 schizophrenia subjects who were randomly assigned to the invention group received targeted training involving auditory, verbal, visual, and social cognitive processes, whereas 14 randomly assigned schizophrenia controls were given commercial computer games, such as Hangman, Tic-Tac-Toe, and Tetris, for 5 hours a week over 16 weeks in the laboratory.

After 16 weeks, 15 schizophrenia subjects in the intervention group, 14 in the games group, and 12 healthy controls participated in another fMRI reality-monitoring experiment. And 6 months later, 25 of the schizophrenia subjects returned for a reassessment of their clinical and functional status, reported Dr. Subramaniam, also of the University of California, San Francisco.

Intervention subjects showed significant improvement on delayed verbal memory recall at 16 weeks, compared with baseline (P = .02), whereas computer games subjects showed no significant improvement in this measure (P = .30). Intervention subjects also showed significant improvement performing a complex reality-monitoring task that was not part of the training exercises at 16 weeks, compared to baseline (P = .03), whereas games subjects showed no significant improvement in this measure (P = .89).

Compared with patients who played computer games, the trained patients showed a significant improvement in their accuracy when they performed a complex task, as well as a significant increase in mPFC activation during performance; a significant relationship was seen between mPFC activation after training and better social functioning after 6 months, Dr. Subramaniam and colleagues found.

"To our knowledge, this is the first time that a complex higher-order cognitive process in a serious neuropsychiatric illness – in this case, the ability to distinguish the source of information generated by the ‘self’ from information generated by the ‘other’ – has been the targeted outcome of a neuroscience-informed cognitive training strategy," the researchers wrote in their analysis.

The findings show, they wrote, that "it is possible to significantly improve brain function in schizophrenia, even in patients who have been ill for an average of 20 years, and it appears that these improvements set the stage for an enduring improvement in social functioning that occurs even in the absence of other psychosocial therapies."

Dr. Subramaniam reported no relevant financial disclosures. The study was funded by the National Institute of Mental Health. Two coauthors, Gregory V. Simpson, Ph.D., and Dr. Sophia Vinogradov, disclosed employment and consulting relationships, respectively, with the Brain Plasticity Institute, which has a financial interest in computerized cognitive training programs.

Schizophrenia patients who underwent 80 hours of computerized training showed significant and sustained improvements in the ability to distinguish between internal experience and outside reality, a group of researchers has shown.

Improvements in reality monitoring – in which patients can distinguish a self-generated image, sound, or written phrase from one presented to them – corresponded to improvements in activation of the medial prefrontal cortex (mPFC), as confirmed by functional magnetic resonance imaging (fMRI).

The findings suggest that it is possible to improve brain function even among people who have lived decades with their disease.

The researchers, led by Karuna Subramaniam, Ph.D., of the San Francisco VA Medical Center, also recorded improved mPFC activity corresponding with behavioral improvements 6 months after the intervention had ended, suggesting a broader benefit to the training (Neuron 2012;73:842-53).

For their research, Dr. Subramaniam and colleagues recruited 31 clinically stable, persistently ill, volunteer schizophrenia patients, five of whom were women. The mean age of all subjects was 40 years, and mean illness duration was 19.4 years. A separate group of 16 healthy controls was recruited.

All underwent a baseline reality monitoring experiment in which brain activation patterns were recorded. The 16 schizophrenia subjects who were randomly assigned to the invention group received targeted training involving auditory, verbal, visual, and social cognitive processes, whereas 14 randomly assigned schizophrenia controls were given commercial computer games, such as Hangman, Tic-Tac-Toe, and Tetris, for 5 hours a week over 16 weeks in the laboratory.

After 16 weeks, 15 schizophrenia subjects in the intervention group, 14 in the games group, and 12 healthy controls participated in another fMRI reality-monitoring experiment. And 6 months later, 25 of the schizophrenia subjects returned for a reassessment of their clinical and functional status, reported Dr. Subramaniam, also of the University of California, San Francisco.

Intervention subjects showed significant improvement on delayed verbal memory recall at 16 weeks, compared with baseline (P = .02), whereas computer games subjects showed no significant improvement in this measure (P = .30). Intervention subjects also showed significant improvement performing a complex reality-monitoring task that was not part of the training exercises at 16 weeks, compared to baseline (P = .03), whereas games subjects showed no significant improvement in this measure (P = .89).

Compared with patients who played computer games, the trained patients showed a significant improvement in their accuracy when they performed a complex task, as well as a significant increase in mPFC activation during performance; a significant relationship was seen between mPFC activation after training and better social functioning after 6 months, Dr. Subramaniam and colleagues found.

"To our knowledge, this is the first time that a complex higher-order cognitive process in a serious neuropsychiatric illness – in this case, the ability to distinguish the source of information generated by the ‘self’ from information generated by the ‘other’ – has been the targeted outcome of a neuroscience-informed cognitive training strategy," the researchers wrote in their analysis.

The findings show, they wrote, that "it is possible to significantly improve brain function in schizophrenia, even in patients who have been ill for an average of 20 years, and it appears that these improvements set the stage for an enduring improvement in social functioning that occurs even in the absence of other psychosocial therapies."

Dr. Subramaniam reported no relevant financial disclosures. The study was funded by the National Institute of Mental Health. Two coauthors, Gregory V. Simpson, Ph.D., and Dr. Sophia Vinogradov, disclosed employment and consulting relationships, respectively, with the Brain Plasticity Institute, which has a financial interest in computerized cognitive training programs.

Schizophrenia patients who underwent 80 hours of computerized training showed significant and sustained improvements in the ability to distinguish between internal experience and outside reality, a group of researchers has shown.

Improvements in reality monitoring – in which patients can distinguish a self-generated image, sound, or written phrase from one presented to them – corresponded to improvements in activation of the medial prefrontal cortex (mPFC), as confirmed by functional magnetic resonance imaging (fMRI).

The findings suggest that it is possible to improve brain function even among people who have lived decades with their disease.

The researchers, led by Karuna Subramaniam, Ph.D., of the San Francisco VA Medical Center, also recorded improved mPFC activity corresponding with behavioral improvements 6 months after the intervention had ended, suggesting a broader benefit to the training (Neuron 2012;73:842-53).

For their research, Dr. Subramaniam and colleagues recruited 31 clinically stable, persistently ill, volunteer schizophrenia patients, five of whom were women. The mean age of all subjects was 40 years, and mean illness duration was 19.4 years. A separate group of 16 healthy controls was recruited.

