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The New England Journal of Medicine -- February 25, 1999 -- Vol. 340, No. 8 Understanding the Causes of Schizophrenia Schizophrenia is one of our most important public health problems. It is a common, tragic, and devastating mental illness that typically strikes young people just when they are maturing into adulthood. Once it strikes, morbidity is high (60 percent of patients are receiving disability benefits within the first year after onset), (1) as is mortality (the suicide rate is 10 percent). (2) Despite the fact that people with schizophrenia are all around us (the lifetime prevalence is 1 percent worldwide), (2) this illness is often misunderstood, and people with schizophrenia are stigmatized by both the medical profession and the public. Our understanding of the causation of schizophrenia has increased in the past several decades. Schizophrenia is a disease of the brain that is expressed clinically as a disease of the mind. Both its symptoms and signs and its associated cognitive abnormalities are too diverse to permit its localization in a single region of the brain. The working hypothesis shared by most investigators is that schizophrenia is a disease of neural connectivity caused by multiple factors that affect brain development. (3,4,5) Our current model of the causation of schizophrenia is very similar to that used to understand cancer. That is, schizophrenia probably occurs as a consequence of multiple "hits," which include some combination of inherited genetic factors and external, nongenetic factors that affect the regulation and expression of genes governing brain function or that injure the brain directly. Some people may have a genetic predisposition that requires a convergence of additional factors to produce the expression of the disorder. This convergence results in abnormalities in brain development and maturation, a process that is ongoing during the first two decades of life. (6) The abnormalities are typically not focal but, rather, involve distributed neural circuits and neurotransmitter systems. When the connectivity and communication within neural circuitry are disrupted, patients have a variety of symptoms and impairments in cognition. Behind this diversity, however, is a final common pathway that defines the illness. For schizophrenia, it is misregulation of information processing in the brain. Ongoing etiologic studies must focus on finding the origins of abnormalities that lie beneath the clinical surface. The symptoms and signs of schizophrenia are very diverse, and they encompass the entire range of human mental activity. They include abnormalities in perception (hallucinations), inferential thinking (delusions), language (disorganized speech), social and motor behavior (disorganized behavior and abnormal or stereotyped movements), and initiation of goal-directed activity (avolition), as well as impoverishment of speech and mental creativity (alogia), blunting of emotional expression (flattened affect), and loss of the ability to experience pleasure (anhedonia). These symptoms and signs occur in patterns that may not overlap; one patient may have hallucinations and affective flattening, whereas another has disorganized speech and avolition. The diversity and nonoverlapping pattern of symptoms and signs suggest a more basic and unifying problem: abnormalities in neural circuits and fundamental cognitive mechanisms. (7,8) Patients with schizophrenia also have impairment in many different cognitive systems, such as memory, attention, and executive function. This is often referred to as a generalized deficit, and its existence provides additional support for the likelihood that the disorder is the result of a basic process such as a general impairment in the coordination of information processing. (7,8) Unlike other mental illnesses that are also characterized by deficits in multiple cognitive systems (e.g., Alzheimer's disease), however, schizophrenia does not usually involve deterioration or progress to dementia. Instead, the degree of impairment is relatively stable after an initial fulminant course, which may last for several years. After that point, cognitive function may even improve. (9) Schizophrenia also differs from the classic dementias in that there are no visible neuropathological markers such as plaques, tangles, or Lewy bodies. The gliosis that is a marker of neuronal death in neurodegenerative diseases is not present in schizophrenia. This suggests that the etiology and pathophysiology of schizophrenia must be related to maturational or developmental brain processes such as formation of neurites, synaptogenesis, neuronal pruning, or apoptosis. (1,4,5,10) This defines the period for the changes that result in schizophrenia as sometime between the beginning of neuron formation and migration (around the second trimester) and young adult life. Although this is a long period, it focuses our thinking about pathophysiology and etiology by suggesting the importance of examining the molecular processes that regulate and shape brain development and the external factors that may influence those processes. The most typical age for the onset of schizophrenia is during the late teens