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Exemplified by the Influenza^Schizophrenia Theory BRITISH JOURNAL OF PSYCHIATRY 2001), 178suppl. 40), s30^ s32 Epidemiology in neurobiological research: overshadowed, and new approaches are re- quired %Eaton & Harrison, 1998); for ex- exemplified by the influenza ^ schizophrenia theory ample, it is increasingly recognised that the external environment is non-random, in the sense that individuals' interaction POVL MUNK-JÒRGENSEN and HENRIK EWALD with and experience of the external envir- onment also seems to be influenced by their genes. This has been called the `nature of nurture', and interesting studies of genetic influences on experience of life events have been reported %McGuffin et aletal, 1988;,1988; KendlerKendler et aletal, 1993; Kendler & Karkowski- Background During recent years the The importance of genetic factors in schizo- Shuman, 1997). strategy for aetiologicalresearchinaetiologicalresearch in phrenia aetiology has long been recognised. The role of epidemiology in investigat- As early as the 18th century, the British ing neurobiological causal factors can best schizophrenia has been to concentrate on physician William Battie speculated about be illustrated by an example. In 1988 a now two closelycloselyconnected connected directions: the heredity as a cause of madness, while in famous paper by Mednick et aletal was pub-pub-was search for the genetic element and the the first years of the 19th century Esquirol lished in the Archives of General Psychiatry.. search for environmental factors.Damage regarded 23% %110 of 482) of melancholic The reported study was the result of clever to the immature brain during pregnancy patients in the SalpeSalpetriereÃtrieÁre and 57% %150 of thinking. We had for many years known 264) of patients in his private asylum as about seasonal variations in birth rates of and delivery hasgiven us the most having hereditary conditions %Shorter, persons later developing schizophrenia, with interesting results fromrecentfrom recent 1997). Since the early 20th century the a higher incidence among those born in win- environmentalenvironmentalresearch. research. importance of nature or nurture in relation ter than in summer in the northern hemi- to human behaviour, whether normal or sphere, and the reverse occurring in the Aims To examine the validity of the abnormal, has been heavily debated. southern hemisphere. Making the connection influenza^ schizophrenia hypothesis. The interest in genes gained momentum from this information to the influenza±influenza± after the rediscovery of Mendel's laws schizophrenia theory may now seem obvious, MethodMethod A review of register-based around 1900, the year in which Sigmund but in fact psychiatry hadfor many years epidemiological studiesstudiesin in Denmark Freud published Die Traumdeutung. Social.Social fumbled for the hypothesis that was first conducted over a10-year period. Darwinism and later, sociobiology further clearly formulated andtested in 1988. As stressed the importance of biology and long ago as the 1920s Menninger %1928) ResultsResults The studies reviewed provided genes. Misuse as part of the so-called scien- had suggested a connection, but the critical strong inferential evidence in favour of the tific evidence for Nazi ideology discredited mass of scientific methodology, knowledge genetics after the Second World War. For and statistical material was not to hand hypothesis, but some methodological the younger generation of psychiatrists the until 60 years later. The Mednick paper problems are unresolved and not all relevance of genetics is self-evident, but was thus a breakthrough in research and replication studies have been positive. many of the generation trained during the stimulated many replications. 1950s to the 1970s have had to acquire this The study used case records from the Conclusions The brain-damage knowledge from the beginning. Helsinki Mental Hospital's files. The hypothesis points to possibilities for Great efforts are now being concentrated authors found that individuals whose sec- identifying high-risk individuals at an early on the identification of specific genes that ond trimester of foetal life coincided with increase or decrease the risk of psychiatric the 1957 influenza epidemic had an in- stage of life and perhaps establishing disorders. Furthermore, genes of importance creased risk of developing schizophrenia specific preventive programmes.There is, for treatment response or side-effects of later in life. The next step was to design a however, a great need for closer current psychotropic medication, interaction larger-scale survey, controlling for more of international collaborationincollaboration in future with the environment and personality factors the epidemiological variables. research. are also being sought, as