All underwent a baseline reality monitoring experiment in which brain activation patterns were recorded. The 16 schizophrenia subjects who were randomly assigned to the invention group received targeted training involving auditory, verbal, visual, and social cognitive processes, whereas 14 randomly assigned schizophrenia controls were given commercial computer games, such as Hangman, Tic-Tac-Toe, and Tetris, for 5 hours a week over 16 weeks in the laboratory.

After 16 weeks, 15 schizophrenia subjects in the intervention group, 14 in the games group, and 12 healthy controls participated in another fMRI reality-monitoring experiment. And 6 months later, 25 of the schizophrenia subjects returned for a reassessment of their clinical and functional status, reported Dr. Subramaniam, also of the University of California, San Francisco.

Intervention subjects showed significant improvement on delayed verbal memory recall at 16 weeks, compared with baseline (P = .02), whereas computer games subjects showed no significant improvement in this measure (P = .30). Intervention subjects also showed significant improvement performing a complex reality-monitoring task that was not part of the training exercises at 16 weeks, compared to baseline (P = .03), whereas games subjects showed no significant improvement in this measure (P = .89).

Compared with patients who played computer games, the trained patients showed a significant improvement in their accuracy when they performed a complex task, as well as a significant increase in mPFC activation during performance; a significant relationship was seen between mPFC activation after training and better social functioning after 6 months, Dr. Subramaniam and colleagues found.

"To our knowledge, this is the first time that a complex higher-order cognitive process in a serious neuropsychiatric illness – in this case, the ability to distinguish the source of information generated by the ‘self’ from information generated by the ‘other’ – has been the targeted outcome of a neuroscience-informed cognitive training strategy," the researchers wrote in their analysis.

The findings show, they wrote, that "it is possible to significantly improve brain function in schizophrenia, even in patients who have been ill for an average of 20 years, and it appears that these improvements set the stage for an enduring improvement in social functioning that occurs even in the absence of other psychosocial therapies."

Dr. Subramaniam reported no relevant financial disclosures. The study was funded by the National Institute of Mental Health. Two coauthors, Gregory V. Simpson, Ph.D., and Dr. Sophia Vinogradov, disclosed employment and consulting relationships, respectively, with the Brain Plasticity Institute, which has a financial interest in computerized cognitive training programs.

People with schizophrenia are more likely to report having had a wide range of unhappy childhood experiences than are healthy, age-matched controls, a group of Australian researchers has found.

Childhood adversity has been associated with higher risk for numerous adult psychiatric disorders. Childhood physical abuse, sexual abuse, neglect, and other types of abuse have been shown in a recent meta-analysis to be associated with an increase in the risk of psychosis (Schizophr. Bull. 2012 March 29 [doi:10.1093/schbul/sbs050]). This new study adds to the catalog of childhood hardships seen as bearing on risk for schizophrenia (J. Psychiatr. Res 2012;46:600-7).

Ph.D. candidate Kathryn L. McCabe and her colleagues used data from 675 adults (aged 18-65 years), all of whom previously had been recruited as part of a national schizophrenia study cohort, the Australian Schizophrenia Research Bank.

Of the subjects, 408 were diagnosed with schizophrenia (268 men, 140 women). The remaining 267 (116 men, 151 women) were healthy, age-matched controls. Subjects and controls completed extensive clinical interviews that included the use of a standardized childhood adversity questionnaire measuring 19 types of adversity, from sibling loss to the feeling that parents "did not do their best for me," reported Ms. McCabe of the Schizophrenia Research Institute in Darlinghurst, New South Wales, and her colleagues. Schizophrenia subjects reported higher rates of abusive, neglectful, and dysfunctional parenting than did controls. After controlling for age, sex, and education, the researchers found that subjects with schizophrenia were significantly more likely to report experiencing childhood trauma than were controls (86.8% vs. 69.5%; odds ratio, 2.87; 95% confidence interval, 1.95-4.23; P less than .001), and to report suffering more of the types of 19 adversities listed in the questionnaire (mean, 5.4 vs. 2.3), wrote Ms. McCabe, who also is affiliated with the University of Newcastle (New South Wales).

Humiliation by a parent, growing up in a household characterized by conflict, and witnessing the physical or sexual abuse of others all were associated with statistically significant increases in risk. Having had a parent who was "not affectionate at all" was associated with an OR of 2.89 (95% CI, 1.84-4.52; P less than .001), the researchers found, whereas verbal abuse by a parent was associated with an OR of 2.32 (95% CI, 1.53-3.51; P less than .001).

Severity of positive symptoms – including auditory hallucinations, delusions, and disordered thoughts – was also seen as correlating with numbers of adversities reported. No relationship was seen between reported childhood adversities and negative symptoms of schizophrenia, which have been shown in studies to antedate the onset of psychosis, the researchers wrote, "and may therefore be likely to reflect neurodevelopmental dysfunction that is a core component of the schizophrenia syndrome and less subject to environmental influences."

The researchers noted that despite their study’s limitations – which included the fact that experiences of adversity were self-reported and subject to recall bias, and also that the cohort of schizophrenia patients was relatively high functioning – "the rate of childhood adversity reported in this sample was high, suggesting greater exposure to adverse childhood events among participants with schizophrenia in comparison with healthy controls. These findings are consistent with previous research indicating that childhood adversity is related to subsequent development of a range of mental illnesses, including schizophrenia."

The research was funded by the National Health and Medical Research Council of Australia, the Pratt Foundation, Ramsay Health Care, the Viertel Charitable Foundation, and the Schizophrenia Research Institute. None of the researchers declared conflicts of interest.

People with schizophrenia are more likely to report having had a wide range of unhappy childhood experiences than are healthy, age-matched controls, a group of Australian researchers has found.

Childhood adversity has been associated with higher risk for numerous adult psychiatric disorders. Childhood physical abuse, sexual abuse, neglect, and other types of abuse have been shown in a recent meta-analysis to be associated with an increase in the risk of psychosis (Schizophr. Bull. 2012 March 29 [doi:10.1093/schbul/sbs050]). This new study adds to the catalog of childhood hardships seen as bearing on risk for schizophrenia (J. Psychiatr. Res 2012;46:600-7).

