Acta Psychiatr Scand zyxwvutsrqponm 1998: 98: 443450 Printed in zyxwvutsrqponmlkjih UK zyxwvutsrqponm - all rights reserved Copyright zyxw J Munksgaard 1998 zy ACTA PSYCHIATRICA SCANDINAVICA ISSN 0001-69OX zyx Mode of inheritance in mood disorder families according to fluvoxarnine response Serretti A, Franchini L, Gasperini M, Rampoldi R, Smeraldi E. Mode of inheritance in mood disorder families according to fluvoxamine response. Acta Psychiatr Scand 1998: 98: 443-450. G Munksgaard 1998. Mood disorders are known to cluster within families, but the mode of transmission remains largely unknown. The purpose of our analysis was to determine whether selection of a sample that was homogeneous in its response to an antidepressant provided stronger evidence for a single major locus. Complex segregation analysis was applied to a sample of 171 Italian families of bipolar and unipolar probands that were responsive to the antidepressant fluvoxamine. We used regressive logistic analyses to determine the best fit from among environmental, arbitrary Mendelian, dominant, recessive and additive models. For the 171 affective families with probands that were responsive to the antidepressant fluvoxamine, a Mendelian model of inheritance was rejected. When considering 68 families of bipolar probands, the best fit was obtained for a Mendelian dominant model of transmission. The identification of a Mendelian mode of transmission in bipolar subjects who were selected according fo their response to fluvoxamine supports the use of a pharmacological criterion as a tool for identifying true genetic disorders. Introduction It is widely accepted that mood disorders aggregate within families, and family, twin and adoption studies clearly demonstrate the contribution of heritable factors to the aetiology of mood disorders (1-5). However, despite decades of investigation, no definitive mode of transmission has been established. An X-linked dominant model was proposed for a subsample of bipolar (BP) families (6), but a high rate of father-to-son transmission challenged this hypothesis (3,7). Single major locus (SML) inheritance has been repeatedly proposed and rejected since the earliest studies @-lo), and the inclusion of possible sources of heterogeneity such as polarity or severity of illness was also unable to define this issue unequivocally (11, 12). Two complex segregation analyses were performed on the 187 pedigrees collected in the National Institute of Mental Health (NIMH) Collaborative Program on the Psychobiology of Depression (4, 13), and inclusion of age of onset in the analyses indicated that an SML might be present. However, the transmission probabilities differed from Men- delian expectations, and a subsequent re-analysis of A. Serretti, 1. Franchini, M. Gasperini, R. Rampoldi, E. Smeraldi lstituto Scientifico zyxwv H San Raffaele. Department of Neuroscience. University of Milan School of Medicine, Milan, Italy Key words: bipolar disorder: depressive disorder, fluvoxamine: dominant genes; genetic models Alessandro Serretti. Department of Neuroscience, lstituto Scientifico H San Raffaele. University of Milan - School of Medicine, Via Luigi Prinetti 29, 20127 Milan, Italy Accepted for publication August 7, 1998 the same data-set revealed that it also fitted a polygenic model of transmission (14). More recently, Spence et al. (15) indicated that an SML transmission model fitted if only BP I and I1 probands were considered, while the inclusion of unipolar (UP) probands decreased the evidence for an SML. On the other hand, Pauls et al. (16) rejected an SML transmission model when con- sidering both BP and UP probands, but focusing on the most closely related subset of families revealed that an autosomal dominant was consistent with transmission of BP I disorder. The ongoing debate has failed to offer conclusive arguments (17, 18). A number of explanations have been suggested for the lack of consensus between different studies. The ascertainment methods may heavily influence transmission results, the aetiological heterogeneity of mood disorders could explain most of the inconclusive or conflicting results and, finally, the definition of phenotype for mood disorders should still be regarded as provisional, and external validation is needed. The proposed similarity between mechanisms linked to the pathophysiology 443