Not only is schizophrenia often considered one of the worst diseasesaffecting humanity, it's mystifying. Its very identity is a question mark:One disease or many? Between one-third and one-half of homelessAmericans have schizophrenia, according to a review article in theNew England Journal of Medicine (NEJM) for March 10.Defining schizophrenia's cause, or causes, is the stuff of educatedguesswork.Its treatment with new generations of psychoactive drugs half-emptiedthe major mental institutions in the 1950s and 1960s, and has sincefilled the streets with homeless victims of the baffling psychosis. Nowa mutant gene has surfaced that correlates statistically with the severityof schizophrenia in 156 Japanese patients, compared with some 300controls. A report of this apparently unprecedented finding appears inthe current Lancet (March 19), titled "Association of dopamine D2receptor molecular variant with schizophrenia."In their Lancet paper, the Japanese investigators note that "although theDRD2 gene has been cloned, no structural change in [its] receptor inschizophrenia has been reported."The paper concludes, "If our findings are confirmed, [they] would helpto elucidate the pathogenesis of schizophrenia, as well as to developprevention and treatment methods for this serious disease."Just how serious is suggested by data in the NEJM overview, byWilliam Carpenter of the University of Maryland's PsychiatricResearch Center in Baltimore. "The worldwide lifetime prevalence ofthe disorder," he wrote, "is about 0.85 percent across diversegeographic, cultural and socioeconomic categories," he said.In 1990, Carpenter stated, direct and indirect costs of schizophrenia inthe U.S. amounted to an estimated $33 billion, and treatment absorbed2.5 percent of total health care expenditures.The straw that neuroscientists have grasped in the trackless wildernessof schizophrenia's etiology is its apparent connection to dopamine inthe brain. This dopamine hypothesis, Carpenter explained, "is based onobservations that drugs that reduce the firing rates of mesolimbicdopamine neurons have an antipsychotic effect."That's the effect shared by the many psychotropic medicationsdeveloped to treat schizophrenia, albeit empirically, beginning withchlorpromazine in 1952 and haloperidol later. "Dopamine has beenthought of for a very long time as very important in thepathophysiology of schizophrenia," neuroscientist Michael Flaum toldBioWorld, "primarily because the clinical efficacy of the medicationsused seems to go along with the degree to which they block thedopamine receptor." Flaum is co-director of the Mental Health ClinicalResearch Center at the University of Iowa.So far, researchers have identified five dopamine receptors, each with adifferent mode of action. At Tsukuba University's department ofmedical genetics, Tadao Arinami and his co-authors used polymerasechain reaction (PCR) methods to find a point mutation at codon 311 ofthe gene for dopamine's second receptor, D2.Instead of TCC (thymine-cytosine-cytosine), which encodes the aminoacid, serine, the mutated triplet, TGC (thymine-guanine-cytosine)produces cysteine instead. This heritable variant, they found, associateswith schizophrenic symptoms. In 50 patients, it was the only variantform of the receptor gene they encountered.The 156 patients (99 men and 57 women) met the AmericanPsychiatric Association's criteria for schizophrenia: delusions,hallucinations, incoherent and irrelevant speech, flattened, incongruousaffect, etc.The 156 schizophrenics had, of course, inherited D2 receptor genesfrom both parents. Of these 312 alleles (156 X 2), 17 had cysteinevariants vs. 295 serines (0.6 percent). The control group counted only11 cysteines to 589 serines (0.2 percent), and these were associatedwith no negative symptoms.Only three of the 156 patients had inherited the cysteine-311 mutationfrom both parents. These homozygotes had "more noticeable clinicalfeatures" of the disorder than did the 11 who had received only a singlemutant allele. Moreover, they were diagnosed with schizophrenia at anearlier age (20) than the serine/cysteine heterozygotes (21.3) or the 142without the variant (25.7 years).Arimani said that the increased susceptibility to schizophrenia amongthe cystine-311 Japanese patients "may not hold in non-Japanesepatients, because the variants have not been found among more than 50whites."The University of Iowa's Flaum commented on the Japanese study: "Ifindeed they have found a point mutation in one of the candidate genesand certainly the gene for D2 would be a reasonable candidatethat is of interest, and that is new."But, he added: "Although this is a potentially interesting finding,caution should be taken in generalizing from it. Most schizophreniaresearchers think it is very likely that the disorder will prove to beextremely heterogeneous with respect to its pathophysiology andetiology. Therefore it's unrealistic to expect that finding a pointmutation in one gene is going to account for a large percentage of thecases."

-- David N. Leff Science Editor

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