Ph.D. candidate Kathryn L. McCabe and her colleagues used data from 675 adults (aged 18-65 years), all of whom previously had been recruited as part of a national schizophrenia study cohort, the Australian Schizophrenia Research Bank.

Of the subjects, 408 were diagnosed with schizophrenia (268 men, 140 women). The remaining 267 (116 men, 151 women) were healthy, age-matched controls. Subjects and controls completed extensive clinical interviews that included the use of a standardized childhood adversity questionnaire measuring 19 types of adversity, from sibling loss to the feeling that parents "did not do their best for me," reported Ms. McCabe of the Schizophrenia Research Institute in Darlinghurst, New South Wales, and her colleagues. Schizophrenia subjects reported higher rates of abusive, neglectful, and dysfunctional parenting than did controls. After controlling for age, sex, and education, the researchers found that subjects with schizophrenia were significantly more likely to report experiencing childhood trauma than were controls (86.8% vs. 69.5%; odds ratio, 2.87; 95% confidence interval, 1.95-4.23; P less than .001), and to report suffering more of the types of 19 adversities listed in the questionnaire (mean, 5.4 vs. 2.3), wrote Ms. McCabe, who also is affiliated with the University of Newcastle (New South Wales).

Humiliation by a parent, growing up in a household characterized by conflict, and witnessing the physical or sexual abuse of others all were associated with statistically significant increases in risk. Having had a parent who was "not affectionate at all" was associated with an OR of 2.89 (95% CI, 1.84-4.52; P less than .001), the researchers found, whereas verbal abuse by a parent was associated with an OR of 2.32 (95% CI, 1.53-3.51; P less than .001).

Severity of positive symptoms – including auditory hallucinations, delusions, and disordered thoughts – was also seen as correlating with numbers of adversities reported. No relationship was seen between reported childhood adversities and negative symptoms of schizophrenia, which have been shown in studies to antedate the onset of psychosis, the researchers wrote, "and may therefore be likely to reflect neurodevelopmental dysfunction that is a core component of the schizophrenia syndrome and less subject to environmental influences."

The researchers noted that despite their study’s limitations – which included the fact that experiences of adversity were self-reported and subject to recall bias, and also that the cohort of schizophrenia patients was relatively high functioning – "the rate of childhood adversity reported in this sample was high, suggesting greater exposure to adverse childhood events among participants with schizophrenia in comparison with healthy controls. These findings are consistent with previous research indicating that childhood adversity is related to subsequent development of a range of mental illnesses, including schizophrenia."

The research was funded by the National Health and Medical Research Council of Australia, the Pratt Foundation, Ramsay Health Care, the Viertel Charitable Foundation, and the Schizophrenia Research Institute. None of the researchers declared conflicts of interest.

People with schizophrenia are more likely to report having had a wide range of unhappy childhood experiences than are healthy, age-matched controls, a group of Australian researchers has found.

Childhood adversity has been associated with higher risk for numerous adult psychiatric disorders. Childhood physical abuse, sexual abuse, neglect, and other types of abuse have been shown in a recent meta-analysis to be associated with an increase in the risk of psychosis (Schizophr. Bull. 2012 March 29 [doi:10.1093/schbul/sbs050]). This new study adds to the catalog of childhood hardships seen as bearing on risk for schizophrenia (J. Psychiatr. Res 2012;46:600-7).

Ph.D. candidate Kathryn L. McCabe and her colleagues used data from 675 adults (aged 18-65 years), all of whom previously had been recruited as part of a national schizophrenia study cohort, the Australian Schizophrenia Research Bank.

Of the subjects, 408 were diagnosed with schizophrenia (268 men, 140 women). The remaining 267 (116 men, 151 women) were healthy, age-matched controls. Subjects and controls completed extensive clinical interviews that included the use of a standardized childhood adversity questionnaire measuring 19 types of adversity, from sibling loss to the feeling that parents "did not do their best for me," reported Ms. McCabe of the Schizophrenia Research Institute in Darlinghurst, New South Wales, and her colleagues. Schizophrenia subjects reported higher rates of abusive, neglectful, and dysfunctional parenting than did controls. After controlling for age, sex, and education, the researchers found that subjects with schizophrenia were significantly more likely to report experiencing childhood trauma than were controls (86.8% vs. 69.5%; odds ratio, 2.87; 95% confidence interval, 1.95-4.23; P less than .001), and to report suffering more of the types of 19 adversities listed in the questionnaire (mean, 5.4 vs. 2.3), wrote Ms. McCabe, who also is affiliated with the University of Newcastle (New South Wales).

Humiliation by a parent, growing up in a household characterized by conflict, and witnessing the physical or sexual abuse of others all were associated with statistically significant increases in risk. Having had a parent who was "not affectionate at all" was associated with an OR of 2.89 (95% CI, 1.84-4.52; P less than .001), the researchers found, whereas verbal abuse by a parent was associated with an OR of 2.32 (95% CI, 1.53-3.51; P less than .001).

Severity of positive symptoms – including auditory hallucinations, delusions, and disordered thoughts – was also seen as correlating with numbers of adversities reported. No relationship was seen between reported childhood adversities and negative symptoms of schizophrenia, which have been shown in studies to antedate the onset of psychosis, the researchers wrote, "and may therefore be likely to reflect neurodevelopmental dysfunction that is a core component of the schizophrenia syndrome and less subject to environmental influences."

The researchers noted that despite their study’s limitations – which included the fact that experiences of adversity were self-reported and subject to recall bias, and also that the cohort of schizophrenia patients was relatively high functioning – "the rate of childhood adversity reported in this sample was high, suggesting greater exposure to adverse childhood events among participants with schizophrenia in comparison with healthy controls. These findings are consistent with previous research indicating that childhood adversity is related to subsequent development of a range of mental illnesses, including schizophrenia."

The research was funded by the National Health and Medical Research Council of Australia, the Pratt Foundation, Ramsay Health Care, the Viertel Charitable Foundation, and the Schizophrenia Research Institute. None of the researchers declared conflicts of interest.

Nearly half of U.S. surgeons who routinely perform high-risk operations do not regularly ask patients about their advance directives – also known as living wills – before proceeding with a high-risk procedure, results of a survey indicate. Perhaps more importantly, more than half of survey respondents said they would not operate if they were aware of a restrictive directive.

