Disclosure forms provided by the authors are available with the full text of this article at NEJM.org.

This article (10.1056/NEJMp1102022) was published on March 23, 2011, at NEJM.org.

March 21, 2011 — Regular consumption of fish and omega-3 fatty acids is associated with a significantly reduced risk for the development of age-related macular degeneration (AMD) in women, according to the results of a study reported online March 14 in the Archives of Ophthalmology.

"An estimated nine million U.S. adults aged 40 years and older show signs of ...AMD," write William G. Christen, ScD, from Brigham and Women's Hospital and Harvard Medical School in Boston, Massachusetts, and colleagues. "An additional 7.3 million persons have early AMD, which is usually associated with moderate or no vision loss but does increase the risk of progression to advanced AMD .... Dietary intake of fish, and specifically omega-3 fatty acids concentrated in fish (docosahexaenoic acid [DHA] and eicosapentaenoic acid [EPA]), has been linked with reduced rates of cardiovascular events in epidemiologic studies and could have a similar beneficial effect in AMD."

The goal of the study was to evaluate the association of omega-3 fatty acid and fish consumption with incidence of AMD in women. Of 39,876 female health professionals (mean age, 54.6 ± 7.0 years) enrolled in the Women's Health Study, 38,022 women without a diagnosis of AMD completed a detailed food-frequency questionnaire at baseline. The primary endpoint was incident AMD causing a reduction in best-corrected visual acuity to 20/30 or worse, as identified by self-report and confirmed by medical record review.

During follow-up of average duration 10 years, there were 235 confirmed cases of AMD, most of which were characterized by some combination of drusen and retinal pigment epithelial changes.

Compared with women in the lowest tertile of DHA intake, those in the highest tertile had a multivariate-adjusted relative risk (RR) for AMD of 0.62 (95% confidence interval [CI], 0.44 - 0.87). Women in the highest vs the lowest tertile of EPA intake had an RR of 0.66 (95% CI, 0.48 - 0.92).

As would be expected from these findings, the RR for AMD was 0.58 (95% CI, 0.38 - 0.87) for women who consumed at least 1 serving of fish per week vs those who consumed less than 1 serving per month. This lower risk appeared to be mostly attributed to consumption of canned tuna fish and dark-meat fish, such as mackerel, salmon, sardines, bluefish, and swordfish.

"These prospective data from a large cohort of female health professionals without a diagnosis of AMD at baseline indicate that regular consumption of docosahexaenoic acid and eicosapentaenoic acid and fish was associated with a significantly decreased risk of incident AMD and may be of benefit in primary prevention of AMD," the study authors write.

Limitations of this study include lack of generalizability to populations other than female health professionals, reliance on participant self-report, and possible surveillance bias.

"These data appear to be the strongest evidence to date to support a role for omega-3 long-chain fatty acids in the primary prevention of AMD, and perhaps a reduction in the number of persons who ultimately have advanced AMD, and need to be confirmed in randomized trials."

The National Institutes of Health supported this study. Bayer Healthcare and the Natural Source Vitamin E Association provided pills and packaging.

Arch Ophthalmol. Published online March 14, 2011. Full text

Major Depression and Menopause

Major depressive episodes become more common during and immediately after the menopausal transition.

Menopause is thought to increase the risk for depression. However, studies have had conflicting results and methodological flaws, such as measuring depressive symptoms rather than major depression, not controlling for past episodes, not following women prospectively through the menopausal transition, and not extending follow-up into postmenopause. In this 10-year study, researchers examined the development of major depressive episodes through menopause in 221 premenopausal women who were participating in a longitudinal study of health in menopause and aging (144 whites; 77 blacks; age range at study entry, 42–52).

Participants had at least one visit in perimenopause, and 131 had at least one visit in postmenopause. By year 10, 30% of whites and 34% of blacks had at least one major depressive episode. Higher rates of major depression were associated independently with history of major depression, psychotropic medication use, high body-mass index, and upsetting life events (but not with frequent vasomotor symptoms or reproductive hormone levels). Even after adjustment for significant factors, major depression was two to four times more likely during perimenopause and postmenopause than premenopause. Depression was more common in the first 2 years after menopause (but not later) than in perimenopause.

