Scientists, Clinicians Optimistic About New Antischizophrenia Drugs

A boom is under way in developing drugs for treating schizophrenia. Several new pharmaceuticals are now available or in trials, and research is continuing on even better compounds that will target particular symptoms while avoiding side effects. This approach is one of many recent advances in research on pharmacological treatments for mental illness. As sales of psychoactive drugs soar, opportunities abound for scientists who want to be involved in the creation of yet more of these compounds, which are becoming increasingly complex, effective, and safe. p Olanzapine, one of four new antischizophrenia drugs, received Food and Drug Administration (FDA) approval late last year; it is now marketed as Zyprexa by Indianapolis-based Eli Lilly and Co. The other three compounds-quetiapine, sertindole, and ziprasidone-are under FDA review. Each of the four drugs differs somewhat in the effect it has on the brain and subsequently on the drug's ability to address the symptoms of schizophrenia, which are not yet totally controllable by any one medication. The key to their efficacy is their ability to increase or lessen the activity at receptors, the brain cell proteins that receive chemical messages. LOOKING FORWARD: Recent improvements in antipsychotics are good, but likely to be bettered in the future, says Eli Lilly's Steve Paul. Steve Paul, vice president of Eli Lilly Research Laboratories' therapeutics area, says, "Even though we're very excited about the progress we've made with olanzapine, I believe in the future we may be able to get much more robust efficacy than now. We don't yet have a drug that can cure schizophrenia." Over recent years, scientists have discovered that receptor proteins have more than just one or two variations, as was previously thought. This discovery is important, because different receptors are involved in different bodily functions and emotions. All schizophrenia drugs, including the latest ones, bind indiscriminately to receptors of a given neurotransmitter, the chemical agent that transmits nerve impulses. Accordingly, unwanted side effects-including nasal congestion, weight gain, nausea, and ejaculation difficulties-accompany the therapeutic effects. At least five receptors bind to dopamine, the neurotransmitter most closely associated with schizophrenia. The same proliferation of receptor discoveries applies to other neurotransmitters, like serotonin, which is involved in depression, part of schizophrenia's symptomatology. Two decades ago, only two serotonin receptors were known to exist, but to date, 15 have been identified. Antischizophrenia drugs not only bind to receptors of dopamine and serotonin, but also variously bind to noradrenergic, histaminergic, muscarinic, and other neurotransmitter receptors. Each drug's specific interaction with each of these many sites is helpful in predicting how well it will work on patients. However, exactly which functions or emotions are controlled by each receptor is not yet thoroughly understood. The current learn-as-you-go research is helping to unlock the secrets of schizophrenia's neurobiology, showing which emotions or other reactions are regulated at which receptors. As part of the current generation of "atypical" compounds for treating schizophrenia, the new drugs vary more in their potency and range in treating specific symptoms than do the "conventional" antipsychotics such as chlorpromazine and haloperidol. The newer compounds also have relatively low rates of extrapyramidal side effects (EPS) like the twitches and contortions of tardive dyskinesia. Researchers think they know why. The conventional antipsychotics bind to about 70 percent of the dopamine D2 receptor at clinically effective doses, whereas the atypicals bind to only 40 percent to 50 percent of those receptors. Moreover, the atypical drugs block 70 percent to 80 percent of the serotonin 5-HT 2A receptor. This combination of relatively low D2 and high 5-HT 2A receptor activity is thought to be important to the newer compounds' effectiveness and lower EPS rates (P. Buckley, Journal of Clinical Pharmacology, 37:363-78, 1997). One of the most widely effective atypical drugs for treating schizophrenia is clozapine. While it has been available in Europe since the 1960s, FDA was reluctant to approve the drug because it presents a low risk of death from agranulocytosis, or weakening of the bone marrow. However, a double-blind trial of 268 treatment-refractory patients showed far superior clinical improvement with clozapine than with chlorpromazine (J. Kane et al., Archives of General Psychiatry, 45:789-96, 1988), prompting FDA to grant restricted approval of the drug in 1990. The limited approval was for treatment-refractory schizophrenia or for patients who were intolerant to the side effects of the conventional antipsychotics. American College of Clinical Pharmacology Susan Ulrich, Executive Director 3 Ellenwood Court New Hartford, N.Y. 13413-1105 (315) 768-6117 - Fax: (315) 768-6119 http://www.cop.ufl.edu/departments/PC/accpgen.htm American Society for Pharmacology and Experimental Therapeutics Christine K. Carrico, Executive Officer 9650 Rockville Pike Bethesda, Md. 20814-3995 (301) 530-7060 - Fax: (301) 530-7061 http://www.faseb.org/aspet Drug and Market Development 225 Turnpike Rd. Southborough, Mass. 01772-1749 (508) 481-6400 - Fax: (508) 481-7911 Jim Kupiec, director of central nervous system and clinical research at the Philadelphia offices of Sanofi Winthrop Inc., says his group also is experimenting with antischizophrenia