The findings were derived from a survey mailed to 2,100 randomly selected vascular, neurological, and cardiothoracic surgeons in 2010. Of these, 912 eligible responses were entered into analysis, with the three types of surgeons responding at about the same rate: 56% for vascular surgeons and neurosurgeons and 54% for cardiothoracic surgeons (Ann. Surg. 2012;255:418-23).

A majority of respondents (81%), however, reported having conversations about patients’ preferences for limiting the use of life-sustaining procedures postoperatively. The surgeons said they tend to view factors such as a patient’s predicted postoperative quality of life, age, comorbidities, and mental readiness as vastly more important in determining whether to operate than the existence of an advance directive, which 48% said they do not routinely confirm, according to the study’s authors, led by Dr. Margaret L. Schwarze of the University of Wisconsin, Madison.

Because most information about advance directives and the surgical decision-making process thus far has been anecdotal, she and her colleagues investigated how conversations about formal directives actually proceed in a surgical setting and their role in decision making.

A total of 54% of all surgeons who responded said that they would not operate if they knew a patient had an advance directive that might limit the postoperative options. Among cardiothoracic surgeons, who routinely rely on ventilator support as part of postoperative care, 63% said they would not operate with prior knowledge of a restrictive advance directive. Multivariate analysis showed that cardiac surgeons were almost twice as likely to operate compared with their neurosurgeon counterparts (odds ratio, 1.96) and somewhat more likely than were vascular surgeons (OR, 1.35).

Younger surgeons – those with 20 or less years of experience – were less likely to discuss advance directives regularly (44%) than were those with more than 20 years of experience (69%).

Several of the survey results strongly suggest that surgeons view advance directives as "an impediment to the goals of surgical therapy" and that they interpret them as "a signal that patients with advance directives are not truly committed to the operation and the invasive postoperative therapy the operation necessarily entails," wrote the investigators. Furthermore, surgeons "often find it difficult to shift goals when surgery does not go as planned – the result of a surgical ethos which discourages moving from a curative model to a palliative mode of care."

Dr. Schwarze and her colleagues noted that their findings raise the question of whether it is ethical for surgeons to deny a patient a procedure because of a restrictive advance directive.

However, directives are not generally designed with high-risk surgical procedures in mind. They may be vague, and can potentially create confusion in a postoperative context. Thus, the investigators concluded that communication prior to surgery is urgently needed to "clarify patient preferences with respect to the surgical endeavor and the patient’s advance directive," and that such communication should be documented.

The investigators had no relevant disclosures.

Nearly half of U.S. surgeons who routinely perform high-risk operations do not regularly ask patients about their advance directives – also known as living wills – before proceeding with a high-risk procedure, results of a survey indicate. Perhaps more importantly, more than half of survey respondents said they would not operate if they were aware of a restrictive directive.

The findings were derived from a survey mailed to 2,100 randomly selected vascular, neurological, and cardiothoracic surgeons in 2010. Of these, 912 eligible responses were entered into analysis, with the three types of surgeons responding at about the same rate: 56% for vascular surgeons and neurosurgeons and 54% for cardiothoracic surgeons (Ann. Surg. 2012;255:418-23).

A majority of respondents (81%), however, reported having conversations about patients’ preferences for limiting the use of life-sustaining procedures postoperatively. The surgeons said they tend to view factors such as a patient’s predicted postoperative quality of life, age, comorbidities, and mental readiness as vastly more important in determining whether to operate than the existence of an advance directive, which 48% said they do not routinely confirm, according to the study’s authors, led by Dr. Margaret L. Schwarze of the University of Wisconsin, Madison.

Because most information about advance directives and the surgical decision-making process thus far has been anecdotal, she and her colleagues investigated how conversations about formal directives actually proceed in a surgical setting and their role in decision making.

A total of 54% of all surgeons who responded said that they would not operate if they knew a patient had an advance directive that might limit the postoperative options. Among cardiothoracic surgeons, who routinely rely on ventilator support as part of postoperative care, 63% said they would not operate with prior knowledge of a restrictive advance directive. Multivariate analysis showed that cardiac surgeons were almost twice as likely to operate compared with their neurosurgeon counterparts (odds ratio, 1.96) and somewhat more likely than were vascular surgeons (OR, 1.35).

Younger surgeons – those with 20 or less years of experience – were less likely to discuss advance directives regularly (44%) than were those with more than 20 years of experience (69%).

Several of the survey results strongly suggest that surgeons view advance directives as "an impediment to the goals of surgical therapy" and that they interpret them as "a signal that patients with advance directives are not truly committed to the operation and the invasive postoperative therapy the operation necessarily entails," wrote the investigators. Furthermore, surgeons "often find it difficult to shift goals when surgery does not go as planned – the result of a surgical ethos which discourages moving from a curative model to a palliative mode of care."

Dr. Schwarze and her colleagues noted that their findings raise the question of whether it is ethical for surgeons to deny a patient a procedure because of a restrictive advance directive.

However, directives are not generally designed with high-risk surgical procedures in mind. They may be vague, and can potentially create confusion in a postoperative context. Thus, the investigators concluded that communication prior to surgery is urgently needed to "clarify patient preferences with respect to the surgical endeavor and the patient’s advance directive," and that such communication should be documented.

The investigators had no relevant disclosures.

Nearly half of U.S. surgeons who routinely perform high-risk operations do not regularly ask patients about their advance directives – also known as living wills – before proceeding with a high-risk procedure, results of a survey indicate. Perhaps more importantly, more than half of survey respondents said they would not operate if they were aware of a restrictive directive.

The findings were derived from a survey mailed to 2,100 randomly selected vascular, neurological, and cardiothoracic surgeons in 2010. Of these, 912 eligible responses were entered into analysis, with the three types of surgeons responding at about the same rate: 56% for vascular surgeons and neurosurgeons and 54% for cardiothoracic surgeons (Ann. Surg. 2012;255:418-23).

A majority of respondents (81%), however, reported having conversations about patients’ preferences for limiting the use of life-sustaining procedures postoperatively. The surgeons said they tend to view factors such as a patient’s predicted postoperative quality of life, age, comorbidities, and mental readiness as vastly more important in determining whether to operate than the existence of an advance directive, which 48% said they do not routinely confirm, according to the study’s authors, led by Dr. Margaret L. Schwarze of the University of Wisconsin, Madison.

Because most information about advance directives and the surgical decision-making process thus far has been anecdotal, she and her colleagues investigated how conversations about formal directives actually proceed in a surgical setting and their role in decision making.

