Tactical Shift in Treating Schizophrenia

(November 29, 2005) -- Copy machines that talk. Co-workers conspiring to kill. These are the kinds of bizarre hallucinations and delusions that have driven people with schizophrenia from schools and workplaces and deposited them on the lonely margins of society.

Now, however, doctors are discovering that other well-known, but much less flamboyant, symptoms of the brain disorder may be just as significant in preventing schizophrenics from engaging in the real world. Mental confusion, apathy and the inability to experience pleasure are now thought to be major barriers to a return to mainstream life.

Such symptoms are hard to treat. Although a number of antipsychotic medications can help blot out the so-called "positive" symptoms of schizophrenia - the disorienting and disturbing hallucinations and delusions - there are no medications to treat the cognitive impairment and emotional symptoms.

In recent years, researchers have started seeking therapies for these so-called "negative" symptoms of schizophrenia, says Dr. Stephen Marder, a professor of psychiatry at the Semel Institute for Neuroscience and Human Behavior at the University of California, Los Angeles, and director of the mental health research, education and clinical center for the VA Greater Los Angeles Health Care System.

The impetus has been the recovery movement, an effort by patients, their families and other mental health advocates that aims not to "cure" the disease but to restore schizophrenics as functioning members of society.

"The recovery movement is saying, 'You can go just so far in improving positive symptoms, but we also want to be able to socialize, to work and make progress in our lives,'" says Marder, who has helped spearhead a national research effort on the problem. "If that is going to happen, it's likely we're going to have to develop drugs that address those areas."

The cognitive and emotional problems can be deeply crippling. People with schizophrenia "seem like they have a lack of ability to express themselves," Marder says. "They are also oftentimes apathetic. Some will say, 'I would really like to do things, but I can't get myself interested in doing it.'"

College students experiencing their first psychotic episode often find they can no longer continue school even if promptly treated with antipsychotics and the hallucinations are resolved, he says. "Reading and studying and focusing their attention becomes so difficult."

The search for treatments for these problems represents a dramatic shift in drug development goals for schizophrenia. As recently as a decade ago, doctors and patients rejoiced in a new family of antipsychotic medications aimed at reducing hallucinations and delusions without many of the severe side effects linked to the older antipsychotic drugs. Older drugs, such as Haldol, typically cause tremors and muscle rigidity.

But the new so-called atypical antipsychotics, though helpful to many, haven't led to sweeping improvements in quality of life, experts acknowledge. In an 18-month study released in September, researchers found that three-quarters of the patients stopped taking their assigned drugs before the trial's conclusion because the medications didn't improve their condition enough or because of side effects such as tremors or significant weight gain.

Even with treatment, about 85 percent of schizophrenics are unemployed, according to the National Institute of Mental Health.

"Ten years ago, there was a hope that the newer medications would give us a greater chance at recovery, the vanishing of the disorder," says Dr. Thomas R. Insel, director of NIMH. "I think (the study) makes clear that the medications we currently have are necessary but not sufficient."

Several drug companies are continuing to seek better antipsychotic drugs. But the main focus of research within the government and academia is on better understanding the negative symptoms of the disease.

For decades, scientists have blamed schizophrenic symptoms on abnormalities in the brain chemical dopamine - and these are, indeed, linked to the delusions and hallucinations.

But new research suggests other brain chemicals are involved in the disorder, contributing to such symptoms as confusion and emotional unresponsiveness.

NIMH is collaborating with universities and industry to identify possible new medications for cognitive deficits and develop better instruments for assessing improvements. Ideally, these new medications would give people with schizophrenia the ability to concentrate, carry out tasks and interact socially.

One promising substance is a drug, D-cycloserine, that is used to control tuberculosis. D-cycloserine works on a structure in the brain known in shorthand as the NMDA receptor, which plays a key role in learning and memory. It's believed that some of the symptoms of schizophrenia are caused by a blockage or abnormality of this receptor; D-cycloserine appears to unblock it.

Studies on D-cycloserine drugs for schizophrenia are still in early stages. But one study, reported in March in the journal Biological Psychiatry, showed that 39 people with schizophrenia taking D-cycloserine in addition to a traditional antipsychotic experienced improvements in a range of symptoms, including hallucinations, delusions, apathy, withdrawal and cognitive deficits.

Another avenue of study involves targeting a serotonin receptor that is critical to cognitive function. Saegis Pharmaceuticals, a company in Half Moon Bay, Calif., is teaming with Eli Lilly & Co. in phase 2 testing of a drug, SGS518, which blocks this receptor, with the hope of improving cognitive functioning.

Meanwhile, San Diego's Acadia Pharmaceuticals is studying a chemical that may help subdue psychotic symptoms as well as improve cognition. The company is on track to present results from phase 2 studies within a year, said CEO Uli Hacksell.

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"There is a lot of excitement about the ability to improve the negative symptoms in schizophrenia," Hacksell says. "It's time to do something about this part of the symptomology of the disease that hasn't been dealt with so far."

Drugs, however, will take recovery only so far. Non-drug treatments are also important. For example, Insel says, a program called supportive employment - in which employees receive job coaching, support, even transportation - can boost employment rates from 10 percent to 50 percent. Educating family members, and engaging them as part of the treatment team, can also sharply reduce the relapse rate.

"This whole push for recovery is very important, but I don't think medications are going to be the largest part of that story," Insel says. "I think we have some very good (nonmedical) treatments that are not used nearly enough. We need multiple forms of care, not just medication."

By Shari Roan

Last updated: 12/05

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