Apolipoprotein E ɛ4 and clinical phenotype in schizophrenia

Abstract

David Pickar and colleagues (Sept 27, p 930)1Pickar D Malhotra AK Rooney W Breier A Goldman D Apolipoprotein E ɛ4 and clinical phenotype in schizophrenia.Lancet. 1997; 350: 330-331Summary Full Text Full Text PDF PubMed Scopus (24) Google Scholar report an association between severity of psychotic symptoms and genetic variants of apolipoprotein E (APOE) in patients with schizophrenia or schizoaffective disorder. They found significantly lower scores of psychotic symptoms (Brief Psychiatric Rating Scale [BPRS]2Overall JE Gorham DE The brief psychiatric rating scale.Psychol Rep. 1961; 10: 799-812Crossref Google Scholar items 4, 11, 12, and 15) in patients who carried an APOE ɛ4 allele compared with non-carriers. However, the relative distribution of APOE genotypes was consistent with no association between APOE genotype and risk of developing the disease, which accords with our previous observation3Zhu S Nöthen MM Uhlhaas S et al.Apolipoprotein E genotype distribution in schizophrenia.Psychiatric Genet. 1996; 6: 75-79Crossref PubMed Scopus (24) Google Scholar in 98 patients who met DSM/III-R criteria for schizophrenia, based on structured clinical interview (SADS).4Endicott J Spitzer RL A diagnostic interview: the schedule for affective disorders and schizophrenia.Arch Gen Psychiatry. 1978; 35: 837-844Crossref PubMed Scopus (4774) Google Scholar In 62 of these patients, Operational Criteria Checklist (OPCRIT)5McGuffin P Farmer A Harvey IA Polydiagnostic application of operational criteria in studies of psychotic illness.Arch Gen Psychiatry. 1991; 48: 764-770Crossref PubMed Scopus (1261) Google Scholar data are available. BPRS reflects the present state of the disorder, which changes during lifetime, and the OPCRIT documents the presence or absence of symptoms during a lifetime, which makes it most valuable for genetic studies which search for trait rather than state markers. The frequency distributions of the APOE genotypes in the 62 patients were: three (5%) with 2/2; eight (13%) with 2/3·34 (55%) with 3/3; 16 (26%) with 3/4; and one (2%) with 4/4. Age at interview, age at onset of disease, male/female ratio, and DSM-III-R subtype diagnosis of schizophrenia did not differ significantly between patients who carried the APOE ɛ4 allele and those who did not. Since OPCRIT items of clinical symptoms (n=53) and BPRS items (n=18) are not identical, we tested the OPCRIT equivalents (collapsing the corresponding items) for the BPRS items. Significantly more APOE ɛ4-positive than APOE ɛ4-negative patients showed “incoherence” and “speech difficult to understand” (OPCRIT items 27 and 26, corresponding to BPRS item 4 “conceptual disorganisation”) (χ=6·7, p=0·035) and “persecutory delusions” (OPCRIT item 54, corresponding to BPRS item 11 “suspiciousness, paranoid thoughts”) (χ=3·9, p=0·046). There was no between-group difference in OPCRIT items 73 to 77 (“third person auditory hallucinations”, “running commentary voices”, “abusive/accusatory/persecutory hallucinations”, “other (non-affective) auditory hallucinations”, “non-affective hallucination in any modality”, corresponding to BPRS item 12 “hallucinatory behaviour”), and OPCRIT items 55, 58, 59, 66, 67, 68 (“well organised delusions”, “delusions of influence,” “bizarre delusions”, “thought insertion”, “thought withdrawal”, “thought broadcast”, corresponding to BPRS item 15 “unusual thought contents”). To address the issue of heterogeneity in schizophrenia, it has been suggested that psychopathological dimensions might be easier to link to causative mechanisms than diagnostic categories. Psychotic (positive) symptoms have an important role in the diagnosis of schizophrenia; their presence during a defined time period—at least once during lifetime—is mandatory for a DSM diagnosis of schizophrenia. Whereas Pickar and colleagues tested an association of APOE ɛ4 alleles with the degree of severity of positive symptoms in a standardised clinical setting during a single drug-free period, we tested whether APOE ɛ4 alleles are associated with specific positive symptoms, and looked for the presence or absence of different psychotic symptoms during the lifetime course of the disorder. Our findings suggest that positive symptoms of “incoherence”, “speech difficult to understand”, and “persecutory delusions” are preferentially displayed by patients who carry the APOE ɛ4 allele but who manifest less severe positive symptoms of schizophrenia than patients who do not carry this allele.