The Neurodevelopmental Hypothesis of Schizophrenia

Clare Holtam


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 

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 

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 

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 

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. 


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 

Volume reductions:


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. 

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 

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) 


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)


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. 


1. McGuffin P. et al Genetic basis of schizophrenia. Lancet 1995 346 September 9 678-682
2. World Health Organisation. International Classification of diseases 10th edn Geneva WHO 1994
3. American Psychiatric Association. Diagnostic and statistical manual of mental disorders, 4th edition (DSM-IV) 
Washington DC American Psychiatric Press 1994
4. Knapp M. Costs of schizophrenia. Br. J. Psychiatry 1997 171 509-18
5. Lidz R.W. and Lidz D. The family environment of schizophrenic patients. American Journal Psychiatry 1949 106 332-45
6. Lidz T. et al Schizophrenia and the family. International University Press New York 1968
7. Ferreira A.J. & Winter W.D. Family interaction and decision making. Archives of General Psychiatry 1965 13 214-23
8. Sharan S.N. Family interaction with schizophrenia and their siblings. Journal of Abnormal Psychology 1965 71 345-53
9. Bateson G. et al Towards a theory of schizophrenia. Behavioural Science 1956 1 251-64
10. Wynne L.C. & Singer M.T. Thought disorder and family relations of schizophrenics. I A research strategy. Archives 
General Psychiatry 1963 9 191-8
11. Brown G.W. & Birley J.L.T. Crisis and life change at the onset of schizophrenia. Journal of Health and Social Behaviour 
1968 9 203-24
12. Jacobs S. et al Recent life events in schizophrenia and depression. Psychological medicine 1974 4 444-52
13. Jacobs S. & Myers J. Recent life events and acute schizophrenic psychosis: a controlled study Journal of nervous and 
mental disease 1976 162 75-87
14. Bebbington P.E. et al Life events and psychosis. British Journal of Psychiatry 1993 162 72-9
15. Norman R.M.G. & Malla A.K. Stressful life events and schizophrenia (1) a review of research British Journal of 
Psychiatry 1993 162 161-6
16. Carlsson A et al A glutamergic deficiency model of schizophrenia British Journal of Psychiatry 1999 174 (suppl 37) 2-6)
17. Portin P. et al A critical review of genetic studies of schizophrenia. II. Molecular genetic studies Acta Psychiatrica 
Scandinavica 1997 95 73-80
18. O'Donovan M.C. Psychiatric Genetics '99 Candidate gene association studies of schizophrenia American Journal Human 
Genetics 1999 65 587-592
19. Gottesman I.I. Bertelsen A. Confirming unexpressed genotypes for schizophrenia. Risks in the offspring of Fischer's 
Danish identical and fraternal twins. Arch Gen Psychiatry 1989 46 867-72
20. Kendler K.S. Diehl S.R. The genetics of schizophrenia, a current genetic-epidemiologic perspective. Schizophr Bulletin 
1993 19 261-85
21. Suddath R.L. et al Anatomical abnormalities in the brains of monozygotic twins discordant for schizophrenia. New 
England Journal of Medicine 1990 322 789-794 
22. Reveley A.M. et al Cerebral ventricular size in twins discordant for schizophrenia New England Journal of Medicine 1990 
322 788-94
23. Weinburger D.R. Implications of normal brain development for the pathogenesis of schizophrenia. Archives of General 
Psychiatry 1987 44 660-669