A total of 54% of all surgeons who responded said that they would not operate if they knew a patient had an advance directive that might limit the postoperative options. Among cardiothoracic surgeons, who routinely rely on ventilator support as part of postoperative care, 63% said they would not operate with prior knowledge of a restrictive advance directive. Multivariate analysis showed that cardiac surgeons were almost twice as likely to operate compared with their neurosurgeon counterparts (odds ratio, 1.96) and somewhat more likely than were vascular surgeons (OR, 1.35).

Younger surgeons – those with 20 or less years of experience – were less likely to discuss advance directives regularly (44%) than were those with more than 20 years of experience (69%).

Several of the survey results strongly suggest that surgeons view advance directives as "an impediment to the goals of surgical therapy" and that they interpret them as "a signal that patients with advance directives are not truly committed to the operation and the invasive postoperative therapy the operation necessarily entails," wrote the investigators. Furthermore, surgeons "often find it difficult to shift goals when surgery does not go as planned – the result of a surgical ethos which discourages moving from a curative model to a palliative mode of care."

Dr. Schwarze and her colleagues noted that their findings raise the question of whether it is ethical for surgeons to deny a patient a procedure because of a restrictive advance directive.

However, directives are not generally designed with high-risk surgical procedures in mind. They may be vague, and can potentially create confusion in a postoperative context. Thus, the investigators concluded that communication prior to surgery is urgently needed to "clarify patient preferences with respect to the surgical endeavor and the patient’s advance directive," and that such communication should be documented.

The investigators had no relevant disclosures.

BOGOTÁ, COLOMBIA – Adolescent girls who become pregnant and carry to term experience high morbidity, including psychiatric outcomes, numerous studies have established. And, in Latin America, teenage pregnancy rates are rising, and legal abortion is rarely an option.

Learning how to prevent postpartum depression and psychosis among these girls is something "gleaned over years of clinical practice," says Dr. Roberto Chaskel, who has treated such girls for nearly 3 decades. "No one tells you how."

At the fourth International Congress of Medicine and Women’s Mental Health, Dr. Chaskel presented video of an 11-year-old who had just given birth days earlier by cesarean section and was experiencing psychosis. The girl had been referred for psychiatric care only after the birth.

Adolescent pregnancies have risen in many Latin American countries in recent decades, despite declining fertility trends overall, according to a 2007 United Nations Report. One Latin American study of 854,377 girls aged 15 years and younger found pregnancy associated with a fourfold higher risk of a host of adverse pregnancy outcomes, including maternal death, early neonatal death, and anemia, compared with women aged 20 years or older (Am. J. Obstet. Gynecol. 2005;192:342-9).

(Meanwhile, the Centers for Disease Control and Prevention reported recently that teenage pregnancy rates in the United States declined 9% from 2009 to 2010, which means that the rate is at an historic low of 34.3 births/1,000 adolescents aged 15-19 years. The decline was seen across all ethnicities.)

In most Latin American countries, including Colombia – where access to abortion is highly restricted, pregnancies among girls aged 15 years and younger often result in birth. Only three Caribbean or Latin American states permit abortion without regard to reason, according to a 2012 report by the Guttmacher Institute. Illegal procedures are estimated to represent 95% of all abortions performed in the region, according to the same report.

In 2006, in Bogotá there were 22,228 pregnancies reported among teenage girls between 10 and 19 years of age (170/100,000), placing Bogotá’s teenage pregnancy rates nearly on nearly on par with those of Uganda and Sierra Leone, according to a 2010 study by researchers at the Universidad Nacional de Colombia. A tenth of the reported pregnancies were to women aged 14 years and younger.

It is possible to prevent psychotic and depressive episodes related to pregnancy and birth and "offer teenagers and adolescents, and the babies of these girls, the best possible quality of life" through a family practice that seeks to mitigate some of the traumas associated with early sex, pregnancy, and birth, and also to guide the early attachment process between mothers and children, said Dr. Chaskel of the department of psychiatry at the Universidad El Bosque and coordinator of child psychiatry at the Fundación Santa Fe, both in Bogotá, Colombia,.

In a separate presentation at the congress, Dr. Marta B. Rondón, a psychiatrist affiliated with the Universidad Peruana Cayetano Heredia in Lima, Peru, discussed the difficulty of achieving an evidence-based understanding of the mental health impact of abortion and unwanted pregnancy in nations where access is restricted and "generally speaking, a woman cannot choose just to terminate a nondesired pregnancy."

In a restricted legal environment, "the condition of secrecy means the woman has to go a very hard road – this could have negative consequences for her mental health – but we don’t have the numbers," Dr. Rondón said, adding that discussing how to conduct research on abortion and mental health in Latin America would be a priority of next year’s international congress on women’s mental health, which will be held in Lima.

Any attempt to get a perspective on the mental health impact of abortion and unwanted pregnancy means using studies conducted in the United States and Europe – different cultural environments that could produce different results. "We need prospective research with randomized samples in Latin America, which may become possible as abortion is gradually decriminalized," Dr. Rondón said.

Currently, Peru and Colombia allow legal abortion only in the event of a threat to the life or physical health of the woman. In addition, Colombia allows terminations in cases of rape or to preserve a woman’s mental health.

Dr. Chaskel said in an interview that the 11-year-old patient in his video would have been a candidate for legal abortion under Colombian law and that he would have referred her had she presented to him early. However, he said, her obstetrician had judged her ineligible.

Their options might be limited in terms of a choice to terminate, but pregnant adolescents in Latin America do have the benefit of strong family ties, and Dr. Chaskel’s practice taps into the high level of familial support available to most. "You bring grandma and grandpa, and the new uncles and aunts into clinical practice – right into the office," he said in an interview. A pregnancy in adolescence "generates confusion not only for the girl but also on the whole family group: In Latin America, this usually means three generations confused as to how to approach this situation."

The initial goal of the interventions, he said, is to help pregnant adolescents avoid postpartum depression and psychosis. The longer-term goal is to allow them to continue in their adolescence as normally as possible after the birth, while developing a healthy attachment to the child with the support of their families.

"Are they going to keep listening to Lady Gaga? If you have an 18-month-old baby, how do you behave? We’ve really worked on recuperating adolescence for these girls to make sure that they do listen to Lady Gaga," he said. "We try to make sure that if they’re going to have the baby, to know what they want to do – go back to school, go to a friend’s 15th birthday party [Quinceañera], or have one themselves.

