Diagnostic validity
There is now compelling evidence that schizophrenia can be identified using unmodified adult criteria in children as young as 7 years of age (Green et al. 1984; Russell et al. 1989; Werry 1992). However, simply finding that some children fulfil adult diagnostic criteria for schizophrenia tells us nothing about whether the diagnosis is valid for this age group. In the absence of a biological diagnostic test, demonstrating diagnostic validity requires evidence that these early onset cases more closely resemble adult onset schizophrenia than other disorders in terms of clinical course, treatment response, family history and neurobiological correlates.

There are dangers of slavishly applying unmodified adult diagnostic criteria to children and adolescents. First, if a degree of age-dependent symptom variation exists in schizophrenia then applying unmodified adult criteria may result in some ‘true’ cases being missed (false-negative diagnoses). Secondly, some presentations of schizophrenia in early life could simply be phenocopies of adult schizophrenia (false-positive diagnoses) with a separate aetiology and clinical course. Hence, two issues need to be addressed. First, what is the validity of adult diagnostic criteria for schizophrenia when applied in childhood and adolescence? Secondly, are there partial syndromes or developmental variants of schizophrenia in childhood and adolescence that should be included as part of a broader schizophrenic spectrum?

Good evidence for the validity of the diagnosis of schizophrenia in childhood and adolescence comes from the recent Maudsley Child and Adolescent Psychosis Follow-up Study (Hollis 2000).

The study was based on 110 cases of child and adolescent onset psychoses (mean age of onset 14.2 years, range 10 - 17 years) presenting as a consecutive series to the Maudsley Hospital from 1973 to 1991 (we refer to this subsequently as ‘the Maudsley study’). The study used a ‘catch-up’ longitudinal design in which DSM-IIIR diagnoses were retrospectively applied to adolescent first-episode case notes and 85% (93/110) of the original cohort were then reassessed on average 11 years after their first admission. Of the 93 cases followed up, 51 had a baseline diagnosis of schizophrenia while 42 had a non-schizophrenic psychosis (bipolar,  schizoaffective or atypical psychosis). The key findings with respect to diagnostic validity were as follows:

1  A DSM-IIIR diagnosis of schizophrenia in childhood and adolescence predicted a significantly poorer adult outcome compared with other non-schizophrenic psychosis.

2  The diagnosis of schizophrenia showed a high level of stability, with 80% having the same diagnosis recorded at adult follow-up.

These findings support the predictive validity of the DSM-IIIR diagnosis of schizophrenia in childhood and adolescence, and are likely to be equally applicable to DSM-IV criteria.  The level of diagnostic stability for child and adolescent onset schizophrenia (using DSM-IIIR criteria)  was very similar to that described in follow-up studies of adult first-episode schizophrenia.

However, there remains the issue of resolving the status of ‘partial syndromes’ that share some diagnostic features, or prodromal symptoms, of schizophrenia but do not meet full DSM-IV (American Psychiatric Association 1994) or ICD-10 (World Health Organization 1992) diagnostic criteria. For example,  in the USA the term ‘multidimensionally impaired’  (MDI) (Jacobsen & Rapoport 1998; Kumra et al. 1998c) has been coined to describe children who have multiple early impairments in cognitive and social functioning and then develop transient psychotic symptoms in late childhood and early adolescence.  A higher than expected rate of schizophrenia among first-degree relatives suggests that MDI children may lie on the schizophrenia spectrum, but longer follow-up studies are needed to tell if these cases progress to more typical schizophrenic presentations (Kumra et al. 1998c). At present, cases with partial or contiguous syndromes, such as the MDI syndrome or schizotypal personality disorder, require careful clinical follow-up to determine if they will develop schizophrenia.

The question of how best to treat these presentations in clinical practice (e.g. whether they should be given low-dose antipsychotics) remains an important but unresolved question.

—-

Developmental issues in assessment of children

The cognitive level of the child influences their ability to understand and express complex psychotic symptoms such as passivity phenomena, thought alienation and hallucinations. In younger children careful distinctions have to be made between developmental immaturity and psychopathology. For example, distinguishing true hallucinations from other subjective phenomena such as dreams may be difficult for young children.

—-

Developmental maturation can also affect the localization of hallucinations in space. Internal localization of hallucinations is more common in younger children and makes these experiences more difficult to differentiate subjectively from inner speech or thoughts (Garralda 1984). Formal thought disorder may also appear very similar to the pattern of illogical thinking and loose associations seen in children with immature language development.  Negative symptoms can appear very similar to nonpsychotic language and social impairments and can also be easily confused with anhedonia and depression.