24. Murray R.M. & Lewis S.W. Is schizophrenia a neurodevelopmental disorder? British Medical Journal 1987 295 681-682
25. Murray R.M. et al A neurodevelopmental approach to the classification of schizophrenia. Schizophreina Bulletin 1992 18 
26. Bloom F.E. Advancing a neurodevelopmental origin for schizophrenia Archives of General Psychiatry 1993 50 224-227
27. Southard E.E. On the topographical distribution of cortex lesions and anomalies in dementia praecox, with some account 
of their functional significance. American Journal of Insanity 1915 71 603-671
28. Kraeplin E. (ed) Dementia Praecox and Paraphrenia 1919 Livingstone Edinburgh
29. Lawrie S.M. et al Brain abnormality in schizophrenia. British Journal of Psychiatry 1998 172 110-120
30. Bogerts B. et al Reduced temporal limbic structures volumes on magnetic resonance images in first episode schizophrenia. 
Psychiatry Res Neuroimaging 1990 35 1-13
31. Turner S.W. et al Computerised tomographic scan changes in early schizophrenia – preliminary findings. Psychological 
Medicine 1986 16 219-25
32. DeLisi L.E. et al Brain morphology in first-episode schizophrenic-like psychotic patients: a quantative magnetic 
resonance imaging study. Biological Psychiatry 1991 129 159-75
33. Degreef G. et al Volumes of the ventricular system subdivisions measured from magnetic resonance images in first 
episode schizophrenic patients Archives of General Psychiatry 1992 49 531-7
34. Noupoulos P. et al Brain morphology in first episode schizophrenia American Journal of Psychiatry 1995 152 1721-3
35. Lieberman J. et al Time course and biological correlates of treatment response in first-episode schizophrenia. Archives of 
General Psychiatry 1993 50 369-376
36. Nasrallah H.A. et al Cerebral ventricular enlargement in schizophrenia: a preliminary follow-up study. Archives of 
General Psychiatry 1986 43 157-9
37. Vita A. et al Brain morphology in schizophrenia: a 2 to 5 years CT scan follow-up study. Acta Psychiatrica Scand. 1988 
78 618-621
38. Jaskiw G.E. et al Cerebral ventricular enlargement in schizophreniform disorder does not progress – a seven year follow-
up study Schizophrenia Research 1994 14 23-8
39. Marsh L. et al Medial temporal lobe structures in schizophrenia: relationship of the size to duration of the illness 
Schizophrenia Research 1994 11 225-238 
40. Illowsky B.P. et al Stability of CT scan findings: results of an 8 year follow-up study Journal of Neurology Neurosurgery 
Psychiatry 1988 51 209-213
41. Abi-Dargham A. et al Evidence against progression of in vivo anatomical abnormalities in schizophrenia Schizophrenia 
Res 1991 5 210
42. Hyde T.H. et al Is there a cognitive decline in schizophrenia? A cross sectional study. British Journal of Psychiatry 1994 
164 494-500
43. Chua S.E. & McKenna P.J. Schizophrenia: a brain disease? A critical review of structural and functional cerebral 
abnormality in the disorder. British Journal of Psychiatry 1995 166 563-582
44. Kemali D. et al Ventricle to brain ratio in schizophrenia: a controlled study follow-up. Biological Psychiatry 1989 26 
45. Woods B.T. et al Progressive ventricular enlargement in poor outcome schizophrenia: comparison with bipolar affective 
disorder and correlation with clinical course Biological Psychiatry 1990 27 341-352 
46. Davis K.L. et al Ventricular enlargement in poor outcome schizophrenia Biological Psychiatry 1998 43 783-793
47. Hoffman W.F. et al Three year follow up of older schizophrenics: extrapyramidal syndromes, psychiatric symptoms and 
ventricular brain ratio. Biological Psychiatry. 1991 30 913-926
48. Sponheim S.R. et al Stability of ventricular size after the onset of psychosis in schizophrenia .Psychiatry Research 