and early 20s, a time when brain maturation is reaching completion (6); this suggests that the pathogenesis of the disease must involve a neurodevelopmental process related to the final stages of "brain sculpturing," such as pruning or activity-dependent changes (psychological experiences that affect brain plasticity). (4) As discussed by Mortensen et al. in this issue of the Journal, (11) schizophrenia runs in families, and twin and adoption studies indicate that such familial aggregation is largely accounted for by genetic factors. However, the same studies also indicate that familial genetic transmission can account for only a portion of the cases of schizophrenia; for example, the concordance rate in monozygotic twins is approximately 40 percent, suggesting that nongenetic factors must also have a role. Genetically, schizophrenia resembles other complex illnesses, such as diabetes mellitus, in that it is nonmendelian, probably polygenic, and probably multifactorial. Recent linkage, association, and candidate-gene studies suggest multiple susceptibility loci, including some on chromosomes 6, 8, and 22. (12) Not only are multiple genes probably involved, but the nongenetic factors are likely to be multiple as well, as demonstrated by the study by Mortensen et al. (11) They found that both a family history of schizophrenia and nongenetic factors, such as birth during the winter and birth in an urban area, increased the relative risk of schizophrenia. These findings highlight the probability that the clinical manifestations of schizophrenia result from an unfortunate convergence of interacting causal factors. Their results suggest that infections during pregnancy or childhood and other factors related to urban birth may play a part in causing schizophrenia. Other possible nongenetic factors contributing to increased risk include the effects of poor nutrition on fetal and childhood brain development, exposure to toxins that damage neurons or affect neurotransmitter systems (e.g., alcohol, amphetamines, and retinoids), and exposure to radiation that might induce mutations. (12) Since schizophrenia persists as an illness despite the fact that the majority of its victims do not marry or procreate, and since it appears to have the same lifetime prevalence throughout the world, it seems likely that multiple different, nonspecific, nongenetic factors that affect neurodevelopment are implicated. Such nongenetic factors could come into play at any time during brain development and may primarily affect the regulation of the expression of the many genes that influence brain development and function. The causation of schizophrenia is clearly a complicated matter. As our understanding of it progresses, however, our hope for improving the lives of patients with the disease increases. If we are able to identify the critical periods in brain development during which causative factors work their mischief, and if we can delineate the molecular and cellular processes that impair brain development and neural connectivity, then we can begin to identify preventive techniques that could be implemented before injury occurs. We can also potentially improve the treatment of schizophrenia, which currently focuses on reversing abnormal neural communication by blocking dopamine or serotonin receptors. Although newer treatments such as the recently developed atypical neuroleptic drugs have already substantially improved the outcome of schizophrenia, they remain blunt instruments that have relatively generalized effects on neurotransmitter systems. As we identify more precisely the cascade of events leading to schizophrenia -- neurodevelopmental abnormalities that lead to neural misconnections that lead, in turn, to impaired cognitive processing -- we will also identify better and more specific targets for future treatment. Nancy C. Andreasen, M.D., Ph.D. University of Iowa Iowa City, IA 52242 The Neurodevelopmental Hypothesis of Schizophrenia Clare Holtam Introduction to Schizophrenia The Aetiology of Schizophrenia Neuropathology The Premorbid Child Aetiological Factors Mechanisms of delayed onset Conclusion References Schizophrenia by Ben Green Introduction Schizophrenia is a term used to describe a group of mental illnesses which are diverse in nature and cover a broad range of cognitive, emotional and behavioural disturbances. It is a common disorder with up to 600,000 sufferers in the UK. The incidence and prevalence rates are considered to be consistent World wide at 0.15-0.20 per 1000 per year and 2-4 per 1000 per year, respectively. The lifetime risk of schizophrenia in the general population is about 1% but for first-degree relatives of sufferers this is increased to 10%. (1) Core features of schizophrenia include: auditory hallucinations, particularly in the third person; changes in thought construction and form; and bizarre delusions in which, for example, the patient believes their thoughts to be available to others or that they are influenced by outside forces. These positive psychotic phenomena comprise the key diagnostic features, and usually occur together with changes in an individual's behaviour or social functioning. In addition, there may be negative features, such as restriction