"We think it over together."

After the birth, infants and their young mothers are observed and evaluated interacting in-office, where such details as the distance the child crawls away from the mother is measured as a way of gauging healthy attachments. The girls, who are at high risk of having second babies while still in their teenage years, need to be followed up for years.

Neither Dr. Chaskel nor Dr. Rondón reported disclosures.

BOGOTÁ, COLOMBIA – Adolescent girls who become pregnant and carry to term experience high morbidity, including psychiatric outcomes, numerous studies have established. And, in Latin America, teenage pregnancy rates are rising, and legal abortion is rarely an option.

Learning how to prevent postpartum depression and psychosis among these girls is something "gleaned over years of clinical practice," says Dr. Roberto Chaskel, who has treated such girls for nearly 3 decades. "No one tells you how."

At the fourth International Congress of Medicine and Women’s Mental Health, Dr. Chaskel presented video of an 11-year-old who had just given birth days earlier by cesarean section and was experiencing psychosis. The girl had been referred for psychiatric care only after the birth.

Adolescent pregnancies have risen in many Latin American countries in recent decades, despite declining fertility trends overall, according to a 2007 United Nations Report. One Latin American study of 854,377 girls aged 15 years and younger found pregnancy associated with a fourfold higher risk of a host of adverse pregnancy outcomes, including maternal death, early neonatal death, and anemia, compared with women aged 20 years or older (Am. J. Obstet. Gynecol. 2005;192:342-9).

(Meanwhile, the Centers for Disease Control and Prevention reported recently that teenage pregnancy rates in the United States declined 9% from 2009 to 2010, which means that the rate is at an historic low of 34.3 births/1,000 adolescents aged 15-19 years. The decline was seen across all ethnicities.)

In most Latin American countries, including Colombia – where access to abortion is highly restricted, pregnancies among girls aged 15 years and younger often result in birth. Only three Caribbean or Latin American states permit abortion without regard to reason, according to a 2012 report by the Guttmacher Institute. Illegal procedures are estimated to represent 95% of all abortions performed in the region, according to the same report.

In 2006, in Bogotá there were 22,228 pregnancies reported among teenage girls between 10 and 19 years of age (170/100,000), placing Bogotá’s teenage pregnancy rates nearly on nearly on par with those of Uganda and Sierra Leone, according to a 2010 study by researchers at the Universidad Nacional de Colombia. A tenth of the reported pregnancies were to women aged 14 years and younger.

It is possible to prevent psychotic and depressive episodes related to pregnancy and birth and "offer teenagers and adolescents, and the babies of these girls, the best possible quality of life" through a family practice that seeks to mitigate some of the traumas associated with early sex, pregnancy, and birth, and also to guide the early attachment process between mothers and children, said Dr. Chaskel of the department of psychiatry at the Universidad El Bosque and coordinator of child psychiatry at the Fundación Santa Fe, both in Bogotá, Colombia,.

In a separate presentation at the congress, Dr. Marta B. Rondón, a psychiatrist affiliated with the Universidad Peruana Cayetano Heredia in Lima, Peru, discussed the difficulty of achieving an evidence-based understanding of the mental health impact of abortion and unwanted pregnancy in nations where access is restricted and "generally speaking, a woman cannot choose just to terminate a nondesired pregnancy."

In a restricted legal environment, "the condition of secrecy means the woman has to go a very hard road – this could have negative consequences for her mental health – but we don’t have the numbers," Dr. Rondón said, adding that discussing how to conduct research on abortion and mental health in Latin America would be a priority of next year’s international congress on women’s mental health, which will be held in Lima.

Any attempt to get a perspective on the mental health impact of abortion and unwanted pregnancy means using studies conducted in the United States and Europe – different cultural environments that could produce different results. "We need prospective research with randomized samples in Latin America, which may become possible as abortion is gradually decriminalized," Dr. Rondón said.

Currently, Peru and Colombia allow legal abortion only in the event of a threat to the life or physical health of the woman. In addition, Colombia allows terminations in cases of rape or to preserve a woman’s mental health.

Dr. Chaskel said in an interview that the 11-year-old patient in his video would have been a candidate for legal abortion under Colombian law and that he would have referred her had she presented to him early. However, he said, her obstetrician had judged her ineligible.

Their options might be limited in terms of a choice to terminate, but pregnant adolescents in Latin America do have the benefit of strong family ties, and Dr. Chaskel’s practice taps into the high level of familial support available to most. "You bring grandma and grandpa, and the new uncles and aunts into clinical practice – right into the office," he said in an interview. A pregnancy in adolescence "generates confusion not only for the girl but also on the whole family group: In Latin America, this usually means three generations confused as to how to approach this situation."

The initial goal of the interventions, he said, is to help pregnant adolescents avoid postpartum depression and psychosis. The longer-term goal is to allow them to continue in their adolescence as normally as possible after the birth, while developing a healthy attachment to the child with the support of their families.

"Are they going to keep listening to Lady Gaga? If you have an 18-month-old baby, how do you behave? We’ve really worked on recuperating adolescence for these girls to make sure that they do listen to Lady Gaga," he said. "We try to make sure that if they’re going to have the baby, to know what they want to do – go back to school, go to a friend’s 15th birthday party [Quinceañera], or have one themselves.

"We think it over together."

After the birth, infants and their young mothers are observed and evaluated interacting in-office, where such details as the distance the child crawls away from the mother is measured as a way of gauging healthy attachments. The girls, who are at high risk of having second babies while still in their teenage years, need to be followed up for years.

Neither Dr. Chaskel nor Dr. Rondón reported disclosures.

BOGOTÁ, COLOMBIA – Adolescent girls who become pregnant and carry to term experience high morbidity, including psychiatric outcomes, numerous studies have established. And, in Latin America, teenage pregnancy rates are rising, and legal abortion is rarely an option.

Learning how to prevent postpartum depression and psychosis among these girls is something "gleaned over years of clinical practice," says Dr. Roberto Chaskel, who has treated such girls for nearly 3 decades. "No one tells you how."

At the fourth International Congress of Medicine and Women’s Mental Health, Dr. Chaskel presented video of an 11-year-old who had just given birth days earlier by cesarean section and was experiencing psychosis. The girl had been referred for psychiatric care only after the birth.

