Biological markers and psychosis

There is consistent evidence from family, twin and adoption studies that schizophrenia (Gottesman & Shields, 1982) and the major affective disorders (Reich et al. 1982) receive an important genetic contribution to their aetiology. Given that there is this contribution, there must exist some mediating biological processes which constitute the pathway from abnormal genes to abnormal behaviour. The search for biological markers is the search for signposts on this pathway. As Penrose (1971) has pointed out, psychiatric disorders present peculiar problems for genetic analysis in that they are not characters which 'segregate and are unequivocally recognisable in different surroundings'. Syndromes defined by clinical signs and symptoms, what Gottesman & Shields (1972) have called 'exophenotypes', may possibly be refined down to more manageable characters if biological markers or 'endophenotypes', lying a step nearer the primary gene product, can be discovered. A nice demonstration of the utility of various kinds of phenotypes in distinguishing between genotypes was given by Penrose (1952). He showed that measuring head size or hair reflectancy (as an indicator of blondness) on normal children and those with phenylketonuria provided overlapping distributions. IQ provided better separation but, again, with two distributions overlapping. However, when phenylalanine levels in the blood were measured the two groups were clearly and widely separated, with the means 13 standard deviations apart. Thus a character which is very near to the primary gene product provides the most unequivocal discrimination and, although the mode of transmission of manic-depressive psychosis or schizophrenia is likely to prove much more complex than this simple autosomal recessive example, the model remains a valid one for psychiatry. The list of potential candidates for a schizophrenic or manic-depressive endophenotype is large (Nurnberger & Gershon, 1982; Gottesman & Shields, 1982). The search has ranged widely over biochemical, endocrinological, and neurophysiological territory. In the absence of any clear-cut lead, what has tended to happen is that whenever a new discovery is made or some new technique evolved in an area that might feasibly be related to the aetiology of psychosis, then it is soon applied in clinical studies. In the majority of cases confusion, contradiction, and failure of replication have been the result. Two possible exceptions are the studies of the dexamethasone suppression test and of platelet monoamine oxidase. In these areas there has been enough consistency at least to suggest that the results are indicators of pathophysiological pathways and not merely the signposts of temporarily fashionable blind alleys. As such, a brief consideration of their relationship to the genetics of psychosis is merited and is of some heuristic value. The dexamethasone suppression test (DST) has recently been extensively studied in affective disorder (Carroll, 1982), and failure of suppression of blood cortisol levels has been found consistently in 50% or more of patients with an endogenous pattern of illness. Although there is no excess of non-suppressors among psychiatric patients with other conditions, non-suppression occurs among healthy controls in whom the rate in some recent studies has been more than 10% (Coppen et al. 1983; Hallstrom et al. 1983). How good then is the test as a means of defining a group of endogenous depressives? If the proportion of non-suppressors among endogenous depressives (i.e. the sensitivity) is 50% and the proportion among non-depressives is 10% (i.e. the specificity is 90%) then on a psychiatric ward where the prevalence of endogenous depression is, say, 30% Bayes' theorem allows us to calculate that the probability that an individual is suffering from endogenous depression, given that he or she has an abnormal test result, is 68%. However,