Neuroimaging 1991 40 21-29
49. DeLisi .LE. et al A prospective follow-up study of brain morphology and cognition in first episode schizophrenic patients: 
preliminary findings. Biological Psychiatry 1995 38 349-360
50. GurReet et al A follow-up magnetic resonance imaging study of schizophrenia. Archives of General Psychiatry 1998 55 
51. DeLisi L.E. et al Schizophrenia as a chronic active brain process: a study of progressive brain structural change 
subsequent to the onset of schizophrenia Psychiatric Research 1997 74 129-140
52. Vita A. et al Stability of cerebroventricular size in from the appearance of first psychotic symptoms to the later diagnosis 
of schizophrenia. Biological psychiatry 1994 35 960-962
53. Rapoport J.L. et al Childhood onset schizophrenia: progressive ventricular change during adolescence. Archives of 
General Psychiatry 1997 54 897-903
54. Woods B.T. & Yurgelun-Todd D. Brain volume loss in schizophrenia: when does it occur and is it progressive. 
Schizophrenia Research 1991 5 202-204
55. Gur R.E. et al Magnetic resonance imaging in schizophrenia. Archives of General Psychiatry 1991 48 407-412
56. Jakob H. et al Prenatal Developmental disturbances in the limbic allocortex in schizophrenics. Journal Neurological 
Transmission 1986 65 303-26 
57. Arnold S.E. Some cytoarchitectural abnormalities of the entorhinal cortex in schizophrenia. Archivs of Genernal 
Psychiatry 1991 48 625-32 
58. Benes F.M. et al Deficits in small interneurons in prefrontal and cingulated cortices of schizophrenic and schizopaffective 
patients. Archives of General Psychiatry 1991 48 990-1001
59. Abkarian S. et al Altered distribution of nicotamide-adenine dinucleotide phosphate-diaphorase cells in frontal lobe 
schizophrenics implies disturbances of cortical development. Archives of General Psychiatry 1993 50 169-77
60. Zaidel D.W. et al The hippocampus in schizophrenia: literalised increase in neuronal density and altered cytoarchitectural 
asymmetry. Psychological Medicine 1997 
61. Roberts G.W. et al Gliosis in schizophrenia: A survey Biological psychiatry 1986 21 1043-1050 
62. Falkai P. et al Limbic pathology in schizophrenia: the entorrhinal region – a morphometric study. Biological Psychiatry 
1988 24 515-521
63. Bruton C.J. et al Schizophrenia and the brain: A prospective clinico-neuropathological study. Psychological Medicine 
1990 20 285-304
64. Benes F.M. Neurobiological investigation in cingulated cortex of schizophrenic brain. Schizophrenia Bulletin 1993 19 3 
65. Bogerts B. et al A morphometric study of the dopamine-containing cell groups in the mesencephalon of normals, 
Parkinosonian patients, and schizophrenics. Biological Psychiatry 1983 18 951-969
66. Benes F.M. et al Quantitative cytoarchitectural studies of the cerebral cortex of schizophrenics. Archives of General 
Psychiatry 1986 43 31-35
67. Roberts G.W. et al Is there gliosis in schizophrenia? Investigation of the temporal lobe. Biological Psychiatry 1987 22 
68. Stevens C.D. et al Quantitative study of gliosis in schizophrenia and Huntington's chorea. Biological Psychiatry 1988 24 
69. Bertolino A. et al Regionally specific pattern of neurochemical pathology in schizophrenia as assessed by multi-slice 
proton magnetic resonance spectroscopic imaging. American Journal of Psychiatry 1996 153 12 1554-1563
70. Stevens J.R. Neuropathology of schizophrenia Archives of General Psychiatry 1982 39 1131-1139
71. Arnold S.E. et al Recent advances in defining the neuropathology of schizophrenia Acta Neuropathology 1996 92 217-231
72. Selemon L.D. et al Abnormally high neuronal density in the schizophrenic cortex: a morphometric analysis of prefrontal 