of the range of emotions (blunting of affect) and decreased ability to initiate thoughts and ideas (poverty of thought). Currently, operational criterion-based systems are used to diagnose schizophrenia; examples of such systems include the International Classification of Diseases, tenth edition (ICD-10) (1) and the Diagnostic and Statistical Manual of Mental Disorders, fourth edition (DSM-IV). (2) Schizophrenia is divided into a number of subtypes, although many patients present with symptoms and behaviours belonging to more than one category. The most common subtype of schizophrenia currently found in the UK is paranoid schizophrenia which has a later age of onset and a more insidious course than the others. Schizophrenia has a dramatic influence on the lives of sufferers and their families often striking in early adult life just when individuals would be experiencing most independence and starting a productive career. In addition to the social and psychological anguish it causes schizophrenia creates a huge economic burden for society. In the UK 5.4% of the total National Health Service inpatient costs are attributable to schizophrenia. When inpatient, outpatient, primary care, pharmaceutical, community and social services expenses are combined the total cost to the UK of 2.6 billion per year is estimated. (4) The Aetiology of Schizophrenia The cause of schizophrenia is unknown. During this century various theories have been proposed to ranging from social and psychological ideas to biological, genetic and environmental hypotheses. A brief overview some of these theories is presented below. In 1948 Fromm-Reichmann suggested a 'schizophrenogenic' mother, one who is both overprotective and hostile to her children, caused schizophrenia. Lidz proposed the disorder was the consequence of 'marital skew 'and' marital schism. (5, 6) Marital skew describes the situation where one parent dominates the other. Marital schism is when parents have contrary views which are thought to cause a child to have divided loyalties. However, subsequent studies failed to confirm such ideas (7, 8) and it is suggested the findings were the result, as opposed to the cause of schizophrenia. Disorders of communication within families have also been suggested to be of aetiological significance. (9, 10) Life events have been proposed to be a cause of schizophrenia. This suggestion is based on the finding that schizophrenics experience significantly more life events in the three weeks prior to the onset of the illness and that life events appear to precipitate relapses. (11-15) Biochemical theories of schizophrenia include the dopamine and glutamate hypotheses. (16) The dopamine hypothesis was based on the pharmacological findings that the drugs stimulating central dopamine receptors, can produce a disorder indistinguishable from schizophrenia; and that anti-psychotic drugs block dopamine receptors. All the new information produced by studies into schizophrenia, however, cannot be accounted for simply by abnormalities with dopamine. Family, twin, adoption and epidemiological studies provide considerable evidence for the genetic contribution to the aetiology of schizophrenia. (1) However, despite numerous linkage and association studies with candidate genes for schizophrenia no one gene for schizophrenia has been found and results have largely been negative or inconsistent. (17) The possibility that schizophrenia is a single gene disorder has been excluded (18) and transmission is now thought to involve multiple susceptible loci. (1) Although twin studies provide compelling evidence for genetics in the causation of schizophrenia they also establish the importance of environmental influences. The findings that both affected and unaffected monozygotic twins pass the same increased risk of development of schizophrenia to their children; (19, 20) and in monozygotic twins discordant for schizophrenia the affected twin has larger ventricles and less temporal lobe grey matter than the unaffected twin (21, 22) suggests the involvement of more than just genetics in the aetiology of the disorder. The environmental factors implicated in the aetiology of schizophrenia are discussed in the following section. The neurodevelopmental hypothesis of schizophrenia proposes that a proportion of schizophrenia is the result of an early brain insult, either pre or perinatal, which affects brain development leading to abnormalities which are expressed in the mature brain. (23-26) This idea is not new, Kraeplin and others throughout the 20th century argued that some cases of schizophrenia probably resulted from insults that cause cerebral maldevelopment. (27, 28) The cause of the brain lesion is postulated to be either from the inheritance of abnormal genes, which impair brain development, or from some fetal or neonatal adversity. The following section discusses the strength of the neuropathological, clinical and epidemiological findings evidence in support of the neurodevelopmental hypothesis. Firstly, reports of neuropathology will be evaluated followed by data from studies of premorbid children with abnormalities which are interpreted to represent cerebral maldevelopment. The third section reviews studies that have