Long-Term Use of Antidepressants For Depressive Disorders and the Risk of Diabetes Mellitus

Andersohn F, Schade R, Suissa S, Garbe EAm J Psychiatry 2009 May 166(5):591-8
Commentary from Leo Sher and Maria Oquendo
Changes Clinical Practice: Patients receiving a moderate to high daily dose of antidepressants for greater than 12 months should be evaluated for impaired glucose tolerance/diabetes.
The authors of this study have shown that the long-term use of antidepressants in at least moderate daily doses was associated with an increased risk of diabetes. This finding indicates that blood glucose levels should be checked periodically in patients on long-term antidepressant therapy.
Depression is a severe condition that frequently requires a long-term treatment. The authors examined the relationships between the use of antidepressants and a risk of diabetes mellitus in patients of at least 30 years of age and whether the risk is influenced by treatment duration or daily dose. The authors used data from the UK General Practice Research Database (GPRD), which contains medical records for several million patients from about 450 general practices in the UK. Criteria for inclusion in the study included but were not limited to the following: (1) patients had to be at least 30 years of age at the time of cohort entry (only patients ≥30 years of age were included in the cohort to ensure that incident cases of diabetes were most likely to be type 2 diabetes); (2) have had no diagnosis of diabetes or impaired glucose tolerance and no treatment with oral antidiabetics or insulin before cohort entry; and (3) have had a diagnosis of depression within 180 days before or 90 days after cohort entry. Antidepressants were classified into tricyclic and tetracyclic antidepressants, selective serotonin reuptake inhibitors (SSRIs), monoamine oxidase (MAO) inhibitors, and the heterogeneous group of mixed-action "other antidepressants." Recent long-term use of antidepressants in moderate or high daily doses was associated with an increased risk of diabetes whereas recent use of shorter duration, use in lower daily doses, former use, and past use were not. This association was observed for both tricyclic antidepressants and SSRIs. In the analysis of individual antidepressants, increased risk estimates were observed for long-term use of amitriptyline, fluvoxamine, paroxetine, and venlafaxine. The results of this study are consistent with a recent report published by the Diabetes Prevention Program Research Group: the randomized Diabetes Prevention Program trial found an increased risk of diabetes in high-risk patients who used antidepressants.[1] A significant strength of this study is that all information was registered prospectively so that recall bias could be ruled out. An important limitation of this study is that weight gain during follow-up was not systematically recorded, and it was not included in the analysis. It is important to note that depression itself increases risk for diabetes. This may contribute to the results observed by the authors of the study. This study indicates that patients receiving antidepressants long-term should be evaluated for impaired glucose tolerance/diabetes. This study contributes to our knowledge of the use and possible adverse effects of antidepressants in the treatment of depression.

Alogliptin Delayed; Cancer Concerns With Insulin Glargine

June 30, 2009 (Tokyo, Japan) — As expected, the US Food and Drug Administration has turned away the investigational diabetes drug alogliptin (Takeda Pharmaceutical) because of insufficient cardiovascular safety data [1]. The FDA decision will delay the drug's possible launch by at least two years, according to company officials.
Takeda received a "complete-response" letter on Friday, and the letter, according to a company press release, stated that existing clinical data were insufficient to meet the new cardiovascular safety requirements requested by the FDA.
The decision regarding alogliptin, a dipeptidyl peptidase-4 (DPP-4) inhibitor, was expected, given that the FDA issued a guidance document in December 2008 advising sponsors to conduct long-term clinical trials or provide equivalent evidence ruling out an unacceptable cardiovascular safety risk for new diabetes drugs seeking approval. Although the new drug application for alogliptin was filed in 2007, the new cardiovascular safety hurdle applied to all diabetes drugs, even those in development.
The recommendation emerged after concerns were raised about the cardiovascular safety of drugs in this field, especially the thiazolidinediones, including rosiglitazone (Avandia, GlaxoSmithKline). Takeda was informed in March that the available safety data were insufficient for approval and is currently in discussions with the FDA about the protocol for a new study.
Is There a Cancer Risk With Lantus?
The European Association for the Study of Diabetes (EASD) is urgently requesting further study into a possible link between insulin glargine (Lantus, Sanofi-Aventis) and cancer [2].
Concerns are raised based on a large German study of 127 000 patients that showed a dose-dependent increase in the risk of cancer among those treated with insulin glargine. The findings were replicated in a Swedish population-based study, while a Scottish study showed a nonsignificant increase in the risk of breast cancer. Data from a UK database showed no association between insulin glargine and cancer.
The EASD has communicated its concerns to European regulators but urges caution in interpreting the results. Further study is still needed, and in the meantime patients should continue taking the diabetes medication for glucose control or speak with their doctor if they are worried about the risk. The American Diabetes Association said the findings "are conflicting and inconclusive" and "cautions against overreaction until more information is available. [3]"

Vitamin D Deficiency Linked to Greater Risk for Primary Cesarean Delivery

December 23, 2008 — Vitamin D deficiency in pregnancy is associated with increased odds of primary cesarean delivery, according to the results of a study reported in the December 23 Online First issue of the Journal of Clinical Endocrinology & Metabolism.

