Patients are about as happy with new schizophrenia drugs, some of which are a decade old, as they are with a drug from a half century ago, the initial results of a new study show. 

    The study, funded by the National Institutes of Health and published in the September 22 issue of the 

, measured the rate that patients taking one of five different drugs chose to stop treatment or change drugs. It is not uncommon for schizophrenia patients to change medications frequently.

    All five of the drugs studied had high discontinuation rates. Zyprexa (olanzapine), a new drug, had the lowest rate at 64 percent. The 75 percent discontinuation rate for Etrafon, or Trilafon, (perphenazine)-a 1950s drug-was comparable to the second-generation drug Risperdal (risperidone) at 74 percent. It was also lower than the rates for the new drugs, Seroquel (quetiapine) at 82 percent, and Geodon (ziprasidone) at79 percent.

    The researchers designed the study to evaluate not just symptoms but “functional measures” of schizophrenia treatment, said John Hsiao, NIMH’s government project officer for the study. Among these measures were patient satisfaction and compliance. 

    The results demonstrate that the current treatments are not entirely effective, he added. “Many patients only have partial responses to these agents and all of the drugs have substantial side effects,” said Stephen Marder, professor of psychology at the Semel Institute at the University of California Los Angeles. “None of the drugs clearly has an advantage over the others.”

    The discontinuation rates are also high because doctors commonly change schizophrenia patients’ medications several times before they find the best option, explained Robert Rosenheck, professor of psychology at the Yale University School of Medicine and co-investigator on the study.

    “In reality, clinicians use all of the medications until they find the right one,” said Leslie Citrome, professor of psychology at New York University’s School of Medicine.

    Although olanzapine had the lowest discontinuation rate, it also had the most significant side effects, including weight gain and metabolic problems.

    But the results available so far are unlikely to tell the whole story. 

    Marder pointed out that the 18-month trial was too short to detect the neurological side effect, tardive dyskinesia, that clinicians believe is stronger in older schizophrenia drugs. He also noted that trial participants with tardive dyskinesia were not put on the old drug, perphenazine, although the rest of the drugs were assigned randomly.

    Although schizophrenia experts praised the study, they are waiting for additional results to be released. Many are particularly interested in the affect of different drugs on cognition, the patient’s ability to think. Although conclusive data is not yet available, some psychologists and clinicians hold that second-generation drugs are better at improving cognitive functions, Citrome said. 

    The investigators expressed concern that the partial results will prompt financial decision makers to push first-generation schizophrenia drugs like perphenazine, because they cost less than newer treatments.

    “Government agencies will say perphenazine is just as good, so why not use perphenazine because it’s cheaper,” Citrome said.

Articles

Schizophrenia experts interpret the result of an extensive head-to-head comparison of five treatments. Schizophrenia patients frequently change or discontinue treatments. The jury is out on some side effects.

Old and New Schizophrenia Drugs: Study Shows Patient Satisfaction Is About the Same

A viral protein that can change its surface structure and selectively bind to bacterial surface proteins may be a candidate for new biological therapies.

    Two teams of California scientists studying the protein, which is called major tropism determinant (Mtd), believe the biotech industry can harness their discovery to target specific cells.

    Several years ago, a research team at University of California Los Angeles discovered that Mtd’s 10 trillion different configurations allow it to bind to bacterial surface proteins, which can change with every generation. In this respect, it is similar to an antibody.

    Working with a lab at the University of California San Diego, the researchers recently discovered that the viral protein has a much more stable structure than do antibodies, explained lead investigator, said Jeff Miller, professor of microbiology, immunology and molecular genetics at UCLA’s medical school. This makes it a viable candidate for clinical applications.

    Antibodies can generate more than 100 trillion configurations, but a looping structure in the protein can make it difficult to replicate the folds of the molecule in a lab, explained co-lead investigator Partho Ghosh, associate professor of chemistry and biochemistry at UCSD. Even in the body, this type of mis-folding can lead to diseases like light chain amyloidosis, which causes a build-up of mis-folded, sometimes mutated proteins on organ cells, commonly the kidney, heart or liver. This results in organ failure and death. 

    Mtd is stable in comparison to an antibody, because all 10 trillion variations result from changes in only 12 sites on the basic “scaffold” of the protein. This makes Mtd easier to manipulate for drug development purposes than antibodies. Ghosh predicted that all 10 trillion varieties of the Mtd protein would be able to bind to a target molecule.

