This Article  • References  • Full text PDF  • Reply to article  • Send to a friend  • Save in My Folder  • Save to citation manager  • Permissions  Citing Articles  • Citation map  • Citing articles on HighWire  • Contact me when this article is cited  Related Content  • Similar articles in this journal  Social Bookmarking   What's this?

Daniel R. Weinberger, MD

Arch Gen Psychiatry. 1987;44(7):660-669.

Abstract
• Recent research on schizophrenia has demonstrated that in this disorder the brain is not, strictly speaking, normal. The findings suggest that nonspecific histopathology exists in the limbic system, diencephalon, and prefrontal cortex, that the pathology occurs early in development, and that the causative process is inactive long before the diagnosis is made. If these findings are valid and not epiphenomena, then the pathogenesis of schizophrenia does not appear to fit either traditional metabolic, posttraumatic, or neurodegenerative models of adult mental illness. The data are more consistent with a neurodevelopmental model in which a fixed "lesion" from early in life interacts with normal brain maturational events that occur much later. Based on neuro-ontological principles and insights from animal research about normal brain development, it is proposed that the appearance of diagnostic symptoms is linked to the normal maturation of brain areas affected by the early developmental pathology, particularly the dorsolateral prefrontal cortex. The course of the illness and the importance of stress may be related to normal maturational aspects of dopaminergic neural systems, particularly those innervating prefrontal cortex. Some implications for future research and treatment are considered.

Author Affiliations
From the Clinical Brain Disorders Branch, Intramural Research Program, National Institute of Mental Health, Washington, DC.

Footnotes
Accepted for publication Sept 9, 1986.

Reprint requests to Clinical Brain Disorders Branch, Intramural Research Program, National Institute of Mental Health, William A. White Building, Saint Elizabeths Hospital, Washington, DC 20032 (Dr Weinberger).

CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    Twitter     What's this?

THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES

Delusional Infestation
Freudenmann and Lepping
Clin. Microbiol. Rev. 2009;22:690-732.
ABSTRACT | FULL TEXT  

Neuropsychological functioning in first-episode schizophrenia
Kravariti et al.
Br. J. Psychiatry 2009;195:336-345.
ABSTRACT | FULL TEXT  

Diminished dosage of 22q11 genes disrupts neurogenesis and cortical development in a mouse model of 22q11 deletion/DiGeorge syndrome
Meechan et al.
Proc. Natl. Acad. Sci. USA 2009;106:16434-16445.
ABSTRACT | FULL TEXT  

Longitudinal Study of Stressful Life Events and Daily Stressors Among Adolescents at High Risk for Psychotic Disorders
Tessner et al.
Schizophr Bull 2009;0:sbp087v1-sbp087.
ABSTRACT | FULL TEXT  

A Review of the Fetal Brain Cytokine Imbalance Hypothesis of Schizophrenia
Meyer et al.
Schizophr Bull 2009;35:959-972.
ABSTRACT | FULL TEXT  

Anatomical Abnormalities of the Anterior Cingulate Cortex in Schizophrenia: Bridging the Gap Between Neuroimaging and Neuropathology
Fornito et al.
Schizophr Bull 2009;35:973-993.
ABSTRACT | FULL TEXT  

Trimethoprim as Adjuvant Treatment in Schizophrenia: A Double-Blind, Randomized, Placebo-Controlled Clinical Trial
Shibre et al.
Schizophr Bull 2009;0:sbn191v2-sbn191.
ABSTRACT | FULL TEXT  

Association of measures of fetal and childhood growth with non-clinical psychotic symptoms in 12-year-olds: the ALSPAC cohort
Thomas et al.
Br. J. Psychiatry 2009;194:521-526.
ABSTRACT | FULL TEXT  

Widespread Reductions of Cortical Thickness in Schizophrenia and Spectrum Disorders and Evidence of Heritability
Goldman et al.
Arch Gen Psychiatry 2009;66:467-477.
ABSTRACT | FULL TEXT  

Life Events and High-Trait Reactivity Together Predict Psychotic Symptom Increases in Schizophrenia
Docherty et al.
Schizophr Bull 2009;35:638-645.
ABSTRACT | FULL TEXT  

Progressive Gray Matter Reduction of the Superior Temporal Gyrus During Transition to Psychosis
Takahashi et al.
Arch Gen Psychiatry 2009;66:366-376.
ABSTRACT | FULL TEXT  

Precedence-effect-induced enhancement of prepulse inhibition in socially reared but not isolation-reared rats
Du et al.
Cogn Affect Behav Neurosci 2009;9:44-58.
ABSTRACT  

Functional variants of the dopamine receptor D2 gene modulate prefronto-striatal phenotypes in schizophrenia
Bertolino et al.
Brain 2009;132:417-425.
ABSTRACT | FULL TEXT  