Comment: This carefully done, long-term, prospective, cohort study demonstrates increased risk for major depression during the menopausal transition, especially within the first 2 years after menopause. Other factors (e.g., history of depression, life events) that increase risk at other stages of life also independently increase the risk. Given this relatively small study sample, further studies are needed to determine definitively whether frequent or severe vasomotor symptoms or hormone levels contribute to risk. Clinicians should view the menopausal transition and early postmenopause as a high-risk time for major depressive episodes and consider antidepressants and/or psychotherapy, which remain the mainstay of treatment, given conflicting data about the benefit of hormonal interventions.

— Deborah Cowley, MD

Published in Journal Watch Psychiatry March 21, 2011

Journal Watch on line 21 maart 2011

Megan Brooks

Megan Brooks is a freelance writer for Medscape.

From Medscape Medical News > Neurology

Burden of Alzheimer's Disease High and Growing: Report

Megan Brooks

March 15, 2011 — Up to 5.4 million Americans are currently living with Alzheimer's disease, a number that is expected to climb to as many as 16 million by 2050, according to the 2011 Alzheimer's Disease Facts and Figures report.

Released today by the nonprofit Alzheimer's Association, the updated report notes that Alzheimer's disease is now the sixth leading cause of death in the United States and the only one among the top 10 that currently cannot be prevented, cured, or even slowed.

Caregiver Burden High

In their annual report, the Alzheimer's Association makes special note of the effect the disease has on caregivers. They estimate that there are now close to 15 million Alzheimer's and dementia caregivers in the United States, providing 17 billion hours of unpaid care valued at more than $202 billion.

People 65 years and older with Alzheimer's disease survive an average of 4 to 8 years after diagnosis, with some living as long as 20 years after diagnosis, which can exact a tremendous physical, emotional, and financial toll on family and friends.

According to the Alzheimer's Association, more than 60% of caregivers rate the emotional stress of caring for a loved one with Alzheimer's or dementia as high or very high and 33% have signs of depression. The physical health of caregivers may also suffer, adding to the nation's healthcare bill. Alzheimer's disease and dementia caregivers had nearly $8 billion in increased healthcare costs in 2010, the Alzheimer's Association reports.

Alzheimer's disease doesn't just affect those with it. It invades families and the lives of everyone around them.

"Alzheimer's disease doesn't just affect those with it. It invades families and the lives of everyone around them," Harry Johns, president and chief executive officer of the Alzheimer's Association, noted in a prepared statement.

A Costly Disease

The Association estimates that total payments for health and long-term care services for people with Alzheimer's disease and other dementias will reach $183 billion in 2011, which is $11 billion more than in 2010.

Medicare and Medicaid costs will make up most of this increase. By 2050, Medicare costs for people with Alzheimer's and other dementias will increase nearly 600%, and the increase in Medicaid costs will near 400%.

"The projected rise in Alzheimer's incidence will become an enormous balloon payment for the nation — a payment that will exceed $1 trillion dollars by 2050," warns Robert Egge, vice president for public policy for the Alzheimer's Association. "It is clear our government must make a smart commitment in order make these costs unnecessary."

The Alzheimer's Association Facts and Figures report is based on a comprehensive compilation of national statistics and information on Alzheimer's disease and related dementias. Its inaugural issue was released in 2007.

The full text of the 2011 edition is available online. It is also published in the March 2011 issue of Alzheimer's & Dementia: The Journal of the Alzheimer's Association.

• EPA 2011: 19th European Congress of Psychiatry

This coverage is not sanctioned by, nor a part of, the European Congress of Psychiatry.

March 16, 2011 (Vienna, Austria) — Nearly three-quarters of healthy individuals report that they would consent to being prescribed a placebo medication if they experienced depression, according new research presented here at EPA 2011: 19th European Congress of Psychiatry.

Most study participants also reported that they do not believe receiving a placebo pill would interfere with their sense of autonomy or their relationship with their treating physician.

"We believe that our data should provoke a discussion with our colleagues about their longstanding opposition to the use of placebo to treat depression in their clinical practices," study investigator Uri Nitzan, MD, a psychiatry resident at Shalvata Mental Health Center in Hod Hasharon, Israel, told Medscape Medical News.

"While discussion about the ethics of prescribing a placebo has largely been the domain of academicians who have focused on its use as a research tool, our study shows for the first time that laypeople — our potential patients — are receptive to the use of placebo treatment for depression," he said.

