Of Mice and Men…and Mental Health

One in five Americans suffers a major depressive episode in their lifetime. Twenty-eight per cent will develop an anxiety disorder, such as post-traumatic stress, phobias, obsessions, or compulsions. Another 15% will fall prey to alcoholism or drug addiction. If you gather 100 people from any square mile on earth, odds are that one will have autism or schizophrenia.

Just about everything we know about drug treatments for psychiatric disorders we learned from mice.  Just how the mouse became our avatar is part tradition and part biological accident. In the past, rats were traditionally used to test experimental drugs. Rats are small enough to be affordable but big enough to make their brains easy to dissect. And they are smarter than mice. You can swiftly teach a rat to solve a maze, for instance, and then test whether your new drug has a side effect of making rats forgetful.

However, rats missed the knockout revolution of the late 1980s. Knockout technology allows researchers to silence, or knock out, individual genes.

With mice, researchers can insert altered DNA in a mouse stem cell, insert the cell in a newly fertilized egg, and insert the egg in a surrogate mother. That egg might develop as a normal mouse or a knockout. The offspring born with knocked-out genes are mated for a few generations to create a pure strain. Once the geneticists perfected these procedures, mice almost instantly assumed the lead role in modeling human mental malfunctions.

These days, you won’t find more mentally ill mice per square mile anywhere than in Bar Harbor, Maine. Mice with anxiety, depression, autism, learning disabilities, anorexia or schizophrenia – they all congregate here. Name an affliction of the human mind, and you can probably find its avatar on this sprucy, secluded island built for America’s richest and most powerful families — including the Rockefellers, the Fords, the Vanderbilts, the Carnegies, the Astors and the Morgans.

The imbalanced mice are kept under the strictest security, in locked wards at the Jackson Laboratory, a nonprofit biomedical facility internationally renowned for its specially bred deranged rodents.

There are no visiting hours, because strangers fluster the mice and might carry in contagious diseases. The animals are attended only by highly qualified caregivers.

But, accurately reproducing a human mental illness in the tiny brain of a mouse is still hugely challenging. The basic structure of a mouse brain is mostly analogous to a human brain.  They have a hippocampus, we have a hippocampus; they have a prefrontal cortex, we have a prefrontal cortex, albeit one that is much larger. We even share about 99% of their genes. But no one would mistake you for a mouse. The mouse is a nocturnal animal with poor eyesight, adapted to fear predators that strike from above. Mice are fundamentally alarmed by light, open spaces, and sudden movements. It is no surprise then, that they manifest depression and anxiety differently than humans do, if they manifest such ailments at all.

You cannot mimic an entire human psyche in a mouse or a rat,” says 
Jacqueline Crawley, a behavioral neuroscientist at the National Institutes of Health (NIH) “Mice aren’t a one-to-one correspondence to humans. But they are better than zero.”

Disorders like depression and schizophrenia are each linked to hundreds of genes. No one gene is likely to make much difference. But genes are only one part of the story. Other clues to human mental health can be found in the neural circuits of mouse brains. By tracing the wiring that connects one brain region to the next, researchers hope to develop more precisely targeted medications.

Many vintage psychiatric drugs, such as Valium, Ritalin, and antipsychotics, were stumbled upon rather than tailor-made to solve a problem. As a result, they are too broad.  They affect more than one type of receptor, on more than one kind of nerve cell, in more than one part of the brain. Many patients decide the cure is not worth the many side effects.

Mice may be the best models we have of psychiatric disorders, but best does not mean great, or even decent. Gerald Dawson, founder and chief scientific officer of P1Vital, a pharmaceutical consulting firm in the United Kingdom, had his heart broken by the mouse mismatch. In the late 1990s, Dawson set out to eliminate the drowsiness from anxiety drugs.The class of drugs he wanted 
to modify, benzodiazepines such as Valium, Xanax, Ativan, and Klonopin, target the GABAa system.