attributed the cerebral abnormalities to specific aetiological factors. Finally, there will be a discussion of the mechanisms proposed to explain how and why the onset of the illness is delayed until 20-30 years after the initial insult. Neuropathology Post-mortem and brain imaging studies into schizophrenia have shown the disorder to be associated with disturbances in cerebral structure. However, researchers have reported different brain regions to be affected to varying extents. A meta-analysis of 40 MRI studies (29) described the following abnormalities in the brains of schizophrenics: Volume reductions: · Whole Brain (3%) · Temporal lobe (left 6% right 9.5%) · Amygdala/hippocampal complex (left 6.5%, right 5.5%) Volume is increased in the lateral ventricles (left 44%, right 36%) Grey matter is reduced but white matter volumes may be increased These brain abnormalities are thought to be neurodevelopmental in origin, as opposed to neurodegenerative, because of reports they are found in newly diagnosed patients as well as chronic schizophrenics, (30-35) and as they appear to be non- progressive. (36-41) Also, it is argued that if the disease process of schizophrenia were progressive then so would be the neuropsychological profile; but the cognitive deficits found in schizophrenia show no deterioration over the course of the illness. (42) However, reports of changing brain volumes in schizophrenia are inconsistent (43), and since 1989 there have been both positive (44-46) and negative (47, 48) longitudinal computed tomography findings of progressive volume loss in schizophrenia; and both positive (49-51) and negative (38, 52) longitudinal magnetic resonance imaging results in follow-up investigations of first episode schizophrenia. In addition, there is evidence for progressive ventricular enlargement in childhood- onset schizophrenia. (53) Moreover, the failure to find conclusive evidence of brain volume loss over time is not proof that neuronal degeneration does not occur in schizophrenia unless it is assumed that there is a temporal relationship between degeneration and symptomatic illness. Many imaging studies also report the presence of excessive extracerebral CSF in schizophrenia. (54-55) This is difficult to explain using a model of an early static defect in brain development as brain volume triples between birth and the age of five years and any increase in extracerebral volume would tend to be filled up by the outward growth of the brain. Nevertheless, compelling evidence in support of the neurodevelopmental hypothesis comes from studies of cortical cytoarchitecture which discovered neurons in schizophrenic brains to be misplaced, mis-sized and disorganised. (56-59) Such findings are difficult to explain in any other than neurodevelopmental terms as they are suggestive of impaired neuronal migration which takes place during the second trimester of pregnancy. However the findings remain controversial. (60) Gliosis is the neural scarring which accompanies brain lesions other than those which occur during early development and is regarded as a characteristic feature of neuronal degeneration. In schizophrenic brains the balance of neuropathological evidence is strongly against excessive gliosis being characteristic of schizophrenia. (61-68) Also, there is no evidence of increased glial membrane turnover signals in magnetic resonance spectroscopy in either chronic schizophrenia or at the time of disease onset. (69) This is supportive of the idea that the damage to the brain in schizophrenia occurs early in life and is not due to a neurodegenerative process. However, earlier studies of schizophrenic brains did report gliosis, (70) although this could be explained by technical issues; with results being dependent on specific staining procedures (71) or vulnerability to long fixation times. (72) In addition, some researchers report that the brain can respond to injury with gliosis as early as the 20th week of gestation (73) and certainly throughout the third trimester (74) suggesting that any perinatal brain injury should result in gliosis. In schizophrenia there is a failure to develop normal cerebral asymmetries. (75-80) Since normal human brain asymmetries are formed early in development, during the second trimester of gestation, these findings suggest the occurrence a pathological event interfering with this stage of development. However, such findings remain controversial and are only suggestive, not conclusive, of deviant neurodevelopment. (81-83) In some studies, pathological changes appear to affect the left side of the brain more severely than the right. (20, 60, 76, 84, 85) This is potentially explicable in neurodevelopmental terms as the left hemisphere of the brain is thought to develop more slowly than the right hemisphere during early to mid gestation and so could be more vulnerable to injury or vulnerable for a longer period of time. Further evidence in support of the neurodevelopmental hypothesis is the aberrant expression of developmental and plasticity associated markers such as the embryonic isoform of the neural adhesion molecule (NCAM) (86) and the growth-associated protein 43 (GAP-43) (87) in the brains of schizophrenics. Finally, sulcal-gyral