Safety concerns over antipsychotic drug, sertindole

THE LANCET

SCIENCE AND MEDICINE

First isolation of Borna disease virus in affective disorder

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roof of the link between human affective disorder and viral infection moves a tentative step closer with the first isolation of Borna disease virus (BDV) from patients with mood disorders (Mol Psychiatry 1996; 1: 200-12), Liv Bode and colleagues from the Robert Koch Institute and Free University of Berlin have isolated BDV from peripheral blood mononuclear cells (PBMCs) of three out of 23 psychiatric inpatients—two with bipolar disorder and one with obsessive-compulsive disorder—after co-cultivation and longterm passage with a human oligodendroglial cell line. The researchers also claim a possible relation between productive viral infection and disease progression since

infectious virions, as judged by successful infection of rabbits with the three human strains, were isolated from PBMCs taken during acute episodes of the mood disorders. This finding, comments Ljubisa Vitkovic (National Institute of Mental Health, USA) in the same issue of Molecular Psychiatry, raises the possibility of persistent, and perhaps latent, BDV being activated by the onset of an acute episode of illness. Though “in dire need of corroboration and elaboration”, writes Vitkovic, an analogy would be herpesvirus infection in stressed but otherwise normal human beings. BDV is a neurotropic, enveloped, and negative and single stranded RNA virus that persistently infects various domestic animal species, causing behavioural and cognitive

function disturbances. In 1995, development of a western-blot assay to detect antibodies to three BDV proteins from a human neuro-blastoma cell line led researchers from the University of Maryland (Psychiatr Res 1995; 56: 33–44) to show tentative evidence of BDV infection in patients with schizophrenia, though a search for various viral nucleic acids (including BDV) by investigators at Johns Hopkins University School of Medicine (Br J Psychiatry 1995; 166: 55–60) with PCR was fruitless. In the new study, Bode et al speculate that patients with recurrent mood disorders have an inherited predisposition for activation of latent BDV infection. “The presence of infectious virus”, adds Vitkovic, “signified the potential for spread to non-infected individuals, as in natural animal hosts”. Pia Pini

Safety concerns over antipsychotic drug, sertindole

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espite disagreement about its safety, sertindole (Serlect, Abbott Laboratories), an antipsychotic drug was recommended for approval on July 15 by a US Food and Drug Administration advisory committee. A limbic-selective antipsychotic agent, sertindole has been shown to induce fewer extrapyramidal symptoms (EPS) than antipsychotics such as haloperidol. Long-term studies show that only 11% of patients taking sertindole require anti-EPS drugs, said Abbott. The FDA presented evidence that sertindole use prolongs the QT interval, which may lead to torsades de pointes and sudden cardiac death.

As of June 1, there have been 27 deaths—16 due to adverse cardiac events—among the 2194 patients who have participated in trials. FDA officials, Abbott, and committee members disagreed about what the QT prolongation meant. Dr Raymond Lipicky, director of FDA’s division of cardiorenal drug products, urged against approval of “a dangerous drug”. An independent review panel led by Duke University cardiologist Dr Edward Pritchett concluded that no-one in the Abbott study developed torsades, and that sertindole did not contribute to any of the 27 patient deaths. Pritchett also noted that many study patients

had underlying cardiovascular disease, and that sudden cardiac death is common in schizophrenics. Some committee members were still uncomfortable. Dr Emil Coccaro, of the department of psychiatry, Medical College of Penn-sylvania, said, “We don’t know why these people died suddenly, but just because they died makes me worried”. Dr Carl Salzman, a professor of psychiatry, Harvard Medical School, said that another antipsychotic—especially one that reduced the need for anti-EPS medications— was desperately needed. Alicia Ault Barnett

Mifepristone clears US regulatory hurdle

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n July 19, a US Food and Drug Administration advisory committee agreed that mifepristone given with the prostaglandin misoprostol (Cytotec) is safe and effective for aborting pregnancies at 49 days or earlier from the first day of a woman’s last menstrual period. However, since the US data presented were only preliminary, the panellists said that they want to meet again if, in the completed analysis, safety and efficicacy differ substantially from the French data that was

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presented by the New York-based Population Council. This group licensed mifepristone from Hoechst, which did not want to sell in the USA. Despite unfinished data interpretation, FDA pressed for a committee meeting to put mifepristone on track for action within statutory deadlines, said FDA Commissioner David Kessler. In two French studies of 2480 women, the overall efficacy rate was 95·5% for a 600 mg oral dose of mifepristone, followed 2 days later by

a 400 m g oral dose of misoprostol. Women stayed in the clinic for 4h after receiving misoprostol, and returned for a third visit to see whether the pregnancy was terminated. If not, a surgical abortion was offered. 21 women decided not to have abortions; three of the children born later had congenital defects. Efficacy decreased with older pregnancies, and most of the adverse effects were due to misoprostol. Alicia Ault Barnett

Vol 348 • July 27, 1996