Adolescent pregnancies have risen in many Latin American countries in recent decades, despite declining fertility trends overall, according to a 2007 United Nations Report. One Latin American study of 854,377 girls aged 15 years and younger found pregnancy associated with a fourfold higher risk of a host of adverse pregnancy outcomes, including maternal death, early neonatal death, and anemia, compared with women aged 20 years or older (Am. J. Obstet. Gynecol. 2005;192:342-9).

(Meanwhile, the Centers for Disease Control and Prevention reported recently that teenage pregnancy rates in the United States declined 9% from 2009 to 2010, which means that the rate is at an historic low of 34.3 births/1,000 adolescents aged 15-19 years. The decline was seen across all ethnicities.)

In most Latin American countries, including Colombia – where access to abortion is highly restricted, pregnancies among girls aged 15 years and younger often result in birth. Only three Caribbean or Latin American states permit abortion without regard to reason, according to a 2012 report by the Guttmacher Institute. Illegal procedures are estimated to represent 95% of all abortions performed in the region, according to the same report.

In 2006, in Bogotá there were 22,228 pregnancies reported among teenage girls between 10 and 19 years of age (170/100,000), placing Bogotá’s teenage pregnancy rates nearly on nearly on par with those of Uganda and Sierra Leone, according to a 2010 study by researchers at the Universidad Nacional de Colombia. A tenth of the reported pregnancies were to women aged 14 years and younger.

It is possible to prevent psychotic and depressive episodes related to pregnancy and birth and "offer teenagers and adolescents, and the babies of these girls, the best possible quality of life" through a family practice that seeks to mitigate some of the traumas associated with early sex, pregnancy, and birth, and also to guide the early attachment process between mothers and children, said Dr. Chaskel of the department of psychiatry at the Universidad El Bosque and coordinator of child psychiatry at the Fundación Santa Fe, both in Bogotá, Colombia,.

In a separate presentation at the congress, Dr. Marta B. Rondón, a psychiatrist affiliated with the Universidad Peruana Cayetano Heredia in Lima, Peru, discussed the difficulty of achieving an evidence-based understanding of the mental health impact of abortion and unwanted pregnancy in nations where access is restricted and "generally speaking, a woman cannot choose just to terminate a nondesired pregnancy."

In a restricted legal environment, "the condition of secrecy means the woman has to go a very hard road – this could have negative consequences for her mental health – but we don’t have the numbers," Dr. Rondón said, adding that discussing how to conduct research on abortion and mental health in Latin America would be a priority of next year’s international congress on women’s mental health, which will be held in Lima.

Any attempt to get a perspective on the mental health impact of abortion and unwanted pregnancy means using studies conducted in the United States and Europe – different cultural environments that could produce different results. "We need prospective research with randomized samples in Latin America, which may become possible as abortion is gradually decriminalized," Dr. Rondón said.

Currently, Peru and Colombia allow legal abortion only in the event of a threat to the life or physical health of the woman. In addition, Colombia allows terminations in cases of rape or to preserve a woman’s mental health.

Dr. Chaskel said in an interview that the 11-year-old patient in his video would have been a candidate for legal abortion under Colombian law and that he would have referred her had she presented to him early. However, he said, her obstetrician had judged her ineligible.

Their options might be limited in terms of a choice to terminate, but pregnant adolescents in Latin America do have the benefit of strong family ties, and Dr. Chaskel’s practice taps into the high level of familial support available to most. "You bring grandma and grandpa, and the new uncles and aunts into clinical practice – right into the office," he said in an interview. A pregnancy in adolescence "generates confusion not only for the girl but also on the whole family group: In Latin America, this usually means three generations confused as to how to approach this situation."

The initial goal of the interventions, he said, is to help pregnant adolescents avoid postpartum depression and psychosis. The longer-term goal is to allow them to continue in their adolescence as normally as possible after the birth, while developing a healthy attachment to the child with the support of their families.

"Are they going to keep listening to Lady Gaga? If you have an 18-month-old baby, how do you behave? We’ve really worked on recuperating adolescence for these girls to make sure that they do listen to Lady Gaga," he said. "We try to make sure that if they’re going to have the baby, to know what they want to do – go back to school, go to a friend’s 15th birthday party [Quinceañera], or have one themselves.

"We think it over together."

After the birth, infants and their young mothers are observed and evaluated interacting in-office, where such details as the distance the child crawls away from the mother is measured as a way of gauging healthy attachments. The girls, who are at high risk of having second babies while still in their teenage years, need to be followed up for years.

Neither Dr. Chaskel nor Dr. Rondón reported disclosures.

The cost-effectiveness agency for England and Wales says that it will not recommend bevacizumab in combination with capecitabine to treat advanced metastatic breast cancer.

In new draft guidance issued April 18, the National Institute for Health and Clinical Excellence (NICE) cited insufficient evidence in support of the drug combination, one of two bevacizumab regimens licensed in the European Union for the first-line treatment of advanced metastatic breast cancer.

Roche’s bevacizumab (Avastin) is a humanized monoclonal antibody that blocks vascular endothelial growth factor, reducing blood flow to tumors. The U.S. Food and Drug Administration revoked bevacizumab’s breast cancer indications altogether in November 2011, citing an unfavorable risk-benefit ratio.

The European Medicines Agency did not follow suit, however. Bevacizumab is licensed in Europe in combination with paclitaxel and also with capecitabine, which is used when paclitaxel is judged inappropriate, for advanced metastatic breast cancer.

In February 2011, NICE rejected bevacizumab and paclitaxel for the same indication.

In announcing its decision on bevacizumab and capecitabine, NICE cited uncertainties about overall survival benefit in results from RIBBON-1, a randomized controlled trial of bevacizumab in 1,237 women with advanced breast cancer. In the capecitabine arm of the trial, 615 patients were randomized to capecitabine plus bevacizumab or capecitabine plus placebo.

Although the results showed that capecitabine and bevacizumab prolonged progression-free survival by 2.9 months compared with capecitabine monotherapy, it remained unclear whether that benefit translated into an improvement in overall survival, NICE said, because so many patients on monotherapy crossed over to bevacizumab in the trial’s open-label postprogression phase.

