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Now scientists are exploring an entire spectrum of what Dr. Steven Paul, vice president for central-nervous-system research at Eli Lilly, calls "Clozaril wannabes" that they hope will work as well without triggering agranulocytosis. One of the wannabes, risperidone (Risperdal), made by Belgium-based Janssen Pharmaceutica, entered the market in 1993, and four others are nearing approval by the fda, including Lilly's Zyprexa and Abbott Labs' Serlect. Meanwhile, further down the drug-development pipeline are a number of third-generation Clozaril cousins, some of which are specifically targeted at the little-known D3 and D4 receptors.
"We're not curing schizophrenia with these new antipsychotics," says Paul. "But we can treat it better. What would happen if we designed a drug that was 10 times better than Clozaril?" Mount Sinai's Davis, on the other hand, thinks future schizophrenia drugs might well be based on altogether different chemical-messenger systems. "There is evidence that schizophrenics have abnormalities in two very common neurotransmitters, gaba [gamma-aminobutyric acid] and glutamate," he says. "None of the current drugs do anything for the most incapacitating symptom of schizophrenia, the cognitive deficits. Maybe it's time to get off the dopamine merry-go-round we've been on for 40 years."
New drugs have also drastically altered the outlook for panic disorder, a chronic illness characterized by recurrent panic attacks and a lifetime of fear in between. The symptoms of an attack--among them palpitations, breathlessness, sweating, dizziness, tingling sensations, hot flashes or chills, as well as a sense of impending doom--seem so dire and life-threatening that patients frequently turn up in emergency rooms convinced they are having a heart attack or going insane. Thirty percent of the 2.4 million Americans with panic disorder go on to develop agoraphobia, the fear of leaving home lest they succumb to panic on the freeway, in a store or at a concert. Some 20% of patients attempt suicide.
Panic disorder probably results from a "combination of a genetic predisposition and some number of traumatic separations in childhood," according to Dr. Jack Gorman, a Columbia University psychiatrist. But whatever the cause, the brain of a person who suffers from it is different from that of someone who does not. Stimulation studies using the drug yohimbine have revealed an abnormal firing rate in an area of the brain stem called the locus ceruleus, which is rich in cells that release the neurotransmitter norepinephrine, the trigger for human fight-or-flight response. This primal alarm system has obvious survival value--useful for fleeing man-eating tigers and such. But in patients with panic disorder, it appears to kick in at too low a threshold.
A decade ago, many a panic-disorder patient ended up as a tragic, misunderstood recluse. But today panic disorder is one of the most treatable mental illnesses. Studies have shown that 70% of patients benefit from cognitive behavioral therapy, which includes breathing training, "cognitive restructuring" and "exposure therapy." Most patients can be helped by short-acting antianxiety drugs such as Xanax and long-acting antidepressants such as desipramine and imipramine.