When the blues turn black, they can be life-threatening. The deep,relentless, melancholic phase of manic-depressive illness ends insuicide for 10 to 15 percent of individuals afflicted with this disease.So said neuropsychopharmacologist Wade Berrettini, who teachespsychiatry and pharmacology at Thomas Jefferson University inPhiladelphia. He has studied the inheritance pattern of familial manic-depressive illness for the past decade, and recently pinpointed a keymutant gene sequence to the mid-section of chromosome 18.His paper, "Chromosome 18 DNA markers and manic-depressiveillness: Evidence for a susceptibility gene," appears in the current issueof the Proceedings of the National Academy of Sciences (PNAS).Manic-depressive illness also goes by the name of bipolar illness, forreasons apparent from Berrettini's description of the malady. "It is anepisodic illness," he told BioWorld Today, "that typically begins inearly adulthood. Fifty percent get their first symptoms before the age of25. Persistent and severe sadness," he added, characterizes theirdepression, which can last days, weeks or months. "Disturbed sleep andappetite mark the depression, with difficulty concentrating, feelings ofhopelessness, crying spells, inability to experience pleasure andsuicidal ideation."That poignant word picture limns one "pole" of the bipolar moodswings.The opposite extreme is mania, a phase in which the patient "feelseuphoric, cannot judge the consequences of his or her actions, leadingto unwise business decisions, and/or reckless behavior."A typical victim of this chronic, recurrent and "highly familial"condition, Berrettini said, "spends about three-quarters of his or herlifetime in the well state, but the remaining quarter suffering episodesof either depression or mania." During these periods of emotionalextremes, the individual usually knows what ails him or her, but cannotshake off the despondency or furor.In search of a genomic factor, or co-factor, in this obviouslymultifactorial disorder, Berrettini canvassed every human chromosome,and finally fixed on number 18 as the likeliest site of a putativevulnerability gene. He assembled 22 extended families, whichnumbered among their 365 members 159 _ 44 percent _ with bipolarillness.In the world population at large, he said, only one in 100 individualsare diagnosed annually with manic-depressive illness, which still addsup to more than two million new sufferers a year in the U.S. alone.Constance Lieber, board president of the Great Neck, N.Y.-basedNational Alliance for Research in Schizophrenia and Depression,which funds Berrettini's work, told BioWorld Today that "along withschizophrenia, bipolar illness is the most debilitating of the psychiatricdiseases."By linkage analysis, the Jefferson University team isolated a stretch ofDNA near the middle of chromosome 18, where certain other brain-influencing genes also congregate. The sequence they identified tendedto occur in ill patient samples, but not in their well relatives."Within the region examined," reads the PNAS paper, "two candidategenes deserve mention."One, dubbed Golf, because it was initially found in the olfactory tract,(the G stands for guanosine triphosphate) encodes a subunit protein thatbinds to magnesium."Nobody knows how this happens," Berrettini explained, "butapparently it's the binding of Mg that lithium interferes with." Headded, "It's indeed curious that a successful treatment for bipolardisease would interfere with the function of a protein product of a genethat's right in the very area where we have our evidence for avulnerability gene."Golf, said Berrettini, "is expressed only in limited regions of the brain,which are known to be abnormal on computerized axial tomography,or CAT, scans of acutely depressed people." He expects that most ofthe families that appear to be linked in this region of chromosome 18"will most likely have Golf gene mutations."Once able to define a series of such mutations in the suspect gene,Berrettini said, "we could then suggest that some sort of mutationscreening be considered as an adjunct to the diagnosis of manic-depressive illness." He hastens to add that such a screening test willtake several years at least to develop, "and should be applied only tothose cases where the diagnosis appears to be in doubt."Lithium is the most effective of several drugs that treat manic-depressive illness, but it benefits only about half of all patientssignificantly, and has unpleasant side effects.Hence, "more than one" pharmaceutical company "has expressedinterest" to Berrettini, looking toward possible design of a compoundthat would improve the function of the protein product of the Golfgene."On Thursday, Berrettini will inform the Washington biennial meetingof the Collegium Internationale Neuropsychopharmacologicum of thestatus of his research. His presentation will update the PNAS paper"with some preliminary personal communications from others in thefield, stating that they can find the same thing."This Collegium is the parent body of the American College ofeuropsychopharmacology, which meets annually in December in SanJuan, Puerto Rico. In December, Berrettini plans to convene aninternational workshop there to review the bidding on chromosome18's bipolar role. "We have invited investigators studying Finnish,Costa Rican, Icelandic and Western European manic-depressive illnessfamilies, as well as from all over the U.S.," he said. "So we ought to beable to reach a consensus about whether we can go forward withinvestigations of chromosome 18, or should go back to the drawingboard." n

-- David N. Leff Science Editor

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