Led by Shmuel Fennig, MD, head of the outpatient clinic at Shalvata Medical Center, the research team analyzed responses to questionnaires completed by 344 healthy students 18 years or older. The questionnaires were aimed at assessing respondents’ attitudes toward placebo treatments and the physicians who prescribe them.

The investigators decided to focus on depression because the lifetime prevalence of the disorder is reportedly as high as 20% and antidepressants are among the most widely prescribed medications.

At the same time, placebo pills in depressed patients have produced response rates of 30% to 50% with sustained efficacy, minimal side effects, and nominal cost.

Antidepressant Efficacy Questioned

In addition, research is increasingly challenging the magnitude of the reported efficacy of antidepressants over placebo for the treatment of mild to moderate depression. Concern has also been voiced about publication bias in favor of studies with positive results.

Even so, prescribing a placebo for depression, or other conditions, is viewed as unethical and unsound.

Commonly cited reasons are that effective treatment options are available and that the use of a placebo violates the principle of informed consent because physicians are required to hide from their patients the placebo’s mechanism of action to optimize its efficacy.

Also, some physicians believe that the use of a placebo can undermine a patient’s trust in his/her physician and thereby negatively affect the patient-physician relationship and diminish the patient’s autonomy.

Participants in the present survey were provided with a detailed written explanation about the placebo effect and its efficacy and limitations in the treatment of depression. The investigators also confirmed that patients understood the ethical complexity associated with placebo use.

Overall, 243 survey participants (70%) said they would agree to the use of a placebo as a first-line treatment if they developed depression. Also, 248 (73%) said they would consent to receive placebo treatment for other medical conditions.

Also, 275 (88%) said that they did not consider a physician who administered a placebo deceitful, and 256 (75%) did not feel that taking a placebo medication would negatively affect their sense of autonomy or the patient-physician relationship.

"We urge physicians to revise their notion about the use of placebo in clinical practice," Dr. Nitzan said. "In fact, while administering a placebo medication deprives the patient of his/her right to a full informed consent, it seems that in certain settings our patients would opt to waive their rights for complete information."

Placebo-Effect Strategy Used Routinely

In a second study, Kfir Feffer, MD, also a psychiatry resident at Shalvata Mental Health Center, presented data on a study that compared attitudes toward placebo in 81 patients who were currently or formerly depressed and undergoing drug therapy and in 108 healthy controls.

"Contrary to what most physicians assume, our data showed that most patients are willing to use placebo as first-line therapy, even when their depression is severe," Dr. Feffer said.

Ironically, despite controversy about the use of placebo, practitioners routinely aim for a placebo effect using nonpharmacologic and nonsurgical methods, Dr. Nitzan and Dr. Feffer pointed out. For example, the use of verbal suggestions or a confident demeanor can have a placebo effect.

Ethical Issues

"The ethical problems associated with placebo use for conditions without highly effective treatments are related to the inherent deception involved," Paul S. Appelbaum, MD, Elizabeth K. Dollard Professor of Psychiatry, Medicine and Law and director of the Division of Law, Ethics & Psychiatry at Columbia University College of Physicians and Surgeons in New York City, told Medscape Medical News. "Those problems go away if patients consent to use of placebo — as in this study — since they are no longer being deceived."

However, there's an important caveat to this study, he added. "And that is that just because many people are willing to consent to placebo use when healthy, that does not necessary imply that they would feel the same way when they are ill and in need of treatment. Nor does it justify treating them with placebo without their consent."

EPA 2011: 19th European Congress of Psychiatry: Abstracts P02-160 and FC31-02. Presented March 14 and 15, 2011.

Introduction

How much vitamin D is enough? Over the past decade, rickets has re-emerged as a noticeable public health issue in some areas (Lanham-New et al, 2010) and many physicians have been ordering lab values of blood vitamin D levels on their patients and prescribing large doses of the vitamin for the patients whose levels seemed low: <20-30 href="http://books.nap.edu/openbook.php?record_id=13050">Institute of Medicine, 2011). This recommendation is not without controversy.

