A volumetric biochemical niacin flush-based index that noninvasively detects fatty acid deficiency in schizophrenia Basant K. Puri a, *, Steven R. Hirsch b , Terese Easton b , Alexandra J. Richardson a,b,c a MRI Unit, MRC Clinical Sciences Centre, Hammersmith Hospital, Imperial College School of Medicine, Du Cane Road, London W12 0HS, England, UK b Department of Psychiatry, Imperial College School of Medicine, Charing Cross Campus, London, UK c University Laboratory of Physiology, Oxford, England, UK Abstract (1) It is possible to investigate aspects of phospholipid-related signal transduction in humans noninvasively using the niacin skin flush test. (2) Patients with schizophrenia have previously been reported to show a reduced flushing response. (3) The aim of this study was to devise a comprehensive index of cutaneous response to the niacin test, incorporating aqueous methyl nicotinate concentration and time, and to test this index in schizophrenia. (4) A discrete approximation to a continuous volumetric index, which we have named the volumetric niacin response (VNR), was devised. Its value was measured in 27 patients with DSM-IV schizophrenia and 26 age- and sex-matched normal controls. (5) The mean value of the VNR in the patients with schizophrenia (16.26) was significantly smaller than that of 26.77 in the normal controls ( P <.0004). (6) With a threshold value for the VNR of 21, the test differentiated well between schizophrenia and normal controls ( P =.002) with a sensitivity of 78% and a specificity of 65%. (7) The present results confirm that the flushing response is reduced in schizophrenia, and show that calculation of the VNR is an effective means of allowing the total response in different patients or patient groups to be readily compared. D 2001 Elsevier Science Inc. All rights reserved. Keywords: Schizophrenia; Volumetric niacin response 1. Introduction Evidence from clinical, biochemical, neuroimaging and genetic studies has increasingly indicated that schizophrenia involves a disorder of neuronal membrane phospholipid metabolism associated with increased loss of highly poly- unsaturated fatty acids from membranes perhaps owing to enhanced activity of the phospholipase A 2 enzymes (Horrobin, 1998; Horrobin et al., 1994). Evidence that a calcium-independent phospholipase A 2 is elevated in schizophrenia includes the following findings in this dis- order: elevation of circulating phospholipase A 2 biological activity (Gattaz et al., 1990, 1995; Ross et al., 1997); reduction in highly unsaturated fatty acid levels in eryth- rocyte, skin fibroblast and cerebral neuronal membrane phospholipids (Glen et al., 1994, 1996; Mahadik and Mukherjee, 1996; Mahadik et al., 1996); and accumulation in platelets of lysophosphatidylcholine, a product of phos- pholipase A 2 action (Pangerl et al., 1991). There is now also evidence of elevation of a cytosolic calcium-dependent phospholipase A 2 in schizophrenia (Ward et al., 2000). These findings are consistent with evidence from cerebral 31-phosphorus magnetic resonance spectroscopy of in- creased phospholipid breakdown in the cerebral cortex of drug-naı ¨ve and -treated schizophrenia patients (Pettegrew et al., 1991; Williamson et al., 1995). It is now possible to investigate some aspects of phos- pholipid-related signal transduction in humans noninva- sively using the niacin skin flush test. Oral nicotinic acid in an adequate dose produces marked facial and upper body flushing. Horrobin (1980a) linked the evidence for a pros- taglandin deficiency in schizophrenia (Horrobin, 1977) to the potential use of this reaction as an objective biological marker. Following the postulation by Horrobin (1980b) that this reaction could constitute a simple biochemically based test for a major group of patients with schizophrenia, 0278-5846/02/$ – see front matter D 2001 Elsevier Science Inc. All rights reserved. PII:S0278-5846(01)00220-2 Abbreviations: c, concentration of niacin (M); df, degrees of freedom; DSM-IV, Diagnostic and Statistical Manual of Mental Disorders, 4th edition; r, intensity of flush response; S.D., standard deviation; t, time (s); VNR, volumetric niacin response * Corresponding author. Progress in Neuro-Psychopharmacology & Biological Psychiatry 26 (2002) 49 – 52