Shining Light on Madness

At Novartiss research lab in Cambridge, Massachusetts, a large incubator-like piece of equipment is helping give birth to a new era of psychiatric drug discovery. Inside it, bathed in soft light, lab plates hold living human stem cells; robotic arms systematically squirt nurturing compounds into the plates. Thanks to a series of techniques perfected over the last few years in labs around the world, such stem cellscapable of developing into specialized cell typescan now be created from skin cells. When stem cells derived from people with, say, autism or schizophrenia are grown inside the incubator, Novartis researchers can nudge them to develop into functioning brain cells by precisely varying the chemicals in the cell cultures.

Theyre not exactly creating schizophrenic or autistic neurons, because the cells arent working within the circuitry of the brain, but for drug-discovery purposes its the next best thing. For the first time, researchers have a way to directly examine in molecular detail whats going wrong in the brain cells of patients with these illnesses. And, critically for the pharmaceutical company, there is now a reliable method of screening for drugs that might help. Do the neurons look different from normal ones? Is there a flaw in the way they form connections? Could drugs possibly correct the abnormalities? The answer to each of these questions is a very preliminary yes.

The technique is so promising that Novartis has resumed trying to discover new psychiatric drugs after essentially abandoning the quest. Whats more, its been introduced at a time when knowledge about the genetics behind brain disorders is expanding rapidly and other new tools, including optogenetics and more precise genome editing (see Neurosciences New Toolbox), are enabling neuroscientists to probe the brain directly. All these developments offer renewed hope that science could finally deliver more effective treatments for the millions of people beset by devastating brain disorders.

A revival in psychiatric drug development is badly needed: there hasnt been a breakthrough medicine for any of the common mental illnesses, including schizophrenia, bipolar disorder, or severe depression, in roughly 50 years. From the late 1940s through the 1960s, a series of serendipitous discoveries, beginning with the finding that lithium could help bipolar patients, transformed the treatment of the mentally ill. It became possible to quiet the hallucinations and delusions of schizophrenia and offer a drug to the severely depressed. The sudden availability of pharmacological relief transformed psychiatry and played a role in closing down many of the mammoth mental hospitals of the era. But then, almost as suddenly as it had started, the revolution stalled.

Many of the drugs discovered in the 1950s and 1960s are still the most effective treatments available for schizophrenia, anxiety disorders, and depression. But while these medications have improved the lives of some patients, they are ineffective for others, and they are woefully inadequate in treating many of the worst symptoms. Whats more, the drugs can have severe side effects.

Take schizophrenia, for example. Existing antipsychotic drugs can make the hallucinations and delusions disappear, but they dont improve the so-called negative symptomsthe disruption of emotions such as pleasure, which can leave people uninterested in communicating or even in living. Existing drugs also have no effect on the way schizophrenia can impair concentration, decision-making, and working memory (critical in such tasks as language comprehension). These debilitating cognitive problems make it impossible for people to work and difficult for them even to make the seemingly simple logical choices involved in everyday life. Insidiously, such symptoms can strike high-performing individuals, often in their late teens. People dont understand, says Guoping Feng, a professor of neuroscience at MIT who studies the neural basis of psychiatric disorders. They ask, once a patient is given antipsychotic medicine, Why cant you go to work? But [those with schizophrenia] cant work because they dont have cognitive functions, they dont have normal executive functions. And there are no drugs for this. On top of that are the side effects of antipsychotic medicines, which can include Parkinsons-like movement disorders, dramatic weight gain, or a potentially deadly loss of white blood cells. In short, the illness destroys many patients lives.

We were led down a path that said depression is about being a quart low in serotonin, and schizophrenia means you have a bit too much dopamine on board. But that just isnt how the brain works. The brain isnt a bowl of soup.

Finally, many people with brain disorders are simply not helped at all by available drugs. Antidepressants work well for some people but do nothing for many others, and there are no effective drug treatments for the social disabilities or repetitive behaviors caused by autism.

Overall, neuropsychiatric illness is a leading cause of disability. According to the National Institute of Mental Health (NIMH) in Rockville, Maryland, 26 percent of American adults suffer from a diagnosable mental disorder in any given year. Severe depression, the most common of these disorders, is the leading cause of disability in the U.S. for individuals between 15 and 44. Around 1 percent of the American population suffers from schizophrenia; one in 68 American children is diagnosed with an autism spectrum disorder.

Though the need for better treatments is unquestionable, drug companies had until very recently simply run out of good ideas. The drugs developed in the 1950s and 1960s were discovered by accident, and no one knew how or why they worked. In the subsequent decades, drug researchers reverse-engineered the medications to identify the brain molecules that the drugs acted on, such as dopamine and serotonin. In retrospect, however, scientists now realize that while tweaking the levels of these chemicals addressed some symptoms of psychiatric disorders, it was a crude strategy that ignored the biological mechanisms underlying the illnesses.

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Shining Light on Madness