area 9 and occipital area 17. Archives of General Psychiatry 1995 52 805-818
73. Roessmann U. et al Pathological reaction of astrocytes in perinatal brain injury: an immunohistochemical study. Acta 
Neurolpathology 1986 70 302-307
74. Roberts G.W. Schizophrenia: a neuropathological perspective British Journal of Psychiatry 1991 158 8-17
75. Petty R.G. et al Reversal of asymmetry of the planum temporale in schizophrenia. American Journal of Psychiatry 1995 
152 715-21 
76. Crow T.J. et al Schizophrenia as an anomaly of development of cerebral asymmetry: a post-mortem study and proposal of 
the genetic basis of the disease. Archives of General Psychiatry 1989 46 1145-50
77. Bilder R.M. et al Absence of regional hemispheric volume asymmetries in first episode schizophrenia. American Journal 
of Psychiatry 1994 151 1437-47
78. Falkai P. et al Disturbed planum temporale asymmetry in schizophrenia. A quantitative post-mortem study Schizophrenia 
Research 1995 14 161-76
79. Falikai P. et al Loss of sylvian fissure asymmetry in schizophrenia: a quantative post-mortem study. Schizophrenia 
Research 1992 7 23-32
80. Rossi A. et al Planum temporale in schizophreina: a magnetic resonance study Schizophrenia Research 1992 7 19-22
81. Kullynych J.J. et al Normal asymmetry of the planum temporale in patients with schizophrenia. Three dimensional 
cortical morphology with MRI British Journal of Psychiatry 1991 48-996-1001
82. Flaum M. et al Effects of diagnosis, laterality and gender on brain morphology in schizophrenia American Journal of 
Psychiatry 1995 152 704-714
83. Bartley A.J. et al Sylvian fissure asymmetries in monozygotic twins: a test of laterality in schizophrenia. Biological 
Psychiatry 1993 34 853-863
84. Waddington J.L. et al Neurodynamics of abnormalities in cerebral metabolism and structure in scizhophrenia. 
Schizophrenia Bulletin 1993 19 55-69
85. Shenton M.E et al Abnormalities of the left temporal lobe and thought disorder in schizophrenia. A quantative magnetic 
resonance imaging study New England Journal of Medicine 1992 327 604-612
86. Barbeau D. et al Decreased expression of the embryonic form of the neural cells adhesion molecule in schizophrenic 
brains Proceedings of National Academy of Sciences USA 1995 92 2785-2789
87. Perrone-Bizzozero N.I. et al Levels of growth associated proteins GAP-43 are selective increased in association cortices in 
schizophrenia Proceedins of the Nationall Acadamy of Sciences 1996 93 14182-14187
88. Jakob H. et al Prenatal developmental disturbances in the limbic allocortex in schizophrenia. Journal of Neural 
Transmission 1986 65 303-26 
89. Jakob H. et al Gross and histological criteria for developmental disorders in brains of schizophrenics Journal of the Royal 
Society of Medicine 1989 82 466-9
90. Armstrong E. et al The ontogeny of human gyrification. Cerebral Cortex 1995 1 56-63
91. Gentleman S.M. Quantitative analysis of temporal lobe gyral patterns in schizophrenics Biological Psychiatry 1991 29 
92. Kikinis R. et al Temporal lobe sulco-gyral pattern anomalies on schizophrenia: an in vivo MR three-dimensional surface 
rendering study Neuroscience Letters 1994 182 7-12
93. Walker E.F. Neuromotor precursors of schizophrenia Schizophrenia Bulletin 1994 20 441-51
94. Jones P. et al Child developmental risk factors for adult schizophrenia in the British 1946 cohort. Lancet 1994 344 1398-
95. Foerster A. et al Premorbid personality in psychosis: effects of sex and diagnosis British Journal of Psychiatry 1991 158 
96. Foerster A. et al Low birth weight and a family history of schizophrenia predict poor premorbid functioning in psychosis. 