    The molecule’s diversity is generated when the gene for Mtd is transcribed from DNA into messenger RNA, explained Miller, Instead of leaving the nucleus to be translated into protein, one segment of the mRNA is transcribed back into DNA by reverse transcriptase. During this process, “mistakes” are made in 12 vulnerable sites. These mistakes generate diversity when the genes are finally translated into protein.

    Each variant of the Mtd protein can potentially bind to a bacterial surface molecule. Ghosh and Miller believe that if this ability to generate diversity can be harnessed, it can be used to develop new therapies.

    Miller suggested that an engineered version of a bacteriophage, or bacterial virus, containing Mtd might be used as an antimicrobial. He also mentioned the possibility of using the Mtd diversity generator to develop protein-based therapies that can bind to targets of interest.

    Ghosh said inserting Mtd into bacteria, such as 

, would produce a number of variants, which scientists could then “pan” for a version that binds to a specific target molecule. Once found, they could isolate the 

 that produce the desired variant and amplify production.

    Mtd variants can be generated to identify and bind to cancer markers, Ghosh predicted. He also speculates that they may target highly infectious bacteria, such as anthrax, which can be used as weapons.

    Less than a year ago, Miller founded a biotech company, AvidBiotics with David Martin, a former vice president of research and development at Genentech.

    Martin said that AvidBiotics’ latest application of Miller’s diversity generator is engineering molecules to combat antibiotic-resistant bacteria. The engineered molecule will attack a resistant bacterium by binding specifically to one of the surface proteins that is not targeted by antibodies or existing drugs. AvidBiotics calls such attack molecules avidocins.

    In the future, AvidBiotics might use this technology to engineer diagnostic and industrial enzymes.

Scientists talk about the medical applications of a protein with 10 trillion possible functional variations. The molecule, present in viruses that infect bacteria, is the closest thing to an antibody ever discovered. And it might be easier to replicate.

California Researchers Investigate Antibody-like Viral Protein

George W. Bush wasted no time naming his family friend and fellow Texan, Andrew von Eschenbach as acting FDA commissioner. 

    Von Eschenbach, a physician and cancer survivor who remains the director of the National Cancer Institute at the National Institutes of Health, replaces Lester Crawford, who resigned on Sept. 23, just two months after being confirmed by the Senate.

    The new commissioner inherits thorny problems that plagued Crawford and delayed his Senate confirmation. Because he served as acting or deputy commissioner during the past five years, Crawford could not escape responsibility for the drug-safety issues in the Vioxx debacle, the flu vaccine shortage, or the agency’s delay in deciding over-the-counter access to Plan B, the morning-after pill. 

    Most of these problems-or similar ones-are likely to follow von Eschenbach into office. But unlike his predecessor, who was a veterinarian and food safety expert, von Eschenbach has strong relationships with the medical research community. As a medical doctor, a cancer survivor and, until he joined NCI, the president-elect of the American Cancer Society, he is popular with many patient groups. 

    “Dr. Andrew von Eschenbach’s appointment as acting chief of the Food and Drug Administration is great news for the patient community,” said Michael Paranzino, president of Psoriasis Cure Now “Dr. von Eschenbach understands the urgent need to speed to market new treatments for patients.”

    On the political front, he shares a Texas connection-and long friendship with George H.W. Bush-with many cabinet-level officials.  In addition, he has successfully passed the Senate confirmation process when he took the position with NCI.

    But von Eschenbach is not without controversy. In 2003, an NCI fact sheet erroneously stated that having an abortion might increase a woman’s risk of breast cancer. He also set a public goal of making cancer a “manageable disease” by 2015, which his sympathetic critics called optimistic at best. Others called the statement a headline-grabbing stunt. 

    But von Eschenbach troubles the administration less than Crawford. Officials hinted that undisclosed financial issues were the immediate cause of Crawford’s departure, and the White House appeared content to let him go at a time when a leader with strong medical and scientific credentials may restore public trust in the troubled agency.

    Von Eschenbach said he plans to retain his position at NCI. It may take months for the White House to appoint, and the Senate to confirm, a permanent FDA commissioner.

Hours after Lester Crawford resigns, the head of the National Cancer Institute takes his place on the FDA hot seat.

Pharmaceutical Executive-09-27-2005

Old and New Schizophrenia Drugs: Study Shows Patient Satisfaction Is About the Same

California Researchers Investigate Antibody-like Viral Protein

Andrew von Eschenbach Appointed New Acting Head of FDA