Do Antidepressants Really Work?

Three recent books and a series of commentaries and reviews in the press raise the question whether widely used antidepressants are really effective in most of the individuals who take them.  In an especially high-profile article, Marcia Angell, former editor in chief of The New England Journal of Medicine provided a stinging rebuke of psychiatric drugs in general and of course the drug companies that manufacture them. Writing in The New York Review of Books Angell seemed to seriously consider the possibility that “psychoactive drugs are useless”. There were also highly visible pieces in USA Today and Newsweek, the first on a study done by the psychologist Robert DeRubeis headlined “Antidepressant lift may be all in your head,” and the other a cover article on a retrospective “meta-analysis” by the psychologist Irving Kirsch and colleagues of clinical trial data provided to the FDA by pharmaceutical companies and interpreted as evidence that antidepressants were no more effective than placebo in most patients.
Mainstream scientists, however, have and continue to understand the same data as showing that antidepressants work well for at least 20 percent of patients on an initial trial. The scientific dilemma is to separate patients who really need a drug from those who will respond to placebo. In the future this should be possible as the field develops better laboratory tests for measuring relevant brain function. In the meantime, the challenge for doctor and patient is the same as for the scientist – to make as good a decision as possible about whether or not to use an antidepressant in each situation without a laboratory test for guidance.

Off-the-Shelf Drug Rapidly Clears Alzheimer’s Protein in Mice

A drug that is already approved by the FDA for treating a rare skin cancer greatly reduces brain levels of Alzheimer’s-associated amyloid beta (A-beta) protein in mouse models. The drug, bexarotene, works in the mice by boosting the activity of apolipoprotein E, a fat-carrying molecule that normally helps to clear A-beta from the brain (see “Why Does apoE4 Make Alzheimer’s More Likely?”). If bexarotene’s A-beta clearance effect in mice translates to humans, then it may prove useful against Alzheimer’s—though perhaps more as a preventive than as a treatment for established Alzheimer’s dementia.
“This is quite an exciting paper; the effect on A-beta clearance is dramatic and rapid,” says Sam Gandy, who chairs the Alzheimer’s research program at Mount Sinai School of Medicine.
“The drug reduces the soluble forms of A-beta within hours,” says Paige Cramer, the PhD student who was first author of the paper. Cramer works in the laboratory of Gary Landreth, director of the Alzheimer’s Research Laboratory at Case Western Reserve University School of Medicine in Cleveland, Ohio, and principal investigator for the study, which appears today in Science Express.
The study is based on observations, going back to the early 1990s, of a strong connection between Alzheimer’s and apolipoprotein-E (apoE). Researchers have found that apoE proteins normally bind strongly to A-beta, and that apoE4, one of the normal variants of apoE in the population, is linked to a much higher and earlier risk of Alzheimer’s.
Recently scientists have determined the likely reason for the connection: A-beta aggregates, which have a high affinity for fat molecules, normally cling to the fats carried by apo-E molecules, and in this way are brought into, and disposed within, immune-type cells in the brain called microglial cells. ApoE4 is comparatively inefficient at handling fat molecules, and so it does a poorer job of removing A-beta aggregates. Regardless of which apoE variants a person has, boosting apoE production should enhance the clearance of A-beta from the brain—mainly because more apoE means more A-beta-carrying capacity. ApoE production also seems to stimulate the readiness of microglial cells to digest A-beta aggregates.
Bexarotene, a drug approved by the FDA in 2000 for cutaneous T-cell lymphoma, binds and activates the retinoid X receptor, a protein that in brain cells happens to be involved in promoting apoE production. Since bexarotene can cross from the bloodstream into the brain, Landreth reasoned that it might work as an apoE-boosting, A-beta-clearing drug.
In the new study, he and Cramer and their colleagues tested it on “Alzheimer’s mice” that had been genetically engineered to overproduce aggregates of A-beta. Such mice, as they age, show subtle cognitive deficits – which are presumed to be caused by small, soluble “oligomer” aggregates of A-beta. The team found that within only a few days, a modest daily dose of the drug reduced soluble forms of A-beta in the mouse brains by about one-third, compared to control mice, and reduced insoluble A-beta deposits, or “plaques,” by about half. They observed microglial cells stuffed with A-beta, as well as increases in the levels of proteins that normally work with apoE. In mice that lacked apoE, these A-beta clearing effects did not occur. The treated mice showed immediate improvements in standard memory tests, suggesting that the drug quickly reduced brain levels of toxic A-beta oligomers.
Because the drug is already FDA-approved, its safety is already mostly known. “For skin cancer treatment, patients are often on bexarotene doses that are far higher than [the human equivalent of] the dose that we used in mice, and for long periods,” says Cramer. Long-term use of bexarotene can raise triglyceride levels and have other potentially dangerous side-effects, but Cramer says that such side-effects are generally treatable with other drugs, and bexarotene is tolerated by most cancer patients.
Cramer says that she and Landreth are forming a company and hope to set up clinical trials of bexarotene against Alzheimer’s. Even without such trials, neurologists in the U.S. could legally prescribe the drug “off-label” to people with Alzheimer’s, since bexarotine is already approved by the FDA.