C. Hollis
Chris Hollis is Professor of Child and Adolescent Psychiatry and Head of the Developmental Psychiatry Section, University of Nottingham (University Hospital, Queen's Medical Centre, Nottingham NG7 2UH). His research interests include the developmental psychopathology of early psychoses, attention-deficit hyperactivity disorder and developmental language and communication disorders. References

1. Aitchison, K.J. & Kerwin, R.W. (1997) The cost effectiveness of clozapine. British Journal of Psychiatry 171, 125 - 130.
2. Alaghband-Rad, J., McKenna, K., Gordon, C.T. et al. (1995) Childhood onset schizophrenia: the severity of premorbid course. Journal of the American Academy of Child and Adolescent Psychiatry 34, 1273 - 1283.
3. Alaghband-Rad, J., Hamburger, S.D., Giedd, J., Frazier, J.A. & Rapoport, J.L. (1997) Childhood onset schizophrenia: biological markers in relation to clinical characteristics. American Journal of Psychiatry 154, 64 - 68.
4. American Psychiatric Association (1980) Diagnostic and Statistical Manual of Mental Disorders, 3rd edn. American Psychiatric Association, Washington, DC.
5. American Psychiatric Association (1994) Diagnostic and Statistical Manual of Mental Disorders, 4th edn. American Psychiatric Association, Washington, DC.
6. Andreasen, N., Ehrhardt, J.C., Swazye, V.W. et al. (1990) Magnetic resonance imaging of the brain in schizophrenia. Archives of General Psychiatry 47, 35 - 44.
7. Asarnow, J.R. & Ben-Meir, S. (1988) Children with schizophrenia spectrum and depressive disorders: a comparative study of premorbid adjustment, onset pattern and severity of impairment. Journal of Child Psychology and Psychiatry 29, 477 - 488.
8. Asarnow, J.R., Thompson, M.C., Hamilton, E.B., Goldstein, M.J. & Guthrie, D. (1994) Family expressed emotion, childhood onset depression, and childhood onset schizophrenic spectrum disorders: is expressed emotion a non-specific correlate of psychopathology or a specific risk factor for depression? Journal of Abnormal Psychology 22, 129 - 146.
9. Asarnow, R., Granholm, E. & Sherman, T. (1991) Span of apprehension in schizophrenia. In: Handbook of Schizophrenia, Vol. 5. Neuropsychology, Psychophysiology and Information Processing (eds S.R. Steinhauer, J.H. Gruzelier & J. Zubin), pp. 335 - 370. Elsevier, Amsterdam.
10. Asarnow, R., Asamen, J., Granholm, E. et al. (1994) Cognitive/ neuropsychological studies of children with schizophrenic disorder. Schizophrenia Bulletin 20, 647 - 669.
11. Asarnow, R., Brown, W. & Stranberg, R. (1995) Children with schizophrenic disorder: neurobehavioural studies. European Archives of Psychiatry and Clinical Neuroscience 245, 70 - 79.
12. Bassett, A.S., Chow, E., Scutt, L., Hodkinson, K. & Weksberg, R. (1999)
13. Psychiatric phenotype of a genetic subtype of schizophrenia [Abstract]. Schizophrenia Research 36, 87.
14. Bedwell, J.S., Keller, B., Smith, A.K. et al. (1999) Why does postpsychotic IQ decline in childhood onset schizophrenia? American Journal of Psychiatry 156, 1996 - 1997.
15. Beratis, S., Gabriel, J. & Hoidas, S. (1994) Age at onset in subtypes of schizophrenic disorders. Schizophrenia Bulletin 20, 287 - 296.
16. Bertolino, A., Kumra, S., Callicott, J.H. et al. (1998) Common pattern of cortical pathology in childhood onset and adult onset schizophrenia as identified by proton magnetic resonance spectroscopic imaging. American Journal of Psychiatry 155, 1376 - 1383.
17. Bilder, R.M., Lipschutz-Broch, L., Reiter, G. et al. (1992) Intellectual deficits in first-episode schizophrenia: evidence for progressive deterioration. Schizophrenia Bulletin 18, 437 - 448.
18. Birchwood, M., McGorry, P. & Jackson, H. (1997) Early intervention in schizophrenia. British Journal of Psychiatry 170, 2 - 5.
19. Bleuler, E. (1911/1950) Dementia praecox. In: The Group of Schizophrenias. Translated by J. Zinkin. International Universities Press, New York.
20. Breier, A. (1999) Cognitive deficit in schizophrenia and its neurochemical basis. British Journal of Psychiatry 174 (Suppl. 37), 16 - 18.
21. Bullmore, E.T., O'Connell, P., Frangou, S. & Murray, R.M. (1997) Schizophrenia as a developmental disorder or neural network integrity: the dysplastic net hypothesis. In: Neuorodevelopment and Adult Psychopathology (eds M.S. Keshervan & R.M. Murray), pp. 253 - 266. Cambridge University Press, Cambridge.
22. Burgess, C.E., Lindblad, K., Sidransky, E. et al. (1998) Large CAG/CTG repeats are associated with childhood onset schizophrenia. Molecular Psychiatry 3, 321 - 327.
23. Caplan, R., Guthrie, D., Shields, W.D. & Mori, L. (1992) Formal thought disorder in paediatric complex partial seizure disorder. Journal of Child Psychology and Psychiatry 33, 1399 - 1412.
