Insulin: A Possible Treatment for AD?

March 14, 2009

Researchers at Northwestern University, Evanston, Ill, report that insulin, by shielding memory-forming synapses from injury, may slow or prevent the damage and memory loss caused by amyloid b–derived diffusible ligands (ADDLs)-toxic neuroproteins associated with Alzheimer disease (AD). Findings of the study, which provides additional evidence that AD may be caused by a new, third form of diabetes, were published in the February 10 issue of the Proceedings of the National Academy of Sciences of the United States of America.

Researchers at Northwestern University, Evanston, Ill, report that insulin, by shielding memory-forming synapses from injury, may slow or prevent the damage and memory loss caused by amyloid b–derived diffusible ligands (ADDLs)-toxic neuroproteins associated with Alzheimer disease (AD). Findings of the study, which provides additional evidence that AD may be caused by a new, third form of diabetes, were published in the February 10 issue of the Proceedings of the National Academy of Sciences of the United States of America.

 William L. Klein, PhD, professor of neurobiology and physiology, and researcher, Cognitive Neurology and Alzheimer’s Disease Center at Northwestern University, and colleagues took neurons from the hippocampus, one of the brain’s crucial memory centers, and treated them with insulin and rosiglitazone, an insulin-sensitizing drug that is used to treat persons with type 2 diabetes.

Researchers use isolated hippocampal cells to study memory chemistry; the cells are susceptible to injury caused by ADDLs, which form when snippets of a protein clump together in the brain. In AD, when ADDLs bind to nearby neurons, they damage free radicals and cause a loss of neuronal structures crucial to brain function, including insulin receptors. As the neuroproteins build up in persons with AD and attack memory-forming synapses, the synapses lose their capacity to respond to incoming information, which ultimately results in memory loss and other AD symptoms.

The team discovered that damage to neurons exposed to ADDLs was blocked by insulin, which kept ADDLs from attaching to the hippocampal cells. The protective mechanism of insulin works through a series of steps that reduce the number of ADDL binding sites. This, in turn, results in a marked reduction of ADDL attachment to synapses. The researchers also found that protection with low levels of insulin was enhanced by rosiglitazone.

“Sensitivity to insulin can decline with aging, which presents a novel risk factor for AD. Our results demonstrate that bolstering insulin signaling can protect neurons from harm,” said Klein.

“Recognizing that AD is a type of brain diabetes points the way to novel discoveries that may finally result in disease-modifying treatments for this devastating disease,” added lead author of the same study, Fernanda G. de Felice, PhD, associate professor, Institute of Medical Biochemistry at the Federal University of Rio de Janeiro in Brazil.

Escitalopram, Sertraline May Be New Gold Standards for Depression
Escitalopram and sertraline may be better medications than other antidepressants for the acute treatment of persons with major depression, according to a study published online in the Lancet on January 29. The 2 drugs were more efficacious and better tolerated than others in a review of 12 antidepressants.

Previous studies have shown inconsistent results for the efficacy and acceptability of second-generation antidepressants, many of which are structurally related and have similar mechanisms of action. To address this, researchers led by Andrea Cipriani, PhD, professor, department of medicine and public health at the University of Verona, Italy, conducted a meta-analysis of 117 randomized controlled trials that enrolled 25,928 patients between 1991 and November 2007 and looked at bupropion, citalopram, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, mirtazapine, paroxetine, reboxetine, sertraline, and venlafaxine.

In terms of efficacy, mirtazapine, escitalopram, venlafaxine, and sertraline were superior to duloxetine (odds ratios [ORs]: 1.39, 1.33, 1.30, and 1.27, respectively), fluoxetine (ORs: 1.37, 1.32, 1.28, and 1.25, respectively), fluvoxamine (ORs: 1.41, 1.35, 1.30, and 1.27, respectively), paroxetine (ORs: 1.35, 1.30, 1.27, and 1.22, respectively), and reboxetine (ORs: 2.03, 1.95, 1.89, and 1.85, respectively).

In terms of acceptability, escitalopram, sertraline, citalopram, and bupropion were better tolerated than the other second-generation antidepressants, indicating that 2 of the most efficacious treatments-mirtazapine and venlafaxine-may not be the best overall treatments.

Reboxetine, fluvoxamine, paroxetine, and duloxetine were the least efficacious and least tolerated drugs, making them less favorable options for treatment, the researchers said. Reboxetine was the least tolerated agent and was significantly less effective than all the other antidepressants. Cipriani noted that while he would not prescribe reboxetine as a first-line treatment for his patients, he emphasized that if patients are responding well to the drug, there is no need to discontinue it. He also noted that reboxetine is the only serotonin norepinephrine reuptake inhibitor in the review.

Because escitalopram and sertraline topped the list for both efficacy and acceptability, the researchers said they may be the best treatments during the 8-week acute phase of depression. In addition, the researchers recommended sertraline over escitalopram because it costs less in most countries.

“Sertraline is off-patent, and escitalopram is still branded. We felt the bottom line was to prescribe the cheapest medication,” Cipriani said. However, the researchers added, they did not perform a formal cost analysis, so they cannot make their recommendation “unequivocally because several other costs are associated with the use of antidepressants.”

Recording Greets Patients Seeking Psychiatric Care
Two-thirds of persons referred for psychiatric services following an emergency department (ED) visit are likely to reach only an answering machine when they call for help compared with about 20% of persons calling medical clinics with physical symptoms. Only 10% of all calls to behavioral health clinics in 9 US cities resulted in an appointment scheduled within 2 weeks, according to findings of a study published online in the Annals of Emergency Medicine in October.

Since EDs are safety net providers for uninsured and underinsured patients, they are frequently the location where persons with such mental illnesses as depression are first identified. Because EDs are designed to treat persons with acute illnesses and injuries and are not equipped to evaluate and care for nonemergent behavioral health conditions, persons with depression are most often referred for psychiatric care in the community. Lead author Karin V. Rhodes, MD, assistant professor of emergency medicine and director of the Division of Emergency Care Policy Research at the University of Pennsylvania, found that persons with mental illnesses encounter many roadblocks, such as only voicemail on the other end of the telephone or long waits for an appointment, when trying to access that care.

Trained research assistants posing as patients called to obtain an appointment after receiving a diagnosis of depression in a local ED the night before and being referred for urgent follow-up to the number being called. Callers were able to reach appointment personnel only 31% of the time compared with 78% of calls to medical clinics for physical concerns such as pneumonia and severe hypertension. The “depressed” callers also had to make more calls overall in order to get services: 15% of successful callers with behavioral health conditions had to make 5 or more attempts before reaching clinic personnel compared with 3% of callers with physical concerns.

When callers who reached appointment personnel were unable to get an appointment, either because of insurance or capacity constraints, about 75% received information about alternative providers, but only half of them were given a name and contact information for that provider. About 14% were referred to an ED. Among callers who secured appointments, 61% had to be scheduled for appointments during regular business hours because clinics did not offer night or weekend hours, which the authors say may pose hurdles to employed persons who seek mental health treatment.
“As we approach health care reform, we need to redouble our efforts toward improving mental health parity and design our health systems so as not to discourage people from getting important treatment,” said Rhodes.