A Neonatal Ventral Hippocampal Lesion Causes Functional Deficits in Adult Prefrontal Cortical Interneurons
Tseng et al.
J. Neurosci. 2008;28:12691-12699.
ABSTRACT | FULL TEXT  

Schizophrenia: A Computational Reinforcement Learning Perspective
Frank
Schizophr Bull 2008;34:1008-1011.
FULL TEXT  

Symptom Correlates of Static and Dynamic Facial Affect Processing in Schizophrenia: Evidence of a Double Dissociation?
Johnston et al.
Schizophr Bull 2008;0:sbn136v1-sbn136.
ABSTRACT | FULL TEXT  

Mice lacking the schizophrenia-associated protein FEZ1 manifest hyperactivity and enhanced responsiveness to psychostimulants
Sakae et al.
Hum Mol Genet 2008;17:3191-3203.
ABSTRACT | FULL TEXT  

Variants in the estrogen receptor alpha gene and its mRNA contribute to risk for schizophrenia
Weickert et al.
Hum Mol Genet 2008;17:2293-2309.
ABSTRACT | FULL TEXT  

Deficiency of Aph1B/C-{gamma}-secretase disturbs Nrg1 cleavage and sensorimotor gating that can be reversed with antipsychotic treatment
Dejaegere et al.
Proc. Natl. Acad. Sci. USA 2008;105:9775-9780.
ABSTRACT | FULL TEXT  

Science and Recovery in Schizophrenia
Lieberman et al.
Psychiatr. Serv. 2008;59:487-496.
ABSTRACT | FULL TEXT  

Premorbid IQ in Schizophrenia: A Meta-Analytic Review
Woodberry et al.
Am. J. Psychiatry 2008;165:579-587.
ABSTRACT | FULL TEXT  

The Dimensional Structure of the Wisconsin Schizotypy Scales: Factor Identification and Construct Validity
Kwapil et al.
Schizophr Bull 2008;34:444-457.
ABSTRACT | FULL TEXT  

Frontal Lobe Syndrome in a Patient without Structural Brain Abnormalities
Hennings et al.
J. Neuropsychiatry Clin. Neurosi. 2008;20:244-245.
FULL TEXT  

Overcoming Stigma: Involving Families in Medical Student and Psychiatric Residency Education
Schmetzer and Lafuze
Acad. Psychiatry 2008;32:127-131.
ABSTRACT | FULL TEXT  

Progressive Changes in the Development Toward Schizophrenia: Studies in Subjects at Increased Symptomatic Risk
Wood et al.
Schizophr Bull 2008;34:322-329.
ABSTRACT | FULL TEXT  

The Concept of Progressive Brain Change in Schizophrenia: Implications for Understanding Schizophrenia
DeLisi
Schizophr Bull 2008;34:312-321.
ABSTRACT | FULL TEXT  

Infections in the CNS During Childhood and the Risk of Subsequent Psychotic Illness: A Cohort Study of More Than One Million Swedish Subjects
Dalman et al.
Am. J. Psychiatry 2008;165:59-65.
ABSTRACT | FULL TEXT  

The Stability of Inhibitory and Working Memory Deficits in Children and Adolescents Who are Children of Parents With Schizophrenia
Ross et al.
Schizophr Bull 2008;34:47-51.
ABSTRACT | FULL TEXT  

Limbic Structures and Networks in Children and Adolescents With Schizophrenia
White et al.
Schizophr Bull 2008;34:18-29.
ABSTRACT | FULL TEXT  

Catechol-O-Methyltransferase Val158Met Modulation of Prefrontal Parietal Striatal Brain Systems during Arithmetic and Temporal Transformations in Working Memory
Tan et al.
J. Neurosci. 2007;27:13393-13401.
ABSTRACT | FULL TEXT  

Structural brain abnormalities in individuals with an at-risk mental state who later develop psychosis
BORGWARDT et al.
Br. J. Psychiatry 2007;191:s69-s75.
ABSTRACT | FULL TEXT  

Specific developmental disruption of disrupted-in-schizophrenia-1 function results in schizophrenia-related phenotypes in mice
Li et al.
Proc. Natl. Acad. Sci. USA 2007;104:18280-18285.
ABSTRACT | FULL TEXT  

Evidence That the BLOC-1 Protein Dysbindin Modulates Dopamine D2 Receptor Internalization and Signaling But Not D1 Internalization
Iizuka et al.
J. Neurosci. 2007;27:12390-12395.
ABSTRACT | FULL TEXT  

Computational Model Predicts a Role for ERG Current in Repolarizing Plateau Potentials in Dopamine Neurons: Implications for Modulation of Neuronal Activity
Canavier et al.
J. Neurophysiol. 2007;98:3006-3022.
ABSTRACT | FULL TEXT  