24. Castle, D. & Murray, R. (1991) The neurodevelopmental basis of sex differences in schizophrenia. Psychological Medicine 21, 565 - 575.
25. Chakos, M.H., Lieberman, J.A., Alvir, J. et al. (1995) Caudate nuclei volumes in schizophrenic patients treated with typical antipsychotics or clozapine. Lancet 345, 456 - 457.
26. Childs, B. & Scriver, C.R. (1986) Age at onset and causes of disease. Perspectives in Biology and Medicine 29, 437 - 460.
27. Clark, A. & Lewis, S. (1998) Treatment of schizophrenia in childhood and adolescence. Journal of Child Psychology and Psychiatry 39, 1071 - 1081.
28. Davidson, M., Reichenberg, M.A., Rabinowitz, J. et al. (1999) Behavioral and intellectual markers for schizophrenia in apparently healthy male adolescents. American Journal of Psychiatry 156, 1328 - 1335.
29. De Sanctis, S. (1906) On some varieties of dementia praecox. In: Rivista Sperimentale de Freniatria e Medicina Legale Delle Alienazioni Mentale (ed. J.G. Howell), pp. 141 - 165. Translated by M.L. Osbourn. Brunner Mazel, New York.
30. Dixon, L.B. & Lehman, A.F. (1995) Family interventions for schizophrenia. Schizophrenia Bulletin 21, 631 - 643.
31. Dolan, R.J., Fletcher, P., Frith, C.D. et al. (1996) Dopaminergic modulation of impaired cognitive activation in the anterior cingulate cortex in schizophrenia. Nature 378, 180 - 182.
32. Done, J.D., Crow, T.J., Johnstone, E. & Sacker, A. (1994) Child-hood antecedents of schizophrenia and affective illness: social adjustment at ages 7 and 11. British Medical Journal 309, 699 - 703.
33. Dye, S.M., Spence, S.A., Bench, C.J. et al. (1999) No evidence for left superior temporal dysfunction in asymptomatic schizophrenia and bipolar disorder: PET study of verbal fluency. British Journal of Psychiatry 175, 367 - 374.
34. Eggers, C. (1978) Course and prognosis in childhood schizophrenia.Journal of Autism and Childhood Schizophrenia 8, 21 - 36.
35. Eggers, C. & Bunk, D. (1997) The long-term course of childhood onset schizophrenia: a 42-year follow-up. Schizophrenia Bulletin 23, 105 - 117.
36. Erlenmeyer-Kimling, L., Rock, D., Roberts, S.A. et al. (2000) Attention, memory and motor skills as childhood predictors of schizophrenia related psychoses: the New York High Risk Project. Archives of General Psychiatry 157, 1416 - 1422.
37. Feinberg, I. (1983) Schizophrenia: caused by a fault in programmed synaptic elimination during adolescence. Journal of Psychiatric Research 17, 319 - 344.
38. Feinberg, I. (1997) Schizophrenia as an emergent disorder of late brain maturation. In: Neuorodevelopment and Adult Psychopathology (eds M.S. Keshervan & R.M. Murray), pp. 237 - 252. Cambridge University Press, Cambridge.
39. Fish, B. (1957) The detection of schizophrenia in infancy. Journal of Nervous and Mental Diseases 125, 1 - 24.
40. Fish, B. & Rivito, E.R. (1979) Psychoses of childhood. In: Basic Handbook of Child Psychiatry, Vol. 2 (ed. J.D. Noshpitz), pp. 249 - 304. Basic Books, New York.
41. Foerster, A., Lewis, S., Owen, M. & Murray, R.M. (1991) Pre-morbid adjustment and personality in psychosis. British Journal of Psychiatry 158, 171 - 176.
42. Frazier, J.A., Giedd, J.N., Kaysen, D. et al. (1996) Childhood onset schizophrenia: brain magnetic resonance imaging rescan after 2 years of clozapine maintenance. American Journal of Psychiatry 153, 564 - 566.
43. Frazier, J.A., Alaghband-Rad, J., Jacobsen, L. et al. (1997) Pubertal development and the onset of psychosis in childhood onset schizophrenia. Psychiatry Research 70, 1 - 7.
44. Friedman, L., Finding, R.L., Buch, J. et al. (1996) Structural MRI and neuropsychological assessments in adolescent patients with either schizophrenia or affective disorders. Schizophrenia Research 18, 189 - 190.
45. Friston, K.J., Herold, S., Fletcher, P. et al. (1995) Abnormal frontotemporal interactions in schizophrenia. In: Biology of Schizophrenia and Affective Diseases (ed. S.J. Watson), pp. 449 - 481. Raven, New York.
46. Frith, C.D. (1994) Theory of mind in schizophrenia. In: The Neuropsychology of Schizophrenia (eds A. David & J.S. Cutting), pp. 147 - 161. Lawrence Erlbaum, Hove.
47. Galdos, P.M., van Os, J. & Murray, R. (1993) Puberty and the onset of psychosis. Schizophrenia Research 10, 7 - 14.
48. Gallhofer, B., Trimble, M.R., Frackowiak, R., Gibbs, J. & Jones, T. (1985) A study of cerebral blood flow and metabolism in epileptic psychosis using positron emission tomography and oxygen. Journal of Neurology, Neurosurgery and Psychiatry 48, 201 - 206.