As with most neurotransmitters, the GABAa system is so evolutionarily ancient that it has diversified to serve many purposes. Hence, the brain has six different GABAa receptor types, presumably to perform six different jobs. Dawson had a suspicion that the sleepiness side effect originated from just one of those six receptors. If he could determine which one, corporate chemists could design a molecule that would avoid activating it. He began to make mice.

One by one, he manipulated the receptor genes, breeding a new line of mice each time. With each new strain, he would administer a tiny dose of Valium. If the animals grew drowsy, he knew he had not yet knocked out the right receptor. Knocking out receptor 1 made little difference. Receptor 3 proved too hard to knock out. Receptor 5 seemed to account for the amnesia that people (and mice) experience when they take anxiety drugs. Targeting receptor 2, Dawson identified a chemical that reduced a mouse’s startle response—a measure of anxiety—without impairing its ability to balance. Success!

Or, so he thought. “When these compounds went into humans, they turned out to be just as sedating as the original drugs.”

Dawson blames the mice. “There’s not enough predictability in animal research.”

But, for all Dawson’s frustration with mice, the rodents did yield a couple of interesting drug leads.

That receptor 5 implicated in the amnesia side effect?  An experimental chemical that blocked its action created temporary geniuses: Mice on it were whizzes in the Morris water maze. A drug company is testing the compound to treat people with Down syndrome. And in the process of trying to eliminate drowsiness, Dawson and his team homed in on one of the chemical switches that cause mammals to go to sleep. Ambien locks onto that switch associated with receptor 1.

So, despite the problems, mice remain the undisputed top animal for research on mental health therapies.

Which just goes to show that mice, like us, have minds of their own.

Should Pharma Pay Patients?

Paying patients to take their medicine. It may sound crazy, it may freak out compliance folks, but apparently it works. As previously reported by Word on Health, one -third to one-half of all patients do not take their medication as prescribed, and up to one-quarter never fill their prescriptions. These lapses cost more than $100 billion dollars annually because those patients often get sicker.

To combat this, both the US and Europe, have begun to use financial incentives to improve patient adherence. Here in the US, insurance companies have started to fund incentive schemes as they have found it costs them less in the long run if medication adherence improves. Last year, the New York Times published an article advocating the use of incentives to improve adherence. They cited a successful Philadelphia program whereby people prescribed the blood-thinner drug warfarin could win $10 or $100 each day they took the drug. A computerized Informedix Med-eMonitor pillbox recorded if they took the medicine and whether they won that day. Among patients enrolled in the program, the average amount of incorrectly taken pills or missed pills dropped from 22% to 2.3%.

Another study at Queen Mary’s hospital in London looked at the effect of incentives on the adherence of schizophrenia patients. Investigators found that offering financial incentives increased adherence, improved health and social outcomes and prevented rehospitalizations in 4 out of 5 patients. Preventing re-hospitalization saves a vast amount of money and is far better for the patient.

But, is paying patients really the answer? Maybe not.  A review of patient targeted incentives by The Health Care Foundation concluded that, while “financial incentives can work to bring about discrete, one-off changes in patient behavior…there is insufficient evidence to say that financial incentives can affect complex behavior change, although there is some evidence for temporary improvements.” The key words here are ‘one-off’ and ‘temporary’ – this is a short-term solution, not long-term. In both the aforementioned studies adherence went back down after the incentives finished.  In the study at Queen Mary’s, lead investigator and psychiatry professor Dr. Stefan Priebe admitted that, for most patients, you would probably have to keep the incentive going. The Philadelphia study showed similar results. However, given the potential long-term savings, if payments must continue indefinitely, Dr. Kevin Volpp said “it wouldn’t necessarily be a bad thing.”

So, is there another option? In 2004, Malotte et al. constructed one of the only incentive experiments that simultaneously looked at other methods of improving adherence. They compared different  methods to increase repeat testing in persons treated for gonorrhoea and/or chlamydia at sexually transmitted disease clinics. The results suggested that monetary incentive did not increase return rates. In this study, a reminder telephone call was the most effective intervention.

Although financial incentives work, they are not a realistic long-term solution. Better communication and patient empowerment appears to be the key. Find out how SRxA’s team of Health Outcomes specialists can improve your adherence programs.