Schizophrenia Research 1991 5 3-20
97. Done D.J. et al Childhood antecedents of schizophrenia and affective illness: social adjustments at ages 7 and 11. British 
Medical Journal 1994 309-703 
98. Walker E.F. Prediction of adult onset schizophrenia from childhood home movies of the patients American Journal of 
Psychiatry 1990 147 1052-6
99. Aylward E. et al Intelligence in schizophrenia. Schizophrenia Bulletin 1984 10 430-59
100. Green M.F. et al Minor physical anomalies in schizophrenia patients, bipolar patients and their siblings. Schizophrenia 
Bulletin 1994 20 433-40
101. Fananas L. et al Dermatoglyphic a-b ridge count as a possible marker for developmental disturbance in schizophrenia: 
replication in two samples. Schizphrenia Research 1996 20 307-314
102. Bracha H.S. et al Second trimester markers of fetal size in schizophrenia a study of monozygotic twins. American Journal 
of Psychiatry 1992 149 1355-1361
103. Mellor C.S. Dermatoglyphic evidence for fluctuating asymmetry in schizophrenia British Journal of Psychiatry 1992 160 
104. Lewis S. Structural brain imaging in biological psychiatry British Medical Bulletin 1996 52 465-473
105. Green M.F. et al Minor physical anomalies in schizophrenia. Schizophrenia Bulletin 1989 15 91-99
106. Murphy K.C. & Owen M.J. Minor physical anomalies and their relationship to the aetiology of schizophrenia. British 
Journal of Psychiatry 1996 168 139-142
107. Hare E. 1988 Temporal factors and trends, including birth seasonality and the viral hypothesis. In HA Nasrallah (Ed) 
Handbook of schizophrenia (Vol 3 pp345-377) Amsterdam Elsevier
108. Lewis G. et al Schizophrenia and city life. Lancet 1992 340 137-40
109. Takei N et al Schizophrenia: increased risk associated with winter and city birth – a case control study in 12 regions 
within England and Wales. Journal of Epidemiology and Community Health 1995 49 106-9
110. Sham P.C. et al Schizophrenia following prenatal exposure to influenzae epidemics between 1939 and 1960. British 
Journal of Psychiatry 1992160 461-466
111. Benn-Nathan D. et al Stress-induced neuroinvasivenss of a neurovirulent sindbis virus in cold or isolation in subjected 
mice. Life Sciences 1991 48 1493-500
112. Mednick S.A. et al Adult schizophrenia following prenatal exposure to an influenzae epidemic. Archives of General 
Psychiatry 1988 45 189-92 
113. Cooper S.J. Schizophrenia after prenatal exposure to 1957 A2 influenzae epidermic. British Journal of Psychiatry 1992 
161 394-96 
114. O'Callaghan E. et al Schizophrenia after prenatal exposure to 1957 A2 influenzae epidemic. Lancet 1991 337 1248-50
115. Sham P.C. et al Schizophrenia following prenatal exposure to an influenza epidemic between 1939 and 1960. British 
Journal of Psychiatry 1992 160 461-6
116. Kinugi H. et al Influenzae and schizophrenis in Japan. British Journal of Psychiatry 1992 161 274-275
117. Barr C.E. et al Exposure to influenzae epidemics during gestation and adult schizophrenia. Archives of General Psychiatry 
1990 47 869-874
118. Adams W. et al Epidemiological evidence that maternal influenzae contributes to the aetiology of schizophrenia. British 
Journal of Psychiatry 1993 163 522-534
119. Crow T.J. Prenatal exposure to influenzae as a cause of schizophrenia: there are inconsistencies and contradictions in the 
evidence. Britiah Journal of Psychiatry 1994 164 588-92 
120. Crow T.J. et al Schizophrenia and influenzae. Lancet 1991 338 116-7
121. Kendell R.E. & Kemp I.W. Maternal influenzae in the aetiology of schizophrenia. Archives of General Psychiatry 1989 
46 878-882
122. Knight J. Schizophrenia and infection. Lancet 1991 338 390