49. Garey, L.J., Ong, W.Y., Patel, T.S. et al. (1998) Reduced dendritic spine density on cerebral cortical pyramidal neurons in schizophrenia. Journal of Neurology, Neurosurgery and Psychiatry 65 (4), 446 - 453.
50. Garralda, M.E. (1984) Hallucinations in children with conduct and emotional disorders. I. The clinical phenomena. Psychological Medicine 14, 589 - 596.
51. Geddes, J.R. & Lawrie, S.M. (1995) Obstetric complications and schizophrenia: a meta-analysis. British Journal of Psychiatry 167, 786 - 793.
52. Giedd, J.N., Castellanos, F.X., Rajapaske, J.C. et al. (1996) Quantitative analysis of grey matter volumes in childhood onset schizophrenia and attention deficit/hyperactivity disorder. Society for Neuroscience Abstracts 22, 1166.
53. Gillberg, C., Wahlstrom, J., Forsman, A., Hellgren, L. & Gillberg, J.C. (1986) Teenage psychoses: epidemiology, classification and reduced optimality in the pre-, peri- and neonatal periods. Journal of Child Psychology and Psychiatry 27, 87 - 98.
54. Glantz, L.A. & Lewis, D.A. (2000) Decreased dendritic spine density on prefrontal cortical pyramidal neurones in schizophrenia. Archives of General Psychiatry 57, 65 - 73.
55. Goldstein, M.J. (1987) The UCLA High Risk Project. Schizophrenia Bulletin 13, 505 - 514.
56. Goodman, R. (1988) Are complications of pregnancy and birth causes of schizophrenia? Developmental Medicine and Child Neurology 30, 391 - 406.
57. Gordon, C.T., Frazier, J.A., McKenna, K. et al. (1994) Childhood onset schizophrenia: a NIMH study in progress. Schizophrenia Bulletin 20, 697 - 712.
58. Green, W., Campbell, M., Hardesty, A. et al. (1984) A comparison of schizophrenic and autistic children. Journal of the American Academy of Child Psychiatry 23, 399 - 409.
59. Green, W., Padron-Gayol, M., Hardesty, A. & Bassiri, M. (1992) Schizophrenia with childhood onset: a phenomenological study of 38 cases. Journal of the American Academy of Child and Adolescent Psychiatry 31, 968 - 976.
60. Gualtieri, C.T., Adams, A. & Chen, C.D. (1982) Minor physical abnormalities in alcoholic and schizophrenic adults and hyperactive and autistic children. American Journal of Psychiatry 139, 640 - 643.
61. Gur, R.E., Cowell, P., Turetsky, B.I. et al. (1998) A follow-up magnetic resonance imaging study of schizophrenia: relationship of neuroanatomical changes to clinical and neurobehavioural measures. Archives of General Psychiatry 55, 145 - 152.
62. Gur, R.E., Turetsky, B.I., Cowell, P. et al. (2000a) Temporolimbic volume reductions in schizophrenia. Archives of General Psychiatry 57, 769 - 775.
63. Gur, R.E., Cowell, P., Latshaw, A. et al. (2000b) Reduced dorsal and orbital prefrontal gray matter volumes in schizophrenia. Archives of General Psychiatry 57, 761 - 768.
64. Guy, J.D., Majorski, L.V., Wallace, C.J. & Guy, M.P. (1983) The incidence of minor physical anomalies in adult schizophrenics. Schizophrenia Bulletin 9, 571 - 582.
65. Hafner, H. & Nowotny, B. (1995) Epidemiology of early onset schizophrenia. European Archives of Psychiatry and Clinical Neuroscience 245, 80 - 92.
66. Harris, E.C. & Barraclough, B. (1997) Excess mortality of mental disorder. British Journal of Psychiatry 173, 11 - 53.
67. Hayes, R.L. & McGrath, J.J. (2000) Cognitive rehabilitation for people with schizophrenia and related conditions: a systemic review and meta-analysis [Abstract]. Schizophrenia Research 41, 221 - 222.
68. Hollis, C. (1995) Child and adolescent (juvenile onset) schizophrenia: a case - control study of premorbid developmental impairments. British Journal of Psychiatry 166, 489 - 495.
69. Hollis, C. (1999) A study of the course and adult outcomes of child and adolescent onset psychoses. PhD thesis, University of London.
70. Hollis, C. (2000) The adult outcomes of child and adolescent onset schizophrenia: diagnostic stability and predictive validity. American Journal of Psychiatry 157, 1652 - 1659.
71. Hollis, C. & Taylor, E. (1997) Schizophrenia: a critique from the developmental psychopathology perspective. In: Neuorodevelopment and Adult Psychopathology (eds M.S. Keshervan & R.M. Murray), pp. 213 - 233. Cambridge University Press, Cambridge.
72. Hooley, J.M. (1987) The nature and origins of expressed emotion. In: Understanding Major Mental Disorder: the Contribution of Family Interaction Research (eds K. Hahlweg & M.J. Goldstein), pp. 176 - 194. Family Process, New York.
73. Hughes, C. & Russell, J. (1993) Autistic children's difficulty with mental disengagement with an object: its implications for theories of autism.Developmental Psychology 29, 498 - 510.
74. Huttenlocher, P.R. (1979) Synaptic density in human prefrontal cortex: developmental changes and effects of aging. Brain Research 163, 195 - 205.
