Tackling Anxiety With Less Angst

Jennifer Couzin-Frankel
2009-06-18 (All day)

From panic attacks to an excessive fear of being judged by others, anxiety is the most common mental health disorder. Yet it has few adequate treatments. A novel compound may offer new hope, although it has a long way to go before proving its worth for patients.

Today's antianxiety drugs have two major drawbacks. Drugs belonging to one class, the benzodiazepines, which includes Valium, can be addictive and produce symptoms such as insomnia or restlessness when withdrawn. Drugs of another class, the antidepressants, including selective serotonin reuptake inhibitors such as Prozac, take weeks to kick in, unacceptably long for someone suffering severe anxiety.

A couple of years ago, psychiatrist Rainer Rupprecht of the Ludwig Maximilian University and Max Planck Institute of Psychiatry, both in Munich, Germany, and his colleagues teamed up with the drug company Novartis to probe a new antianxiety compound, called XBD173. The compound seemed to do what the benzodiazepines do, boosting activity of a neurotransmitter called GABA, which in turn depresses the central nervous system. But it did so indirectly, by acting on steroids in the brain that then modulate GABA receptors. XBD173 also seemed to help anxiety in rodents, based on chemical changes in their brains.

Rupprecht and his colleagues wanted to find out whether XBD173 has the same side effects as current antianxiety drugs. So the team gave XBD173 to rats twice a day for 5 days. When anxiety was chemically induced in the animals, the compound seemed about as effective as a common benzodiazepine, alprazolam, at alleviating it (measured partly by the rats' interest in exploring or playing with other rats). But the side effects associated with benzodiazepines, such as drowsiness, were missing. One reason could be that XBD173 acts on the brain in a different way than other antianxiety drugs.

Next, the scientists turned to humans. They used one of the same tactics they'd applied to the animals, something called a CCK-4 challenge. Here, a chemical called CCK-4 is injected and induces a panic attack, leading to feelings of intense anxiety, fear, sweating, nausea, and other symptoms. CCK-4 has often been used in studies that try to better understand anxiety but not, to Rupprecht's knowledge, in those examining how a drug works.

In the new study, 71 healthy young men got a placebo, alprazolam, or XBD173 for 7 days. Then they were given CCK-4, while still on the antianxiety drugs. The highest dose of XBD173 worked about as well as alprazolam at relieving anxiety. And although the side effects from XBD173 were similar to those of placebos, such as gastrointestinal problems, there were far fewer problems than with alprazolam. For example, 57% of those on alprazolam experienced withdrawal symptoms, compared with less than 7% on the new compound. The study was largely paid for by Novartis and is published online today in Science.

This "looks like a drug that we have been waiting for [for] years," says Borwin Bandelow, a psychiatrist at the University of Göttingen in Germany. But, he cautions, it's not ready for prime time yet. One key question is whether the CCK-4 challenge accurately mimics the real panic attacks seen in patients. Vassilios Papadopoulos, who studies steroid biochemistry at McGill University in Montreal and has spent years working on the protein that XBD173 targets, is also hopeful. But like Bandelow, he isn't sure of XBD173's long-term effects—particularly in cells such as the testes and adrenal glands that boast very high levels of the protein the new drug goes after.

Rupprecht agrees that there's "no guarantee" that the drug will work for real anxiety disorders. Novartis, he says, is planning additional clinical trials to find out.

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