123. Wright P. et al Schizophrenia genetics and the maternal immune response to viral infection. American Journal of Medical 
Genetics (Neuropsychiatric genetics) 1993 48 40-46
124. Gunther-Genta F. et al Obstetrical Complications and schizophrenia: a case control study. British Journal of Psychiatry 
1994 164 165-70
125. O'Callaghan E. et al Risk of schizophrenia in adults born after obstetric complications and their association with early 
onset of illness: a controlled study. British Medical Journal 1992 305 1256-1259 
126. Eagles J.M. et al Obstetric complications in DSM-III schizophrenics and their siblings. Lancet 1990 335 1139-1141 
127. Owen M.J. Lewis S.W. & Murray R.M. Obstetric complications and schizophrenia. Psychological Medicine 1988 18 331-
128. Verdoux H. et al Obstetric complications and age at onset in schizophrenia: An international collaborative meta analysis 
of individual patient data. American Journal of Psychiatry 154 1220-1227
129. Kunugi H. et al Perinatal complications and schizophrenia Journal of Nervous and Mental Disorders 1996 184 542-546
130. Gureje O. et al Early brain trauma and schizophrenia in Nigerian patients. American Journal of Psychiatry 1994 151 368-
131. Lewis S.W. & Murray R.M. Obstetric complications, neurodevelopmental deviance and schziophrenia. Jouranl of 
Psychiatric Research 1987 21 414-421
132. Cantor-Graae E. et al Obstetric complications and their relationship to other etiological risk factors in schizophrenia. A 
case-control study. Journal of Nervous and Mental Disorders 1994 182 645-650
133. McNeil T.F. et al Obstetric complications as antecedents of schizophrenia. Empirical effects of using different obstetric 
complication scales. Journal of Psychiatric Research 1994 28 519-530
134. Geddes J.R. & Lawrie S.M. Obstetric events in schizophrenia: a meta analysis British Journal of Psychiatry 1995 167 786-
135. Done D.J. et al 1991 Complications of pregnancy and delivery in relation to psychosis in adult life. British Medical 
Journal 302 1576-1580
136. Buka S.I. et al 1993 Pregnancy/delivery complications and psychiatric diagnosis. A prospective study. Archives of 
General Psychiatry 50 151-156
137. McCreadie R.G. et al The Nithsdale Schizophrenia Surveys X: Obstetric complications, family history, and abnormal 
movements. British Journal Psychiatry 1992 101 799-805
138. Murray R.M. et al Towards an aetiological classification of schizophrenia. Lancet 1985 May 4 1023-6
139. Kerwin R.W. & Murray R.M. A neurodevelopmental perspective on the pathology and neurochemistry of the temporal 
lobe in schizophrenia. Schizophrenia Research 1992 7 1-12
140. Goodman R. Are complications of pregnancy and birth causes of schizophrenia? Develop. Med. Child Neurol. 1988 30 
141. Susser E. et al Schizophrenia after prenatal exposure to famine: further evidence. Archives of General Psychiatry 1996 53 
142. Susser E.S. et al Schizophrenia after prenatal exposure to the Dutch Hunger Winter of 1944-1945. Archives General 
Psychiatry 1992 49 983-8
143. Brown A.S. et al Neurobiological plausibility of prenatal nutritional deprivation as a risk factor for schizophrenia. Journal 
of Nervous and Mental Disorders 1996 Feb 184 (2) 71-85
144. Sutcliffe J.G. et al Control of neuronal gene expression. Science 1984 225 1308-1315
145. Murray R.M. et al A neurodevelopmental approach to the classification of schizophrenia. Schizophrenia Bulletin 1992 18 
146. Bloom F.E. Advancing a neurodevelopmental origin for schizophrenia. Archives of General Psychiatry 1993 50 224-227
147. Beauregard M. et al Sterotypies and loss of social affiliation after early hippocampectomy in primates. Neuroreport 1995 6 