75. Iacono, W.G. & Koenig, W.G.R. (1983) Features that distinguish smooth pursuit eye tracking performance in schizophrenic, affective disordered and normal individuals. Journal of Abnormal Psychology 92, 29 - 41.
76. Jacobsen, L. & Rapoport, J. (1998) Research update: childhood onset schizophrenia - implications for clinical and neurobiological research. Journal of Child Psychology and Psychiatry 39, 101 - 113.
77. Jacobsen, L., Giedd, J.N., Berquin, P.C. et al. (1997a) Quantitative morphology of the cerebellum and fourth ventricle in childhood onset schizophrenia. American Journal of Psychiatry 154, 1663 - 1669.
78. Jacobsen, L., Hamburger, S.D., Van Horn, J.D. et al. (1997b) Cerebral glucose metabolism in childhood onset schizophrenia. Psychiatry Research 75, 131 - 144.
79. Jacobsen, L., Giedd, J.N., Castellanos, F.X. et al. (1998) Progressive reductions in temporal lobe structures in childhood onset schizophrenia. American Journal of Psychiatry 155, 678 - 685.
80. Jones, P. & Done, J. (1997) From birth to onset: a developmental perspective of schizophrenia in two national birth cohorts. In: Neuorodevelopment and Adult Psychopathology (eds M.S. Keshervan & R.M. Murray), pp. 119 - 136. Cambridge University Press, Cambridge.
81. Jones, P., Rogers, B., Murray, R. & Marmot, M. (1994) Child development risk factors for adult schizophrenia in the British 1946 birth cohort. Lancet 344, 1398 - 1402.
82. Joyce, P.R. (1984) Age of onset in bipolar affective disorder and misdiagnosis of schizophrenia. Psychological Medicine 14, 145 - 149.
83. Kallman, F.J. & Roth, B. (1956) Genetic aspects of preadolescent schizophrenia. American Journal of Psychiatry 112, 599 - 606.
84. Karatekin, C. & Asarnow, R.F. (1998) Working memory in childhood onset schizophrenia and attention deficit/hyperactivity disorder. Psychiatry Research 80, 165 - 176.
85. Karayiorgou, M., Morris, M.A., Morrow, B. et al. (1995) Schizophrenia susceptibility associated with interstitial deletions of chromosome 22q11. Proceedings of the National Academy of Sciences of the USA 92, 7612 - 7616.
86. Kendall, R.E., McInneny, K., Juszczak, E. & Bain, M. (2000) Obstetric complications and schizophrenia: two case - control studies based on structured obstetric records. British Journal of Psychiatry 176, 516 - 522.
87. Kjelsberg, E. (2000) Adolescent psychiatric in-patients: a high risk group for premature death. British Journal of Psychiatry 176, 121 - 125.
88. Kolvin, I. (1971) Studies in the childhood psychoses. I. Diagnostic criteria and classification. British Journal of Psychiatry 118, 381 - 384.
89. Kraepelin, E. (1919) Dementia Praecox. Translated by R. Barclay. Livingstone, Edinburgh.
90. Kumra, S., Frazier, J.A., Jacobsen, L.K. et al. (1996) Childhood onset schizophrenia: a double blind clozapine - haloperidol comparison.Archives of General Psychiatry 53, 1090 - 1097.
91. Kumra, S., Jacobsen, L.K., Lenane, M. et al. (1998a) Childhood onset schizophrenia: an open-label study of olanzapine in adolescents. Journal of the American Academy of Child and Adolescent Psychiatry 37, 360 - 363.
92. Kumra, S., Jacobsen, L.K., Lenane, M. et al. (1998b) Case series: spectrum of neuroleptic-induced movement disorders and extrapyramidal side-effects in childhood onset schizophrenia. Journal of the American Academy of Child and Adolescent Psychiatry 37, 221 - 227.
93. Kumra, S., Jacobsen, L.K., Lenane, M. et al. (1998c) 'Multidimensionally impaired disorder': is it a variant of very early onset schizophrenia? Journal of the American Academy of Child and Adolescent Psychiatry 37, 91 - 99.
94. Kumra, S., Wiggs, E., Krasnewich, D. et al. (1998d) Brief report: association of sex chromosome anomalies with childhood onset psychotic disorders. Journal of the American Academy of Child and Adolescent Psychiatry 37, 292 - 296.
95. Lam, D.H. (1991) Psychosocial family intervention in schizophrenia: a review of empirical studies. Psychological Medicine 21, 423 - 441.
96. Lawrie, S.M. & Abukmeil, S.S. (1998) Brain abnormalities in schizophrenia: a systematic and quantitative review of volumetric magnetic resonance imaging studies. British Journal of Psychiatry 172, 110 - 120.
97. Leff, J. & Vaughn, C. (1985) Expressed Emotion in Families: its Significance for Mental Illness. Guilford Press, London.
98. Lewine, R.R.J. (1994) Comments on 'Puberty and the onset of psychosis' by P.M. Galdos et al. Schizophrenia Research 13, 81 - 83.
99. Lewis, S.W. & Murray, R.M. (1987) Obstetric complications, neurodevelopmental deviance and risk of schizophrenia. Journal of Psychiatric Research 21, 414 - 421.
100. Liddle, P., Friston, K.J., Frith, C.D. et al. (1992) Patterns of cerebral blood flow in schizophrenia. British Journal of Psychiatry 160, 179 - 186.