abnormalities have been reported in some post-mortem studies of schizophrenic brains. (88, 89) Since gyrification in the human brain is largely intrauterine between weeks 16 and 29 (90) such abnormalities are highly suggestive of a process affecting the fetal brain at this stage of development. However, these studies were not conducted blind and may not have accounted sufficiently for the sex differences in the sulcal-gyral pattern. (91) Nevertheless, the findings have since been confirmed in a later study (92) The Premorbid Child If schizophrenia is caused by an aberration in the developing brain then it is reasonable to expect some subtle abnormalities of neural function and developmental anomalies to be present in early life. Several lines of circumstantial data support this possibility. Preschizophrenic children have a higher incidence of: neuromotor abnormalities; delayed attainment of developmental milestones; and behavioural and intellectual abnormalities. (93-96) They are also often described as having 'schizoid' personality traits such as being socially withdrawn, aloof and preferring to play alone. (94, 97) One study, using old home movie tapes, revealed that in the first two years of life children who were to become schizophrenic had reduced responsiveness, less positive affect and less eye contact. (98) Another study reported that children who go on to develop schizophrenia perform less well than their contempories in tests of neuropsychological and academic performance. (99) 75% of people who go on to develop schizophrenia have 'soft' neurological signs as children. These include: slightly abnormal gaits in children; dysgraphaesthesia; proprioceptive errors; tics; twitches and epileptic attacks. (93, 94) The results of these studies, while open to other interpretations, are consistent with the possibility of brain maldevelopment. Nevertheless, despite all these reports, many children who go on to develop schizophrenia have shown high levels of social, academic and occupational functioning. So it appears there is a subgroup of schizophrenics who have been subtly impaired for years before the onset of overt positive schizophrenic symptoms, implying a proportion of schizophrenia is attributable to a neurodevelopmental defect. Schizophrenic patients are also reported to have a higher prevalence of minor physical anomalies than the general population. (100) Dermatoglyphic asymmetry, (101-103) and cerebral anomalies, such as agenesis of the corpus callosum and cavum septum pellucidum, and developmental cysts, (104) are both found more commonly in schizophrenics and are both indicative of disturbed intrauterine development. Additionally, minor physical abnormalities including: low set ears; furrowed tongue; high arched palate; curved fingers; greater distance between the eyes and a single palmer crease are also found more frequently in schizophrenics, particularly in males and in those with a positive family history. (100, 105) Both the skin and the central nervous system are derived from the ectodermal tissue in utero, so such visible anomalies can be considered as external markers of damage to ectodermal structures of the fetus and as such can be interpreted as indirect support for the occurrence of aberrant neurodevelopment. Such anomalies are also found in other disorders of neurodevelopment such as Down's syndrome and intrauterine viral encephalopathies. However, this theory remains controversial (106) with the true frequency of these abnormalities in schizophrenia unknown and uncertainty as to whether all the morphological characteristics reported are actually pathological. Aetiological factors If schizophrenia is a neurodevelopmental disorder the causes must act early in development. It is feasible that genes may be involved in the genesis of the brain abnormalities and the finding that environmental risk factors associated with schizophrenia act pre- or perinatally offers further support for the neurodevelopmental hypothesis. However, the presence of risk factors early in life does not necessarily mean that schizophrenia must be developmental in an overall sense, for example, there are early risk factors for stroke. People who develop schizophrenia are born in winter and spring slightly more frequently than the general population. (107) and several studies indicate that the increased risk for winter births is enhanced among those born in large cities and is greater the colder the winter. (108, 109) The possibility that this observed seasonality could be a statistical artefact or merely an accentuation of the seasonality seen in general births has generally been refuted. (110) The findings suggest the influence of some intrauterine factor that varies seasonally. Environmental factors proposed include infectious agents, nutritional factors, and the temperature variations at the time of conception. Maternal infection could affect fetal brain development through in utero infection; maternal fever; maternal antibodies crossing the placenta and acting as fetal anti-brain antibodies; or maternal use of analgesics. Support of infection as the cause of this phenomenon are the reports that viral entry into the CNS is promoted by exposure to cold (111) and the demonstration