Clinically, the level of 25-OH vitamin D is assessed because it is the major form of the vitamin and is readily converted to the active form, 1,25 [OH]₂ vitamin D (also called vitamin D₃ or calcitriol) by CYP27B1, primarily in the kidney. A quick scan of PubMed and internet health sites makes clear that there are wide-ranging opinions about how much vitamin D is enough to maintain growth and skeletal health and the role of vitamin D in a broad spectrum of diseases from the common cold and flu to cancer. Mechanistic research on actions of vitamin D in simple cell systems and rodents provides ample evidence of roles for vitamin D in gene regulation; thus, we know that vitamin D can modulate proliferation, differentiation, and apoptosis of many cell types (e.g., Anet al., 2010; Eganet al., 2010), and have effects on immune function, among others. The precise roles of vitamin D in human health, especially those effects not associated with calcium metabolism, and concentration-response curves of the effects in humans are, however, harder to define, especially since well-controlled, randomized in vivo studies in humans are difficult and expensive. The non-calcemic effects of vitamin D may occur along different concentration-dependence curves and require a re-evaluation of what defines adequate daily intake (Bikle, 2010). At present, however, much of what we think about vitamin D requirements and effects in humans is based on epidemiologic data.

How much vitamin D does a human need every day? The answer is not clear, although most current suggestions agree within a factor of ~3-4. As with many dietary components, and especially for vitamin D, which the human body can make upon exposure to sunlight, serum levels vary widely, probably reflecting genetic background, diet, latitude, time spent out-of-doors, body size, developmental stage, and state of health, as well as plasma levels of vitamin D binding protein. The actions of vitamin D could also vary with the expression of various isoforms of the vitamin D receptor and of the activating and inactivating CYPs, and with the presence of various nuclear co-activators. Because rigorous and well-controlled dietary studies are often lacking in humans, recommended daily intakes for vitamins are sometimes as much matters of opinion as of fact, or are extrapolated from studies in model systems. In practice, most urban dwellers do not get much exposure to sunlight and diet generally does not supply sufficient amounts of vitamin D: a serving of fish may contain 200-500 IU; a cup of a fortified dairy product (cow’s milk, yogurt, soy milk) supplies 100 IU. Thus, for many of us, supplementation is required.

The range of scientific opinion favoring increased vitamin D supplementation is well represented by two papers from a 2009 symposium-in-print: Garland et al. (Garland et al., 2009) used epidemiologic data to argue for increasing the average serum levels of vitamin D to 40-60 ng/ml (100-150 nM), a level that they suggest could be achieved by an intake of 2000 IU/day (50 µg/day) and which might decrease the rate of a number of cancers. Vieth (Vieth, 2009) argues that any benefit of vitamin D needs to be balanced by consideration of the toxicity of vitamin D and the related hypercalcemia, that 2000-4000 IU/day is generally satisfactory, and that toxicity should not be expected below 10,000 IU/day.

A prominent proponent of increasing vitamin D intake is Dr. Michael Holick, an endocrinologist at Boston University Medical Center. Holick summarizes his views and research in a recent review (Holick, 2011) and a book (Holick, 2010). To quote from his review:

"Vitamin D deficiency and insufficiency have been defined as a 25-hydroxyvitamin D <20>

Endocrinology Clinics of North America recently published a compendium of articles by researchers who work on aspects of vitamin D metabolism and action (Multiple Authors, 2010). In general, these authors recommend maintenance of plasma levels of 25-OH-D ≥30 ng/mL, requiring a daily intake of ≥1000 IU for most children and adults, and twice that for pregnant and lactating women. Others argue that in special cases, such as that of pregnant women, up to 6000 IU/day are needed (Hollis, 2007).

The recommendations of the Institute of Medicine fall short of the values advanced by these proponents, but do advise higher daily intakes than previously indicated for both calcium and vitamin D, as discussed below. Thus, the recommended daily allowance of vitamin D will continue to be controversial; happily, proponents of greater increases in vitamin D intake generally recommend an amount at or below what the IOM considers the upper limit of 4000 IU/day.

The Linus Pauling Institute at Oregon State University maintains a well-informed website on vitamin D (Higdon and Drake, 2010).