NICE cited in its negative guidance the fact that no quality of life data had been collected in the trial, and that serious adverse reactions were higher with bevacizumab plus capecitabine (36.6%) than with capecitabine plus placebo (22.9%). "In addition, the number of patients with hypertension, proteinuria, sensory neuropathy, and venous thromboembolic events was higher with bevacizumab plus capecitabine compared with capecitabine plus placebo," NICE said in an April 18 press statement about its decision. "The Committee concluded that bevacizumab plus capecitabine had a less favorable toxicity profile than capecitabine plus placebo."

Finally, as in all NICE decisions, there was the question of cost. The manufacturer’s best-case incremental cost-effectiveness ratio (ICER) for bevacizumab plus capecitabine was £82,000 (U.S.$131,400) per quality-adjusted life year gained, and this only for a subgroup of patients. The ICER placed bevacizumab firmly out of NICE’s cost-effectiveness range.

Bevacizumab, which is administered by intravenous infusion, is dosed at 15 mg/kg every 3 weeks, amounting, NICE said, to an average monthly cost of around £3,689 (U.S.$5,913) per patient.

The cost-effectiveness agency for England and Wales says that it will not recommend bevacizumab in combination with capecitabine to treat advanced metastatic breast cancer.

In new draft guidance issued April 18, the National Institute for Health and Clinical Excellence (NICE) cited insufficient evidence in support of the drug combination, one of two bevacizumab regimens licensed in the European Union for the first-line treatment of advanced metastatic breast cancer.

Roche’s bevacizumab (Avastin) is a humanized monoclonal antibody that blocks vascular endothelial growth factor, reducing blood flow to tumors. The U.S. Food and Drug Administration revoked bevacizumab’s breast cancer indications altogether in November 2011, citing an unfavorable risk-benefit ratio.

The European Medicines Agency did not follow suit, however. Bevacizumab is licensed in Europe in combination with paclitaxel and also with capecitabine, which is used when paclitaxel is judged inappropriate, for advanced metastatic breast cancer.

In February 2011, NICE rejected bevacizumab and paclitaxel for the same indication.

In announcing its decision on bevacizumab and capecitabine, NICE cited uncertainties about overall survival benefit in results from RIBBON-1, a randomized controlled trial of bevacizumab in 1,237 women with advanced breast cancer. In the capecitabine arm of the trial, 615 patients were randomized to capecitabine plus bevacizumab or capecitabine plus placebo.

Although the results showed that capecitabine and bevacizumab prolonged progression-free survival by 2.9 months compared with capecitabine monotherapy, it remained unclear whether that benefit translated into an improvement in overall survival, NICE said, because so many patients on monotherapy crossed over to bevacizumab in the trial’s open-label postprogression phase.

NICE cited in its negative guidance the fact that no quality of life data had been collected in the trial, and that serious adverse reactions were higher with bevacizumab plus capecitabine (36.6%) than with capecitabine plus placebo (22.9%). "In addition, the number of patients with hypertension, proteinuria, sensory neuropathy, and venous thromboembolic events was higher with bevacizumab plus capecitabine compared with capecitabine plus placebo," NICE said in an April 18 press statement about its decision. "The Committee concluded that bevacizumab plus capecitabine had a less favorable toxicity profile than capecitabine plus placebo."

Finally, as in all NICE decisions, there was the question of cost. The manufacturer’s best-case incremental cost-effectiveness ratio (ICER) for bevacizumab plus capecitabine was £82,000 (U.S.$131,400) per quality-adjusted life year gained, and this only for a subgroup of patients. The ICER placed bevacizumab firmly out of NICE’s cost-effectiveness range.

Bevacizumab, which is administered by intravenous infusion, is dosed at 15 mg/kg every 3 weeks, amounting, NICE said, to an average monthly cost of around £3,689 (U.S.$5,913) per patient.

The cost-effectiveness agency for England and Wales says that it will not recommend bevacizumab in combination with capecitabine to treat advanced metastatic breast cancer.

In new draft guidance issued April 18, the National Institute for Health and Clinical Excellence (NICE) cited insufficient evidence in support of the drug combination, one of two bevacizumab regimens licensed in the European Union for the first-line treatment of advanced metastatic breast cancer.

Roche’s bevacizumab (Avastin) is a humanized monoclonal antibody that blocks vascular endothelial growth factor, reducing blood flow to tumors. The U.S. Food and Drug Administration revoked bevacizumab’s breast cancer indications altogether in November 2011, citing an unfavorable risk-benefit ratio.

The European Medicines Agency did not follow suit, however. Bevacizumab is licensed in Europe in combination with paclitaxel and also with capecitabine, which is used when paclitaxel is judged inappropriate, for advanced metastatic breast cancer.

In February 2011, NICE rejected bevacizumab and paclitaxel for the same indication.

In announcing its decision on bevacizumab and capecitabine, NICE cited uncertainties about overall survival benefit in results from RIBBON-1, a randomized controlled trial of bevacizumab in 1,237 women with advanced breast cancer. In the capecitabine arm of the trial, 615 patients were randomized to capecitabine plus bevacizumab or capecitabine plus placebo.

Although the results showed that capecitabine and bevacizumab prolonged progression-free survival by 2.9 months compared with capecitabine monotherapy, it remained unclear whether that benefit translated into an improvement in overall survival, NICE said, because so many patients on monotherapy crossed over to bevacizumab in the trial’s open-label postprogression phase.

NICE cited in its negative guidance the fact that no quality of life data had been collected in the trial, and that serious adverse reactions were higher with bevacizumab plus capecitabine (36.6%) than with capecitabine plus placebo (22.9%). "In addition, the number of patients with hypertension, proteinuria, sensory neuropathy, and venous thromboembolic events was higher with bevacizumab plus capecitabine compared with capecitabine plus placebo," NICE said in an April 18 press statement about its decision. "The Committee concluded that bevacizumab plus capecitabine had a less favorable toxicity profile than capecitabine plus placebo."

Finally, as in all NICE decisions, there was the question of cost. The manufacturer’s best-case incremental cost-effectiveness ratio (ICER) for bevacizumab plus capecitabine was £82,000 (U.S.$131,400) per quality-adjusted life year gained, and this only for a subgroup of patients. The ICER placed bevacizumab firmly out of NICE’s cost-effectiveness range.

Bevacizumab, which is administered by intravenous infusion, is dosed at 15 mg/kg every 3 weeks, amounting, NICE said, to an average monthly cost of around £3,689 (U.S.$5,913) per patient.