"At the turn of the 20th century, women commonly died in childbirth due to 'rachitic pelvis,' " write Anne Merewood, MPH, IBCLC, from Boston University School of Medicine in Massachusetts, and colleagues. "Although rickets virtually disappeared with the discovery of the hormone 'vitamin' D, recent reports suggest vitamin D deficiency is widespread in industrialized nations. Poor muscular performance is an established symptom of vitamin D deficiency, [and] the current US caesarean birth rate is at an all-time high of 30.2%."

The objective of this study was to determine the relationship between maternal serum 25-hydroxyvitamin D [25(OH)D] levels and the rate of primary cesarean delivery.

At an urban teaching hospital in Boston, with 2500 births per year, the investigators measured maternal and infant serum 25(OH)D at birth in 253 mother-infant pairs, of whom 43 (17%) had a primary cesarean delivery. Demographic and medical data were abstracted from the maternal medical record.

The rate of cesarean delivery was 14% in women with 25(OH)D levels of 37.5 nmol/L or higher and 28% in women with serum 25(OH)D levels less than 37.5 nmol/L (P = .012). The risk for cesarean delivery was nearly 4-fold higher in women with 25(OH)D levels less than 37.5 nmol/L vs those with 25(OH)D levels of 37.5 nmol/L or more, based on multivariable logistic regression analysis controlling for race, age, educational level, insurance status, and alcohol use (adjusted odds ratio [OR], 3.84; 95% confidence interval [CI], 1.71 - 8.62).

Limitations of this study include sample too small to determine whether vitamin D deficiency is related to specific types of cesarean deliveries, such as cephalopelvic disproportion or failure to progress.

"Vitamin D deficiency was associated with increased odds of primary caesarean section," the study authors write. "A randomized clinical trial is now needed to determine if adequate vitamin D supplementation during pregnancy to raise blood levels above 37.5 nmol/L can reduce the caesarean section rate."

More Research Urgently Needed on Off-Label Use of 14 Drugs

November 25, 2008 — Fourteen drugs have been identified that most urgently require research regarding off-label uses, according to the results of a retrospective, cross-sectional study and quantitative analysis reported November 24 online ahead of print in the December issue of Pharmacotherapy. The lead author is Surrey Walton, PhD, an assistant professor of pharmacy administration at the University of Illinois at Chicago.

"The issue is that most off-label uses have less evidence and have been less rigorously scrutinized than indications that have gone through the [US Food and Drug Administration] FDA approval process," senior author Randall S. Stafford, MD, PhD, an associate professor of medicine at the Stanford Prevention Research Center in California, told Medscape Medical News. "It is not that there are necessarily harms associated with off-label use, but more that physicians are practicing without the usual reassurance that their use of these drugs is safe and efficacious. There are, of course, some examples of harms that have been identified, as with the use of the atypical antipsychotic medications in dementia."

Earlier research by Dr. Stafford's group suggested that 21% of drug use is for off-label indications, and that of these uses, 76% lack strong evidence. His current research suggests that the most common conditions prompting off-label use with limited evidence are psychiatric conditions, including depression and bipolar disorder.

"[The study authors] have applied their craft of pharmacoeconomic analysis and statistical modeling to a pertinent practice issue: how to rank order priorities for studying off-label prescribing," C. Lindsay DeVane, PharmD, professor and vice chair for research at the Department of Psychiatry & Behavioral Sciences, Medical University of South Carolina in Charleston, told Medscape Medical News when asked for independent comment.

"[They] have performed a service to the field by providing a quantitative approach to rank ordering off-label prescribing practices for further evaluation," Dr. DeVane said. "Their proposal of how to select marketed drugs for further evaluation is a welcome and informed scientific approach to translate clinical practice into evidence-based medicine."