Overview

A report issued on 30 November 2010 by the Institute of Medicine (IOM) of the National Academy of Sciences provides new guidelines for daily vitamin D and calcium supplementation (Institute of Medicine, 2011). These recommendations, referred to as Dietary Reference Intakes (DRIs) are the reference values used for nutrition standards for school meals, food labeling, and are widely employed for assessing vitamin D and calcium sufficiency. These values are more commonly known as the Recommended Dietary Allowance (RDA). The recommendations, new and previous, are shown in Table 1 .

The IOM evaluation focused on three central issues:

• the health outcomes influenced by vitamin D and calcium;
• the vitamin D and calcium requirements to achieve the desirable health outcomes;
• adverse actions arising from over medication.

Background for IOM Study

Increasing medical and public interest over the last 10 years focused on claims of enhanced benefits of vitamin D and calcium on human health. It is also commonly believed that there is negligible risk associated with taking vitamin D and calcium supplements, which are widely available in North America. Scientific research suggested relationships between vitamin D intake and cancer prevention, increased immunity; and possible roles in preventing diabetes or preeclampsia. These findings come on a background of clinical findings that many adults and children may be deficient in vitamin D. Based on this array of issues and several preceding comprehensive reviews (Cranney et al., 2007) [summarized in (Cranney et al., 2008)] and (Chung et al., 2009), the IOM was approached by the U.S. and Canadian governments to conduct a review of data pertaining to calcium and vitamin D requirements and to identify DRIs based on current scientific evidence about the roles of calcium and vitamin D in human health. Health outcomes considered bone and skeletal health, physical performance and falls, cancer and site-specific neoplasms (breast, colorectal, prostate), cardiovascular diseases and hypertension, type 2 diabetes and metabolic syndrome (obesity), falls, immune disorders and infectious diseases, neuropsychological functioning (autism, cognition, and depression), and disorders of pregnancy (preeclampsia).

Summary of IOM Findings

Using an evidence-based approach, the review committee found compelling support favoring a role for calcium and vitamin D in sustaining skeletal health. This, along with analysis of parameters regulating mineral ion homeostasis were used to generate the new DRIs. Evidence for a role of supplemental vitamin D or calcium on non-skeletal outcomes was inconclusive.

The IOM determined that the extent of vitamin D deficiency among the North American population has been overestimated because of inflated cut-points for serum 25(OH) vitamin D. The IOM recommendations now suggest that persons are at risk of deficiency at serum 25(OH) vitamin D levels below 30 nmol/L (12 ng/mL). Some, but not all, persons are potentially at risk for inadequacy at serum 25(OH) vitamin D levels between 30 and 50 nmol/L (12 and 20 ng/mL). Practically all persons are sufficient at serum 25(OH) vitamin D levels of at least 50 nmol/L (20 ng/mL). Serum 25 (OH) vitamin D concentrations above 75 nmol/L (30 ng/mL) are not consistently associated with increased benefit. Serum 25-OH D levels above 125 nmol/L (50 ng/mL) are a cause for concern.

Potential toxicities of vitamin D and calcium were also assessed and revised Upper Limits (UL) for daily supplementation were issued. The UL is the level above which the risk for adverse actions begins to increase. The UL is the highest average daily nutrient intake level likely to pose no risk of adverse health effects for nearly all people in a particular group. The revised ULs are based on increased fortification of foods with nutrients and the use of larger doses of dietary supplements. In general, the risk of adverse effects for vitamin D begins when intake surpasses 4,000 IUs per day. The risk of harm for calcium begins when intake surpasses 2,000 milligrams per day. Side effects of excess vitamin D or calcium most immediately include hypercalcemia and hypercalciuria.

Pharmacology Summary

Serum calcium levels are tightly regulated at 2.2-2.6 mmol/L (9-10.5 mg/dL) for total calcium and 1.1-1.4 mmol/L (4.5-5.6 mg/dL) for ionized calcium. When serum calcium falls, parathyroid hormone (PTH) secretion increases. PTH exerts direct effects on the kidney to retain calcium and on bone, where it mobilizes calcium. PTH also induces the expression of renal 1α vitamin D hydroxylase (CYP1α), which converts 25(OH) vitamin D to its active form, 1,25[OH]₂ vitamin D (calcitriol). Vitamin D, in turn, stimulates intestinal calcium absorption. The major therapeutic uses of vitamin D include treatment of nutritional or metabolic rickets; osteomalacia, particularly in the setting of chronic renal failure; hypoparathyroidism; and osteoporosis. Vitamin D supplementation may help prevent fractures, but the relationship between blood vitamin D concentrations and fracture risk is unclear (Cauley et al., 2008). The IOM investigation failed to find evidence indicating a significant reduction in risk of falls that was related to vitamin D intake or blood levels (Institute of Medicine, 2011). Calcium is used in the treatment of calcium deficiency states and as a dietary supplement. The role of supplemental calcium in supporting skeletal integrity is controversial.