by rubella that viral infection in a pregnant women can cause permanent damage to the fetal nervous system. Maternal infection with the influenzae is also claimed to be associated with the later development of schizophrenia in the unborn child, particularly in females. (112-118) However, the existence and importance of this effect remains controversial, (119- 121) as although ecological studies show an association between schizophrenia and the timing of the great influenzae epidemics there is yet to be a convincing demonstration of this effect in individuals known to both have been exposed to influenzae in utero and to have developed schizophrenia. The mechanism by which maternal influenza increases the risk of schizophrenia in the unborn baby is not established. It is possible it is mediated through maternal antibodies to influenzae cross-reacting with neuronal proteins, a mechanism that has been observed in rabbits (122) or that certain mothers are genetically predisposed to produce a harmful immune response (123) Any theory attempting to explain this association must also account for why only a minority of mothers infected with influenzae during pregnancy have a child who becomes schizophrenic. Several studies have found that obstetric complications during antenatal life or delivery are more frequent in patients with schizophrenia, especially in male, early onset schizophrenics. (124-133) However, a meta-analysis of such studies suggests that there may be considerable publication bias in the literature and that prospective, population based studies tended to be largely negative. (134) Acute late onset and female schizophrenic subjects do not seem to share the excess of obstetric complications which may be one reason why not all studies show such an association. (135-137) Ischaemia is the mechanism by which obstetric complications have been proposed to increase the risk of the later development of schizophrenia. Obstetric complications causing hypoxic ischaemia in the pre- or perinatal period can lead to intraventricular or periventricular bleeds, resulting in ventricular enlargement. (138) Furthermore, the pyramidal cells in the CA1 region of the hippocampus are among the most vulnerable in the human brain to mild ischaemia. Excitotoxic damage associated with perinatal hypoxia could also account for some of the neurochemical abnormalities that are found in schizophrenia. (139) However, pre-existing brain dysfunction may predispose to obstetrical complications and some investigators have interpreted the association between obstetric complications and schizophrenia as being an indication of fetal abnormality. (140) Maternal malnutrition in early gestation (141, 142) is another intrauterine environmental event which appears to increase the risk of developing schizophrenia in a dose dependent way. However, this study (142) did not control for the implication of social class both in access to food and on risk for schizophrenia. Nevertheless, four lines of evidence support prenatal nutritional deficiencies as a plausible set of risk factors for schizophrenia: (143) · Their effects are not incompatible with the epidemiology of schizophrenia · They have adverse effects on brain development · General malnutrition results in neuropathological anomalies of brain regions implicated in schizophrenia · Prenatal malnutrition affects maternal systems critical to the developing fetal nervous system. In the light of the widely accepted data that genetic factors convey susceptibility to schizophrenia, it is not surprising that there have been speculation about genetic factors that may affect brain development in schizophrenia. Since approximately 30% of the genome is expressed in the brain (144) and many genes are turned on and off during discrete phases of brain development, there are many potential candidate genes for aberrant neurodevelopment. It is suggested a mutation in a gene relating to brain development could result in the neuropathological deviations found in the developing brain. (145) Alternatively, it is hypothesized a genetic defect could predispose the schizophrenic brain to be adversely affected by intrauterine or perinatal environmental events. Another possibility is that the genetic control of brain development may be disrupted by adverse environmental events which results in the cerebral pathologies found in the brains of schizophrenics. (146) Mechanisms of delayed onset It is easy to see how the neuronal abnormalities in the frontal and temporal lobes could result in an abnormal pattern of cortical connections and cause the premorbid abnormalities in children and the social and cognitive defects shown by schizophrenic adults. However, the neurodevelopmental hypothesis proposes that such pre or perinatal lesions can produce the positive symptoms of schizophrenia 2-3 decades later. Animal studies have demonstrated that a brain lesion sustained in early life can remain quiescent until early adulthood after which time in influences behavioural and neuropharmacological phenomena that mimic schizophrenia. For example, neonatal damage in the temporal lobe has little effect in juvenile monkeys, but leads to behavioural and pharmacological abnormalities in