101. Lindsay, J., Ounsted, C. & Richards, P. (1979) Long-term outcome of children with temporal lobe seizures. II. Marriage, parenthood and sexual indifference. Developmental Medicine and Child Neurology 21, 433 - 440.
102. Loebel, A.D., Lieberman, J.A., Alvir, J.M.N. et al. (1992) Duration of psychosis and outcome in first episode schizophrenia. American Journal of Psychiatry 149, 1183 - 1188.
103. McGlashen, T.H. & Hoffman, R.E. (2000) Schizophrenia as a disorder of developmentally reduced synaptic connectivity. Archives of General Psychiatry 57, 637 - 648.
104. McGrath, J. & Murray, R. (1995) Risk factors for schizophrenia: from conception to birth. In: Schizophrenia (eds S.R. Hirsch & D.R.Weinberger), pp. 187 - 205. Blackwell Science, Oxford.
105. McGrorry, P. & Sing, B. (1995) Schizophrenia: risk and possibility. In: Handbook of Studies on Preventative Psychiatry (eds B. Raphael & G. Burrows), pp. 491 - 514. Elsvier Science, Amsterdam.
106. McNeil, T.F. (1995) Perinatal risk factors and schizophrenia: selective review and methodological concerns. Epidemiology Review 17, 107 - 112.
107. Malmberg, A., Lewis, G., David, A. & Allebeck, P. (1998) Premorbid adjustment and personality in people with schizophrenia. British Journal of Psychiatry 172, 308 - 313.
108. Matsumoto, H., Takei, N., Saito, H., Kachi, K. & Mori, N. (1999) Childhood onset schizophrenia and obstetric complications: a case - control study. Schizophrenia Research 38, 93 - 99.
109. Maziade, M., Bouchard, S., Gingras, N. et al. (1996) Long-term stability of diagnosis and symptom dimensions in a systematic sample of patients with onset of schizophrenia in childhood and early adolescence.
110. II. Positive/negative distinction and childhood predictors of adult outcome. British Journal of Psychiatry 169, 371 - 378.
111. Murray, R.M. & Lewis, S.W. (1987) Is schizophrenia a neurodevelopmental disorder? British Medical Journal 295, 681 - 682.
112. Nelson, M.D., Saykin, A.J., Flashman, L.A. & Riodan, H.J. (1998) Hippocampal volume reduction in schizophrenia assessed by magnetic resonance imaging: a meta-analytic study. Archives of General Psychiatry 55, 433 - 440.
113. Nicholson, R.M., Giedd, J.N., Lenane, M. et al. (1999) Clinical and neurobiological correlates of cytogenetic abnormalities in childhood onset schizophrenia. American Journal of Psychiatry 156, 1575 - 1579.
114. Nicholson, R.M., Lenane, M., Singaracharlu, S. et al. (2000) Premorbid speech and language impairments in childhood onset schizophrenia: association with risk factors. Schizophrenia Research 41, 55.
115. Nopoulos, P., Torres, I., Flaum, M. et al. (1995) Brain morphology in first-episode schizophrenia. American Journal of Psychiatry 152, 1721 - 1723.
116. Nopoulos, P.C., Giedd, J.N., Andreasen, N.C. & Rapoport, J.L. (1998)
117. Frequency and severity of enlarged septi pellucidi in childhood onset schizophrenia. American Journal of Psychiatry 155, 1074 - 1079.
118. Nuechterlain, K.H. & Dawson, M.E. (1984) Information processing and attentional functioning in the developmental course of schizophrenic disorders. Schizophrenia Bulletin 10, 160 - 203.
119. van Os, J., Jones, P., Lewis, G. et al. (1997) Developmental precursors of affective illness in a general population birth cohort. Archives of General Psychiatry 54, 625 - 631.
120. Ozonoff, S., Pennington, B.F. & Rogers, S.J. (1991) Executive function deficits in high-functioning autistic individuals: relationship to theory of mind. Journal of Child Psychology and Psychiatry 32, 1081 - 1105.
121. Pantelis, C., Velakoulis, D., Suchling, P. et al. (2000) Left medial temporal volume reduction occurs during transition from high-risk to first episode psychosis. Schizophrenia Research 41, 35.
122. Park, S., Holzman, P.S. & Goldman-Rakic, P.S. (1995) Spatial working memory deficits in the relatives of schizophrenic patients. Archives of General Psychiatry 52, 821 - 828.
123. Pennington, B.F., Groisser, D. & Welsh, M.C. (1993) Contrasting deficits in attention deficit hyperactivity disorder versus reading disability. Developmental Psychology 29, 511 - 523.
124. Pettegrew, J.W., Keshavan, M.S., Panchalingam, K. et al. (1991) Alterations in brain high energy phosphate and membrane phospholipid metabolism in first episode, drug naive schizophrenics: a pilot study of the dorsal prefrontal cortex by in vivo phosphorous-31 nuclear magnetic resonance spectroscopy. Archives of General Psychiatry 48, 563 - 568.
125. Pool, D., Bloom, W., Miekle, D.H., Roniger, J.J. & Gallant, D.M. (1976) A controlled trial of loxapine in 75 adolescent schizophrenic patients. Current Therapeutic Research 19, 99 - 104.