are others of import- The Danish National Board of Health ance for many aspects of brain function and has for almost a century registered the inci- Declaration of interest None. development. dence of influenza in the whole of Denmark The development of molecular genetics week by week. All these little peaks through has greatly strengthened the promise of the years were registered in a study data- such investigations, and it is generally be- base. A similar data-set was generated from lieved that information about individual the Danish Psychiatric Central Register genes obtained by molecular genetic re- %Munk-Jùrgensen & Mortensen, 1997), all search will be necessary to advance studies patients with a diagnosis of schizophrenia on environmental factors involved in psy- and subsequently reported to the register chiatric diseases and their interplay with being entered according to date, month the involved genes. Research into the envir- and year of birth. By comparing the two onmental components has been somewhat data-sets, overlap between gestation periods s30 Downloaded from https://www.cambridge.org/core. 30 Sep 2021 at 20:04:17, subject to the Cambridge Core terms of use. EPIDEMIOLOGY: THE INFLUENZA ^ SCHIZOPHRENIA THEORY characterised by high, medium and low the 1994 study by Mednick et aletal, statistical,statistical One further epidemiological finding, influenza incidence and birth cohorts power tends to be greatly reduced owing to which provides tentative support for the characterised by schizophrenia incidence difficulties in obtaining sufficiently large brain-damage theory, is the significant peaks could be searched for. Adding all numbers of probands. decrease in the incidence of treated schizo- the many influenza peaks and the incidence There is now an extensive literature on phrenia in the Western world, which has of treated schizophrenia for the correspond- the viral infection±schizophrenia theory. A now been reported by more than 20 studies ing birth cohorts demonstrated a significant Medline search performed in January 1998 %Munk-Jùrgensen, 1995). There has been correlation between influenza peaks in the using the key wordsINFLUENZA andand much speculation about this phenomenon. population from 1911 to 1950 and an in- SCHIZOPHRENIAfound 99 entries relating The most obvious explanation is the rapid creased schizophrenia risk for those whose to replication studies, studies testing other run-down and closure of many psychiatric gestation coincided with influenza periods, types of viral infection, review articles, institutions. However, there is also a poss- most pronounced for those in the sixth editorials and journal correspondence, with ibility that the post-war improvement in gestation month during the influenza peak an annual frequency peaking in 1994 %Fig. 1). maternity welfare and obstetric care, one periods %Barr et aletal, 1990). The correlation In summary, the 10-year period of of the successful preventive developments was significant, but the finding could ex- influenza±schizophrenia research in the in Western medicine, may have resulted in plain no more than 4% of total variance. 1980s and 1990s has provided strong infer- a reduction of foetal and perinatal brain This is an example of how large-scale ential evidence that influenza infection in damage, and that this could be a partial register epidemiology can be used to exam- pregnancy, especially in the second trime- explanation of the apparent decrease in ine a statistical trend and to test whether a ster, can cause damage to the immature schizophrenia incidence observed decades hypothesis is worth keeping. The various brain which increases the risk for schizo- later.later. methodological problems connected with phrenia later in life. It took 10 years to reach the conclusion this type of epidemiological research will Almost the same story can be told for that influenza in one way or another causes not be discussed here, but the salient point complications other than viral infections minor damage to the immature brain, in- is that one cannot draw conclusions about during pregnancy and birth %Geddes & creasing the risk of schizophrenia in geneti- causation on the basis of such correlations Lawrie, 1995). The influenza hypothesis cally vulnerable persons. Even today this alone. We do not know that the relative has become part of a more general theory connection is not firmly established, since excess of patients with schizophrenia in of the consequences of brain damage during some studies have been unable to replicate certain years were born to mothers who gestation, whether due to viral infections, the association between maternal influenza actually suffered from influenza during obstetric complications or nutritional defi- and schizophrenia %Erlenmeyer-Kimling etet
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