Gender, age, diet, and health impact the requirements for calcium and Vitamin D. Milk, yogurt, cheese, and foods and juices fortified with calcium and vitamin D remain the best dietary sources of calcium and vitamin D. If these do not provide the desired RDA, supplements can be used to supply the balance of recommended daily amounts. A one-cup serving of most dairy products contains 200-300 mg of calcium.

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Abstract and Introduction

Introduction

A series of articles that speculate on the primary prevention of schizophrenia might seem overly optimistic, if not implausible. However, we do not share this degree of nihilism. Much has been learned about risk factors for schizophrenia over the last 3 decades. The incidence of schizophrenia varies between sites and over time.^[1] Some ethnic groups are at increased risk of schizophrenia when they migrate to particular counties but not in their country of origin.^[2,3] Almost certainly, these gradients are driven by environmentally mediated risk factors. It seems reasonable to expect that at least some of these exposures will be potentially modifiable. Epidemiologic research has revealed a range of candidate exposures related to infection and nutrition, which are reviewed in this volume (see Brown and Patterson,^[4] McGrath et al^[5]), as well as a host of other putative risk factors such as psychosocial stress,^[6,7] cannabis use,^[8–10] and advanced paternal age,^[11,12] and other exposures which, in our view, are worthy of careful scrutiny. The stage is now set for the "implausible"—the primary prevention of schizophrenia.

Section 1 of 8

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Summary and Comment

Antihypertensive Treatment in Patients Without Hypertension

Morbidity and mortality were lowered — but only in patients with known cardiovascular disease.

Leonardus Goossens

Jan Mathias Goossens

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More About Bisphosphonates and Atypical Femur Fractures

Long-term bisphosphonate use was associated with a small increase in relative risk.

Summary and Comment Dieting to End ADHD A restricted diet led to equivocal results, and the diet might be difficult to institute. Because studies have suggested possible roles for diet and immunoglobulin (Ig) in attention deficit hyperactivity disorder (ADHD), these researchers compared two diets in children with ADHD (age range, 4–8 years), who were recruited via advertisements. In the multiphase study, 100 unmedicated children (mean age, 6.5) were randomized to an individually tailored, restricted diet or a normal diet for 5 weeks. Restricted-diet responders continued these diets and were rerandomized in a crossover design to challenge with foods that induced low or high IgG levels. Parents were not blinded to diets except for IgG-related foods; behavioral assessments were obtained by physicians, from their own observations and from parent reports, and occurred on different schedules for the two groups. Of 41 patients who completed the restricted diet, 32 met improvement criteria for ADHD or oppositional defiant disorder. Of 30 children entering the second phase, 63% relapsed with a food challenge, but outcomes did not differ by the IgG level of the challenge. Comment: Nonmedication therapies are especially important to study in developing children. This study, however, had several features that may have biased the findings. Physicians administered the assessments to parent informants who knew the diet contents, volunteered for a diet study, and provided a highly tailored diet to their children. Thus, parental objectivity might have been less than if teachers or other informants, who were blind to the diet but able to observe the children, had been used. Combining preschool and school-age children may be problematic, as they respond differently to methylphenidate (J Am Acad Child Adolesc Psychiatry 2006; 45:1284). Even if these findings are replicated, it is not known whether dietary restriction would normalize neurodevelopment, as seen with methylphenidate in imaging studies (e.g., Am J Psychiatry 2010; 167:977). Potential problems with dietary regimens include the psychological effects of nonparticipation in numerous age-appropriate activities (e.g., cake at birthday parties, peer outings to fast food places, same diet as siblings). Practitioners who offer dietary trials to families need to discuss the complicated logistics of tailored diets and lack of knowledge about neurodevelopmental and psychological effects of dietary therapy for ADHD. — Barbara Geller, MD Published in Journal Watch Psychiatry February 28, 2011