The Rest of the Story

The-Scientist has a nice roundup of developments in pharmaceuticals for neurological and psychiatric conditions.  There is one that they do not mention, though: RU-486. Since I always like to add something to news or science articles I find on the 'net, I provide a little bit of information about that.

Volume 18 | Issue 20 | 48 | Oct. 25, 2004
The Ailing Brain: A Pressing Need for New Treatments
Research in Alzheimer disease abounds, but the pipeline also looks promising for other neurological and psychiatric conditions
By Karen Pallarito

Neuroscience has made impressive strides since 1936 Nobel laureates Henry Hallett Dale and Otto Loewi first showed that chemicals transmit signals between nerve cells. Yet decades later, scientists have only begun to tap potential therapeutic treatments that target brain and nervous system disorders.

Enormous demand exists for medicines, vaccines, and devices that not only alleviate neurological or psychiatric symptoms, as many current treatments do, but also stem the progression of these debilitating conditions. Statistics from the World Health Organization underscore the unmet need: As many as 50 million people worldwide have epilepsy, 37 million live with dementia, 5.5 million die each year of stroke, and 121 million have depression. Demand will likely grow as the population ages, people live longer, and treatments for these conditions improve.

The current market for neurological and psychiatric treatments, at roughly $80 billion for the Group of Seven industrialized nations, could climb to $120 billion in five to 10 years, predicts Kate Hohenberg, therapeutic area director at Decision Resources, a Waltham, Mass.-based pharmaceutical research and advisory firm. The projected figure reflects growth of some existing drugs and the introduction of new therapies. Analysts anticipate some impressive winners, even blockbusters, among today's experimental treatments.

The article includes a review of some of the recently-marketed products, and some that may come to the market soon. These include Neurochem's Alzhemed, a drug that seeks to prevent the sticky build-up of beta-amyloid plaque in the brain. The amyloid plaque is one of the pathological features of Alzheimer disease. The drug is entering Phase III trials, the last phase before a drug is approved. They also mention Prana Biotechnology's Clioquinol. That is a drug that binds to copper and zinc; this effect slows the development of plaques. What is interesting here is the history of the drug:

Clioquinol, first introduced decades ago as a diarrhea medication, caused nerve damage and blindness in thousands of people, particularly Japanese; the oral form of the drug eventually was pulled from the market.

That does not look promising. But there are two factors to consider. First, we now have a much better understanding of pathophysiology. and genomic medicine. As a result, we are in a much better position to deal with whatever toxicity the drug may have. Second, the risk presented by a drug must be understood in the context of the condition one is trying to treat. Risks that are plainly unacceptable for treatment of diarrhea may be acceptable for treatment of Alzheimer disease.

The article goes on to mention some upcoming products for treatment of depression, neuropathic pain, insomnia, Parkinson disease, stoke, and multiple sclerosis.  One drug that is promising, but which was not mentioned in the article, is mifepristone, also known as RU-486. 

Mifepristone has been used to treat Cushing disease, induce abortions, and as an emergency contraceptive.  It currently is in Phase II trials  for treatment of bipolar depression.  An earlier study  at Stanford indicated that the drug can be used to treat psychotic depression.  Subsequent studies (1  2)  have offered some degree of confirmation of effectiveness. 

It may seem counterintuitive that an abortion pill could treat severe depression.  However, there is a good theoretical foundation for this dual effect:

Originally mifepristone was developed as a steroid treatment for Cushing's disease, to block the adrenal hormone cortisol.  But since progesterone receptors and cortisol receptors are structurally related, mifepristone also blocks progesterone, an effect that makes it useful as an abortifacient and, in smaller doses, as an emergency contraceptive.

Research over the last 17 years has revealed that cortisol, a hormone released during times of significant stress, is extremely elevated in psychotically depressed patients.  It seems their sustained levels of cortisol create a chronic stress reaction.  This in turn may cause psychotic depression, including memory problems, sleep disturbances and hallucinations.

Blocking glucocorticoid receptors is a serious business.  It is unlikely that such a treatment could be used for chronic maintenance treatment of depression.  However, psychotic depression is imminently life-threatening, so a higher risk may be appropriate.  

Traditionally, patients with psychotic depression receive one of two treatments:  combined antidepressant and antipsychotic medication, or electroconvulsive therapy (ECT).  Even when effective, both treatments are relatively slow and can leave symptoms that last for months.

"With mifepristone (RU-486) there's a very quick intervention.  The patients often feel better and then we can put them on conventional antidepressants without the antipsychotics or ECT," Schatzberg says.  "What's interesting is that the results are not effervescent.  The patients feel better and it lasts.  Nobody's had to come back, nobody's had to undergo ECT."

[presumably, Dr. Schatzberg actually said "evanescent," not "effervescent."]

It will be years before we know if mifepristone has any clinical utility.  Even if it does not pan out, it is possible that research of other glucocorticoid receptor modulators could lead to something useful.  If it does turn out to be a valuable drug, it will be interesting to see what the political response is, when it is introduced for its new purpose.