148. Lipska B.K. et al Age-dependent effects of neonatal excitotoxic hippocampal lesions. Schizophrenia Research 1993 9 149 
149. Lipska B.K. & Weinburger D.R. Delayed effects of neonatal hippocampal damage on haloperidol- induced catalepsy and 
amorphine-induced stereotypic behaviours in the rat. Developmental Brain Research 75 213-222 1993
150. Lipska B.K. et al 1993 Post-pubertal emergence of hyperesponsiveness to stress and to amphetamine after neonatal 
excitotoxic hippocampal damage: A potential animal model of schizophrenia. Neuropsychopharmacology 1993 91 (1) 67-
151. Flores G. et al 1996 Decreased binding of dopamine D3 receptors in limbic subregions after neonatal bilateral lesion of 
the rat hippocampus. Journal of Neuroscience 1996 16 6 2020-2026 
152. Lipska B.K. et al Genetic variation in vulnerability to the behavioural effects of neonatal hippocampal damage in rats 
Proceedings of the Nationall Academy of Sciences USA 1995 92 8906-8910
153. Lipska B.K. et al Neonatal excitotoxic hippocampal damage in rat causes postpubertal changes in prepulse inhibition of 
startle and its disruption by apomorphine. Psychopharmacology (Berl) 1995 122 35-43) 
154. Sams-Dodd F. et al Neonatal lesions of the rat ventral hippocampus result in hyperlocomotion and deficits in social 
behaviour in adulthood. Psychopharmacology (Berl) 1997 132 303-310
155. Goldman P.S. Functional damage of the prefrontal cortex in early life and the problem of early plasticity. Experimental 
Neurology 1971 32 366-387
156. Pilowsky L. & Murray R.M. 1991 Why don't preschizophrenic children have delusions and hallucinations? Behavioural 
and Brain Sciences 1991 14 41-42
157. Feinburg J. Schizophrenia: caused by a fault in programmed synaptic elimination during adolescence. Journal of 
Psychiatric Research 1983 17 319-334
158. Hoffman R.E. et al Synaptic elimination, neurodevelopment and the mechanism of hallucinated voices in schizophrenia 
American Journal Psychiatry 1997 154 1683-1689
159. Hoffman R.E. & Dobscha S. Cortical pruning and the development of schizophrenia: a computer model. Schizophrenia 
Bulletin 1989 15 477-490
160. Keshaven M.S. et al Is schizophrenia due to excessive synaptic pruning in the prefrontal cortex? The Feinburg hypothesis 
revisited. Journal of Psychiatric Research 1994 28 239-265
161. Pettegrew J.W. et al Alterations in brain high energy phosphate and membrane phospholipid metabolism in first episode, 
drug naïve schizophrenics: a pilot study of the dorsal prefrontal cortex in vivo phosphorus 31 nuclear magnetic resonance 
spectroscopy. Archives of General Psychiatry 1991 48 563-568
162. Stanley J.A. et al An in vivo study of the prefrontal cortex of schizophrenic patients at different stages of illness via 
phosphors magnetic resonance spectroscopy. Archives of General Psychiatry 1995 52 399-406
163. Benes F. et al Myelination of cortical-hippocampal relays during late adolescence. Schizophrenia Bulletin 1989 15 585-94
164. Stevens J.R. 1992 Abnormal reinnervation as a basis for schizophrenia. Archives of General Psychiatry 1992 49 238-243
165. Bogerts B. Limbic and paralimbic pathology in schizophrenia: interaction with age and stress related factors. In Schulz SC 
& Tamminga CA (eds) Schizophrenia Scientific progress 1989 pp 216-226
166. Roberts G.W. Done D..J Bruton C. & Crow T.J. A mock up of schizophrenia: temporal lobe epilepsy and schizophrenia 
like psychosis. Biological Psychiatry 1990 6 2521-2526
167. Hyde T.M. Ziegler J.C. Weinburger D.R. Psychiatric disturbances in metachromatic leukodystrophy: insight into the 
neurobiology of psychosis. Archives of Neurology 1992 49 401-6


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