adulthood. (147) Also, prenatal lesions in the hippocampi of rats remain apparently silent until adult life. (148-154) Nevertheless, although these studies do show that a defect in development can result in a latency before the onset of symptoms they do not demonstrate spontaneous late deterioration of function after an early lesion which is what occurs in schizophrenia. A study in monkeys have been interpreted as showing that prenatal lesions of the dorsolateral prefrontal cortex can remain undetected until sexual maturity when deficits in neuropsychological tests arise. (155) However, careful examination of the study does not support this interpretation; the performance of the 'lesioned' monkeys in the tests did not become poorer as they progressed from infancy into adulthood, the 'non-lesioned' monkeys just performed better. It should also be noted that the performance of monkeys who sustained lesions in infancy was always superior to those who sustained lesions in the juvenile period which is implies some degree of compensatory organization. So therefore this study, although frequently cited as supporting the neurobiological plausibility of the neurodevelopmental hypothesis, in fact it does not. It is possible that a similar process as is occurring in these animals with early brain lesions explains why preschizophrenic children do not show the positive symptoms of schizophrenia until early adult life. (156) A large proportion of all the cells generated in the developing nervous system die by the time it is mature. After peaking during childhood, synaptic density in the human frontal cortex declines by 30-40% by adulthood. A process of selective neuronal death and progressive synaptic elimination appears to operate throughout adolescence to eliminate early errors of connection and it is suggested that this sculpting of this nervous system might be abnormal in schizophrenia. (157-160) Integrating this idea with the neurodevelopmental hypothesis results in the suggestion that the maldevelopment in utero sets the stage for secondary synaptic disorganisation in adolescence. This hypothesis has been supported by: phosphorus- 31 magnetic resonance spectroscopy studies of neural membrane phospholipid turnover. (161, 162) Alternatively it is possible that lesion remains dormant until the normal processes of brain maturation in adolescence lead to the use of neuronal circuits that are not greatly developed in children. In support of this idea it has been found that in humans the development (myelination) of circuitry to and from the hippocampus is only complete in adolescence, providing a mechanism whereby a lesion affecting this area may not be apparent until these pathways are mature. (168) Also proposed have been the possibilities of abnormalities of neuronal sprouting (169) or adverse effects of stress related neural transmission. (165) Finally, support for the neurobiological plausibility of the latency period in schizophrenia comes from studying human developmental disorders which also exhibit this phenomenon. Both temporal lobe epilepsy and metachromatic leukodystrophy provide a 'mock-up' of schizophrenia. (166, 167) Conclusion In summary, there is substantial amount of evidence in support of a neurodevelopmental basis for schizophrenia. A specific aetiology is not implicated and multiple genetic and environmental factors may be relevant. These causal factors interact, in an unknown way, to produce aberrant fetal development. It is not certain whether this early developmental aberration is necessary and/or sufficient to 'cause' schizophrenia; probably it just leaves the individual susceptible to the disorder. If, and when the symptoms of schizophrenia occur is thought to be determined by the intervening processes of postnatal cerebral maturation. In order to advance the understanding of the aetiology of schizophrenia future research needs to concentrate on furthering the understanding of brain development and maturation. The genes, proteins and molecular mechanisms involved in normal neuronal proliferation, migration and synapse formation need to be determined. Hopefully, this knowledge will enable the mechanisms involved in aberrant neurodevelopment to be understood. Studies are needed to define the peripubertal trigger which causes the development of psychotic symptoms and explain how and why the disease remains latent for 20-30 years Another area warranting further study is the interactions between the genes and environmental factors associated with the development of schizophrenia. Few of the positive findings supporting the neurodevelopmental hypothesis are undisputed. These inconsistencies probably reflect the fact that schizophrenia is actually a group of pathogenically diverse disorders, of which only one has a neurodevelopmental origin. Indeed, this possibility seems likely because of the clinical diversity of schizophrenia and the many examples elsewhere in medicine where complex phenotypes turn out to be aggregates of discrete diseases. To date, however, attempts to subdivide schizophrenia have yet to provide any evidence of heterogenicity at the neurodevelopmental, or any other, pathogenetic level. References 1. 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