compounds that have no dopaminergic interaction. "The future will be in simple monotherapies to take care of all the problems found in schizophrenia," he predicts. If monotherapeutic agents are not developed, he has another scenario to consider: "physicians using highly specific chemical products in combination, so you'll be seeing polypharmacy." In that case, different medications in very low doses might address the positive and negative symptoms. Kupiec believes the quality of scientists recruited by industry to do such groundbreaking work has improved markedly over the past decade. "Industrial clinical research is no longer for people who can't make it in the academic or the practicing physician worlds," he says. One incentive for recruitment campaigns is that major pharmaceutical companies perceive a demand for more cost-effective treatment of mental illness. According to figures from Abbott Laboratories, schizophrenia alone affects as many as 1 percent of all people and costs Americans approximately $16 billion to $33 billion annually, accounting for 25 percent of hospital beds in use. It follows that the rewards for developing improved psychoactive drugs are huge. Figures from pharmaceutical market consultants IMS America of Plymouth Meeting, Pa., show that U.S. sales of psychotherapeutic medications totaled more than $7 billion in 1996, compared to about $3.8 billion five years ago. BIG DOLLARS: The neuropharmaceutical market could be worth $100 billion annually by 2007, predicts Harvard's Stan Goldin. "By 2007, I wouldn't be surprised if neuropharmaceuticals were a $100 billion-per-year enterprise," says Stan Goldin, a lecturer in Harvard Medical School's department of biological chemistry and molecular pharmacology. Goldin coauthored a new report entitled, "Neurological and Psychiatric Disorders, Neurogenomics and Drug Discovery" (S. Goldin, T. Tankosic, Southborough, Mass., Drug and Market Development, 1997). "It's wide open for geneticists, molecular biologists, and people who like doing epidemiological work, which now is almost a prerequisite to understanding the mechanisms of these drugs and their targets," he says. A major employer of people with such capabilities is Eli Lilly, which has a research and development staff of 4,400. The range of skills sought by research recruitment manager Joerg Pfeifer is broad. Molecular and cellular biology, biochemistry, electrophysiology, pharmacology and behavioral pharmacology, and organic and medicinal chemistry are all on the want list. University graduates at every level, with or without work experience, are sought. Ron Anglea, the company's U.S. recruiting and staffing manager, notes an upsurge in interest among scientists for such positions over the past several years. Another employer is Synaptic Pharmaceutical Corp., a biotechnology company based in Paramus, N.J., that has been collaborating with Lilly since 1991. "We're looking for people with strong backgrounds in areas like G-protein-coupled receptors, second-messenger signaling, in vitro cell systems, in vitro assays, and novel assays," says William Heydorn, Synaptic's director of pharmaceutical operations. "We also do a bit of in vivo work, and that's an area where pre- and postdoctoral students [of pharmacology] don't seem to have a strong background anymore." He says young scientists seem to be more widely possessed of skills in molecular biology and in vitro work than in such likewise useful tasks as anesthetizing animals and monitoring their vital signs. American College of Clinical Pharmacology president David Greenblatt, who chairs the pharmacology department at Tufts University School of Medicine in Boston, believes that advancements in homing in on the molecular mechanisms of disease are creating new capabilities among researchers, and that these skills are being developed across disciplines. "Pharmacology and biochemistry are becoming more and more indistinguishable as time goes on," he maintains. "I've heard people say that they walk through their biochemistry, immunology, and pharmacology departments and can't tell the difference in the work being done, because the molecular biology techniques being used are similar in each area." NEW SYNERGY: NIMH's David Shore believes that more drug development has spawned greater cooperation between industry and academia. David Shore, acting director of the division of clinical and treatment research at the National Institute of Mental Health (NIMH), says a new synergy between academic and industrial research organizations has accompanied the intensified psychiatric drug development of recent years. Many NIMH grantees work in both domains, attracted to industry by research opportunities and by the availability of funding. "I have heard estimates of $200 [million] to $300 million spent by pharmaceutical companies for each new product marketed," Shore comments. NIMH has not been as badly hurt by government cutbacks as have other departments, he notes, its budget having risen by about 4 percent annually over recent years. It funds research into the mechanisms of drug action, which can lead to better understanding of the causes of illness and, in turn, can invigorate the development of new compounds. NIMH also funds studies that compare new drugs against each other, research that pharmaceutical firms are not likely to do. "We are very interested in real-world scenarios," Shore says. "We like to focus on effectiveness rather than just efficacy."

Scientists, Clinicians Optimistic About New Antischizophrenia Drugs

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