The goal of this study was to develop a prioritized list of individual drugs for which future research regarding off-label uses is most warranted, using a commercial database providing ongoing estimates of drug prescribing practices of US office-based physicians and an Internet database of comprehensive evidence-based drug information.

"Presumably, the extent of off-label prescribing will vary according to where a specific drug resides in its life cycle," Dr. DeVane pointed out. "Early on, after initial marketing, off-label prescribing may be high as clinicians explore peripheral indications. Such an example would be prescribing for the anxiety disorders following the marketing of the selective serotonin reuptake inhibitors as treatments for depression."

Volume of off-label use with inadequate evidence, drug safety, and cost and market considerations were evaluated, and the number of off-label drug uses by indication from January 1, 2005, to June 30, 2007, in the United States were estimated from nationally representative prescribing data. These indications were then categorized based on the adequacy of scientific support, and a priority score was calculated from a model incorporating black-box warnings and safety alerts, drug cost, date of market entry, and marketing expenditures, as well as adequacy of scientific support. Varying key model parameters allowed performance of sensitivity analyses.

"Not surprisingly, high volume of use, safety issues, and cost and market considerations were the major factors that identified an off-label prescribing practice as a research priority," Dr. DeVane said. "The authors stayed within their scientific bounds and did not address the appropriateness of off-label prescribing, a practice that is sometimes common and extensive."

For a substantial number of drugs, there was a high volume of off-label prescribing despite the absence of good evidence, especially for antidepressants, antipsychotics, and anxiolytic-sedatives.

"The large magnitude of off-label use suggests that use is not limited to last-resort use in patients who have failed all approved medications," Dr. Stafford said. Although pharmaceutical companies are largely prohibited from marketing off-label uses, they may use exceptions, such as the ability to share published research that supports off-label uses with physicians, he said.

Quetiapine (Seroquel), which was FDA-approved in 1997 for treating schizophrenia, was found to have the highest rate of off-label uses with limited evidence (76% of all uses). Furthermore, this antipsychotic is expensive ($207 per prescription) and heavily marketed and carries a "black-box" warning from the FDA.

Both the base model and sensitivity analyses suggested a high priority for future research regarding 14 drugs. These drugs, and their most common off-label use, are quetiapine (bipolar maintenance), warfarin (hypertensive heart disease), escitalopram (bipolar disorder), risperidone (bipolar maintenance), montelukast (chronic obstructive pulmonary disease), bupropion (bipolar disorder), sertraline (bipolar disorder), venlafaxine (bipolar disorder), celecoxib (fibromatosis), lisinopril (coronary artery disease), duloxetine (anxiety disorder), trazodone (sleep disturbance), olanzapine (depression), and epoetin alfa (anemia of chronic disease).

Limitations of this study include the evaluation only of off-label use involving drugs used for indications not approved by the FDA, and not of other forms of off-label use; a systematic review of the clinical literature on specific drugs was not conducted; coding off-label uses was only applied to the available data on individual drugs and not to whether another drug in the same class was approved; the sample of physicians was not strictly random; and difficulty matching the International Classification of Diseases, Ninth Revision (ICD-9), codes from the National Disease and Therapeutic Index with the indications listed by the FDA and Drugdex.

Dr. Stafford recommends several forms of additional research, beginning with a rigorous systematic review of published and unpublished evidence.

"If evidence remains insufficient after this, then additional studies should be conducted," Dr. Stafford said. "These could take 2 forms: the use of observational data to assess safety and efficacy of off-label use or undertaking additional clinical trials on the off-label uses."

Soon after a new drug is introduced into clinical practice, anecdotal experiences of physicians attempting off-label use may suggest directions that should be explored in organized clinical trials, according to Dr. DeVane: If these trials indicate efficacy and safety, additional FDA-approved indications should result in a dramatic decline in off-label use.

"The ultimate value of this report will depend upon its adoption by the pharmaceutical industry, funding agencies, and consumer groups to guide investment of limited resources into postmarketing, phase 4 studies of already approved drugs," Dr. DeVane concluded. "Knowledge of a drug's pharmacology continues to accumulate throughout its availability for study. How we move from an initial approval to realization of the full extent of the medicinal value of drugs is a process that is both criticized and supported."

Obesity surgery helps diabetics, study finds

CHICAGO, Jan 22 (Reuters) - Weight loss surgery can be especially helpful to patients with diabetes and can even help them reverse the disease, Australian researchers reported on Tuesday.

They found that obese patients with diabetes who had weight loss surgery were five times more likely to get their disease under control than those who dieted -- probably because they lost more weight.