126. Poole, R. & Brabbins, C. (1996) Drug-induced psychosis. British Journal of Psychiatry 168, 135 - 138.
127. Potter, H.W. (1933) Schizophrenia in children. American Journal of Psychiatry 12, 1253 - 1270.
128. Pulver, A., Brown, C.H., Wolyniec, P. et al. (1990) Schizophrenia: age at onset, gender and familial risk. Acta Psychiatrica Scandinavica 82, 344 - 351.
129. Purves, D.L. & Lichtmen, J.W. (1980) Elimination of synapses in the developing nervous system. Science 210, 153 - 157.
130. Rapoport, J.L., Giedd, J., Kumra, S. et al. (1997) Childhood onset schizophrenia: progressive ventricular change during adolescence. Archives of General Psychiatry 54, 897 - 903.
131. Rapoport, J.L., Giedd, J., Blumenthal, J. et al. (1999) Progressive cortical change during adolescence in childhood onset schizophrenia: a longitudinal magnetic resonance imaging study. Archives of General Psychiatry 56, 649 - 654.
132. Remschmidt, H., Schultz, E. & Martin, M. (1994) An open trial of clozapine with thirty-six adolescents with schizophrenia. Journal of Child and Adolescent Psychopharmacology 4, 31 - 41.
133. Roberts, G.W., Colter, N., Lofthouse, R. et al. (1986) Gliosis in schizophrenia: a survey. Biological Psychiatry 21, 1043 - 1050.
134. Robinson, D., Woerner, M.G., Alvir, J.M. et al. (1999) Predictors of relapse following a first episode of schizophrenia or schizoaffective disorder. Archives of General Psychiatry 56, 241 - 247.
135. Rossi, A., Mancini, F., Stratta, P. et al. (1997) Risperidone, negative symptoms and cognitive deficit in schizophrenia: an open study. Acta Psychiatrica Scandinavica 95, 40 - 43.
136. Russell, A.J., Monro, J.C., Jones, P.B., Hemsley, D.R. & Murray, R.M. (1997) Schizophrenia and the myth of intellectual decline. American Journal of Psychiatry 154, 635 - 639.
137. Russell, A.T. (1994) The clinical presentation of childhood onset schizophrenia. Schizophrenia Bulletin 20, 631 - 646.
138. Russell, A.T., Bott, L. & Sammons, C. (1989) The phenomena of schizophrenia occurring in childhood. Journal of the American Academy of Child and Adolescent Psychiatry 28, 399 - 407.
139. Rutter, M. (1972) Childhood schizophrenia reconsidered. Journal of Autism and Childhood Schizophrenia 2, 315 - 407.
140. Rutter, M. & Mawhood, L. (1991) The long-term psychosocial sequelae of specific developmental disorders of speech and language. In: Biological Risk Factors for Psychosocial Disorders (eds M. Rutter & P. Casaer), pp. 233 - 259. Cambridge University Press, Cambridge.
141. Sachdev, P. (1998) Schizophrenia-like psychosis and epilepsy: the status of the association. American Journal of Psychiatry 155, 325 - 336.
142. Saykin, A.J., Shtasel, D.L., Gur, R.E. et al. (1994) Neuropsychological deficits in neuroleptic-naive patients with first episode schizophrenia.Archives of General Psychiatry 512, 124 - 131.
143. Schmidt, M., Blanz, B., Dippe, A., Koppe, T. & Lay, B. (1995) Course of patients diagnosed as having schizophrenia during first episode occurring under age 18 years. European Archives of Psychiatry and Clinical Neuroscience 245, 93 - 100.
144. Selemon, L.D., Rajkowska, G. & Goldman-Rakic, P.S. (1995) Abnormally high neuronal density in the schizophrenic cortex: a morphometric analysis of prefrontal area 9 and occipital area 17. Archives of General Psychiatry 52, 805 - 818.
145. Sensky, T., Turkington, D., Kingdon, D. et al. (2000) A randomized controlled trial of cognitive - behavioral therapy for persistent symptoms in schizophrenia resistant to medication. Archives of General Psychiatry 57, 165 - 172.
146. Sham, P.C., Jones, P.B., Russell, A. et al. (1994) Age at onset, sex, and familial psychiatric morbidity in schizophrenia. Report from the Camberwell Collaborative Psychosis Study. British Journal of Psychiatry 165, 466 - 473.
147. Siefen, G. & Remschmidt, H. (1986) Behandlungsergebnisse mit Clozapin bei schizophrenen Jungendlichen. Zeitschrift fur Kinderund Jungendpsychiatrie 14, 245 - 257.
148. Sigurdsson, E., Fombonne, E., Sayal, K. & Checkley, S. (1999) Neurodevelopmental antecedents of early onset bipolar affective disorder. British Journal of Psychiatry 174, 121 - 127.
149. Slaveska, K., Hollis. C.P. & Bramble, D. (1998) The use of antipsychotics by the child and adolescent psychiatrists of Trent region. Psychiatric Bulletin 22, 685 - 687.
150. Spence, S.A., Hirsch, S.R., Brooks, D.J. et al. (1998) Prefrontal cortex activity in people with schizophrenia and control subjects: evidence from positron emission tomography for remission of 'hypofrontality' with recovery from acute schizophrenia. British Journal of Psychiatry 172, 316 - 323. [Published erratum appears in British Journal of Psychiatry 1998; 172, 543.]
151. Spence, S.A., Liddle, P.F., Stefan, M.D. et al. (2000) Functional anatomy of verbal fluency in people with schizophrenia and those at genetic risk: focal dysfunction and distributed disconnectivity reappraised. British Journal of Psychiatry 176, 52 - 60.
152. Spencer, E.K. & Campbell, M. (1994) Children with schizophrenia: diagnosis, phenomenology and pharmacotherapy. Schizophrenia Bulletin 20, 713 - 725.
153. Strandburg, R.J., Marsh, J.T., Brown, W.S., Asarnow, R.F. & Guthrie, D. (1994) Information processing deficits across childhood and adult onset schizophrenia. Schizophrenia Bulletin 20, 685 - 696.
154. Strandburg, R.J., Marsh, J.T., Brown. W.S. et al. (1999) Continuous-processing ERPS in adult schizophrenia: continuity with childhood onset schizophrenia. Biological Psychiatry 45, 1356 - 1369.
155. Tarrier, N., Beckett, R., Harwood, S. et al. (1993) A trial of two cognitive behavioural methods of treating drug resistant residual symptoms in schizophrenic patients. I. Outcome. British Journal of Psychiatry 162, 524 - 532.
156. Thomas, M.A., Ke, Y., Levitt, J. et al. (1998) Preliminary study of frontal lobe 1H MR spectroscopy in childhood onset schizophrenia. Journal of Magnetic Resonance Imaging 8, 841 - 846.
157. Towbin, K.R., Dykens, E.M., Pearson, G.S. & Cohen, D.J. (1993) Conceptualising 'borderline syndrome of childhood' and 'childhood schizophrenia' as a developmental disorder. Journal of the American Academy of Child and Adolescent Psychiatry 32, 775 - 782.
158. Tsuang, M.T. (1993) Genotypes, phenotypes and the brain: a search for connections in schizophrenia. British Journal of Psychiatry 163, 299 - 307.
159. Tsuang, M.T., Simpson, J.C. & Kronfold, Z. (1982) Subtypes of drug abuse with psychosis. Archives of General Psychiatry 39, 141 - 147.
160. Vita, A., Dieci, M., Giobbio, G.M. et al. (1991) CT scan abnormalities and outcome of chronic schizophrenia. American Journal of Psychiatry 148, 1577 - 1579.
161. Volkmar, F.R. & Cohen, D.J. (1991) Comorbid association of autism and schizophrenia. American Journal of Psychiatry 148, 1705 - 1707.
162. Weinberger, D.R. (1987) Implications of normal brain development for the pathogenesis of schizophrenia. Archives of General Psychiatry 44, 660 - 669.
163. Welsh, M.C., Pennington, B.F. & Groisser, D.B. (1991) A normativedevelopmental study of executive function: a window on pre-frontal function in children? Developmental Neuropsychology 7, 131 - 139.
164. Werry, J.S. (1992) Child and adolescent (early onset) schizophrenia: a review in light of DSM-IIIR. Journal of Autism and Developmental Disorders 22, 601 - 624.
165. Werry, J.S. & McClellan, J.M. (1992) Predicting outcome in child and adolescent (early onset) schizophrenia and bipolar disorder. Journal of the American Academy of Child and Adolescent Psychiatry 31, 147 - 150.
166. Werry, J.S., McClellan, J.M. & Chard, L. (1991) Childhood and adolescent schizophrenia, bipolar and schizoaffective disorders: a clinical and outcome study. Journal of the American Academy of Child and Adolescent Psychiatry 30, 457 - 465.
167. Werry, J.S., McClellan, J.M., Andrews, L. & Ham, M. (1994) Clinical features and outcome of child and adolescent schizophrenia. Schizophrenia Bulletin 20, 619 - 630.
168. Woods, B.T. (1998) Is schizophrenia a progressive neurodevelopmental disorder? Toward a unitary pathogeneic mechanism. American Journal of Psychiatry 155, 1661 - 1670.
169. World Health Organization (1978) International Classification of Diseases, 9th edn (ICD-9). World Health Organization, Geneva.
170. World Health Organization (1992) The ICD-10 Classification of Mental and Behavioural Disorders: Diagnostic Criteria for Research. World Health Organization, Geneva.
171. Wyatt, R.J. (1995) Early intervention in schizophrenia: can the course be altered? Biological Psychiatry 38, 1 - 3.
172. Wykes, T., Reeder, C., Williams, C. et al. (2000) Cognitive remediation: predictors of success and durability of improvements [Abstract]. Schizophrenia Research 41, 221.
173. Yung, A.R., McGorry, P.D., McFarlane, C.A. et al. (1996) Monitoring and care of young people at incipient risk of psychosis. Schizophrenia Bulletin 22, 283 - 303.
174. Zahn, T.P., Jacobson, L.K., Gordon, C.T. et al. (1997) Autonomic nervous system markers of pathophysiology in childhood onset schizophrenia. Archives of General Psychiatry 54, 904 - 912.
175. Zahn, T.P., Jacobson, L.K., Gordon, C.T. et al. (1998) Attention deficits in childhood onset schizophrenia: reaction time studies. Journal of Abnormal Psychology 107, 97 - 108.