The study, published in the Journal of the American Medical Association, is among the first to look at surgery as a potential treatment for obese patients with type 2 diabetes.

Type 2 diabetes, which is closely linked to obesity, is on the rise worldwide. At least 170 million people are estimated to have the disease and the number is predicted to at least double by 2030.

Bariatric surgery, which involves altering the digestive system to limit food intake, has been growing at a rapid pace, with the number of procedures rising to 200,000 in the United States in 2006, from just 13,000 in 1998.

John Dixon of Monash University in Melbourne and colleagues wanted to see if surgically induced weight loss could be an effective treatment for type 2 diabetes.

Dixon's team studied 60 obese people with a body mass index greater than 30 but less than 40. Body mass index or BMI is a ratio of height and weight. A BMI of 30 or greater is considered obese.

Patients got either surgery or a weight loss program that focused on diet and lifestyle changes.

Those in the surgery group were treated with an adjustable gastric banding device that limits food intake. Both groups also received conventional diabetes medications.

At the end of two years, 73 percent of the diabetics who had surgery no longer had diabetes, compared with 13 percent of those in the diet group. People who got surgery also needed far fewer diabetes medications.

The surgical group on average lost 20.7 percent of their body weight, compared with 1.7 percent in the diet and lifestyle group. There were no serious complications in either group.

It was the large weight loss, not the surgery per se, that helped the patients, the researchers said.

"This has important implications as it suggests that intensive weight-loss therapy may be a more effective first step in the management of diabetes than simple lifestyle change," they wrote.

In a commentary in the same journal, Drs. David Cummings and David Flum of the University of Washington in Seattle said policy and health leaders will need to balance the costs and risks of surgery against the chance of reversing diabetes.

But, they said, "the insights already beginning to be gained by studying surgical interventions for diabetes may be the most profound since the discovery of insulin."

(Editing by Maggie Fox and Cynthia Osterman)

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Zinc an Over view

Zinc is an essential mineral that is important for immune function, wound healing, normal taste and smell, and is needed for DNA synthesis. Zinc also supports normal growth and development during pregnancy, childhood, and adolescence.

• Zinc is a co-factor in DNA and protein synthesis and cell division. It is believed to be important in wound healing.


• The UK recommended ranges are 5.5-9.5 mg/day for males and 4.0-7.0 mg/day for females.


• The body contains 2 to 3 g of zinc (Zn), found mainly in bones, teeth, hair, skin, liver, muscle, leukocytes, and testes.


• One third of the of zinc found in plasma is attached loosely to albumin, and about two thirds is firmly bound to globulins.


• Absorption of zinc salts from food is approximately 20-40%. Absorption of zinc is higher from fish and meat but lower from whole-grain bread and cereals, where phytate content impairs absorption. Zinc is mainly lost from body in faeces


• Meat, liver, peas, beans, eggs, and seafood (especially oysters) are good sources of zinc.                                  

Mild deficiency of Zinc  may cause no obvious symptoms, whereas severe deficiency may cause most or even all of the following features.

• Anorexia, lethargy, diarrhoea


• Growth retardation, delayed sexual maturation, hypogonadism and hypospermia


• Alopecia, dermatitis, paronychia


• Mental retardation, impaired nerve conduction and nerve damage


• Hepatomegaly


• Immune disorders and susceptibility to infections


• Iron deficiency anaemia


• Macular degeneration, night blindness


• Impaired taste and smell


• Impaired wound healing


• Maternal zinc deficiency may cause anencephaly in the fetus.

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Antihypertensive Treatment May Help Maintain Memory

Caroline Cassels
Medscape Medical News 2007. © 2007 Medscape

September 27, 2007 — New research indicates antihypertensive treatment leads to increased, joint activation of brain areas responsible for memory performance — a finding that suggests such treatment may help patients maintain cognition and memory.
A study led by J. Richard Jennings, PhD, from the University of Pittsburgh, in Pennsylvania, and presented at the American Heart Association (AHA) 61st Annual Fall Conference of the Council for High Blood Pressure Research, showed patients had a 2-fold increase in the joint activation of these areas of the brain after a year of treatment with either the angiotensin-converting enzyme lisinopril or beta blocker atenolol.
While there is an established link between hypertension and mild cognitive deficits, the mechanism has not been clear. Previous research by Dr. Jennings's team used brain imaging to examine the correlation among the activation of the prefrontal areas, parietal areas, and amygdala/hippocampus in hypertensives compared with controls and found it was higher in individuals with high blood pressure.