Prefrontal Dysfunction in Schizophrenia Involves Mixed-Lineage Leukemia 1-Regulated Histone Methylation at GABAergic Gene Promoters
Huang et al.
J. Neurosci. 2007;27:11254-11262.
ABSTRACT | FULL TEXT  

Dopamine Genes and Schizophrenia: Case Closed or Evidence Pending?
Talkowski et al.
Schizophr Bull 2007;33:1071-1081.
ABSTRACT | FULL TEXT  

Recent Advances in the Development of Novel Pharmacological Agents for the Treatment of Cognitive Impairments in Schizophrenia
Buchanan et al.
Schizophr Bull 2007;33:1120-1130.
ABSTRACT | FULL TEXT  

Dysfunctional and Compensatory Prefrontal Cortical Systems, Genes and the Pathogenesis of Schizophrenia
Tan et al.
Cereb Cortex 2007;17:i171-i181.
ABSTRACT | FULL TEXT  

Molecular Cloning of a Brain-specific, Developmentally Regulated Neuregulin 1 (NRG1) Isoform and Identification of a Functional Promoter Variant Associated with Schizophrenia
Tan et al.
J. Biol. Chem. 2007;282:24343-24351.
ABSTRACT | FULL TEXT  

Molecular activity underlying working memory
Dash et al.
Learn. Mem. 2007;14:554-563.
ABSTRACT | FULL TEXT  

Legal Fallacies of Antipsychotic Drugs
Erickson et al.
J Am Acad Psychiatry Law 2007;35:235-246.
ABSTRACT | FULL TEXT  

Review: Glutamate and dopamine dysregulation in schizophrenia a synthesis and selective review
Stone et al.
J Psychopharmacol 2007;21:440-452.
ABSTRACT  

Progressive and Interrelated Functional and Structural Evidence of Post-Onset Brain Reduction in Schizophrenia
Salisbury et al.
Arch Gen Psychiatry 2007;64:521-529.
ABSTRACT | FULL TEXT  

Catechol-o-Methyltransferase Enzyme Activity and Protein Expression in Human Prefrontal Cortex across the Postnatal Lifespan
Tunbridge et al.
Cereb Cortex 2007;17:1206-1212.
ABSTRACT | FULL TEXT  

Volume, neuron density and total neuron number in five subcortical regions in schizophrenia
Kreczmanski et al.
Brain 2007;130:678-692.
ABSTRACT | FULL TEXT  

DISC1 Regulates Neurotrophin-Induced Axon Elongation via Interaction with Grb2
Shinoda et al.
J. Neurosci. 2007;27:4-14.
ABSTRACT | FULL TEXT  

DISC1 Regulates the Transport of the NUDEL/LIS1/14-3-3{varepsilon} Complex through Kinesin-1
Taya et al.
J. Neurosci. 2007;27:15-26.
ABSTRACT | FULL TEXT  

An Increase in AMPA and a Decrease in SK Conductance Increase Burst Firing by Different Mechanisms in a Model of a Dopamine Neuron In Vivo
Canavier and Landry
J. Neurophysiol. 2006;96:2549-2563.
ABSTRACT | FULL TEXT  

Adverse effects of risperidone on spatial working memory in first-episode schizophrenia.
Reilly et al.
Arch Gen Psychiatry 2006;63:1189-1197.
ABSTRACT | FULL TEXT  

Fronto-cerebellar systems are associated with infant motor and adult executive functions in healthy adults but not in schizophrenia
Ridler et al.
Proc. Natl. Acad. Sci. USA 2006;103:15651-15656.
ABSTRACT | FULL TEXT  

Genetic Heterogeneity, Modifier Genes, and Quantitative Phenotypes in Psychiatric Illness: Searching for a Framework
Fanous and Kendler
Focus 2006;4:423.
ABSTRACT | FULL TEXT  

Neuropsychological Functioning in Adolescents and Young Adults at Genetic Risk for Schizophrenia and Affective Psychoses: Results from the Harvard and Hillside Adolescent High Risk Studies
Seidman et al.
Schizophr Bull 2006;32:507-524.
ABSTRACT | FULL TEXT  

The relation between menarche and the age of first symptoms in a multiple sclerosis cohort
Sloka et al.
Mult Scler 2006;12:333-339.
ABSTRACT  

The time of prenatal immune challenge determines the specificity of inflammation-mediated brain and behavioral pathology.
Meyer et al.
J. Neurosci. 2006;26:4752-4762.
ABSTRACT | FULL TEXT  

The Neuropsychiatry of Niemann-Pick Type C Disease in Adulthood
Walterfang et al.
J. Neuropsychiatry Clin. Neurosi. 2006;18:158-170.
ABSTRACT | FULL TEXT  

Altered Prefrontal Dopaminergic Function in Chronic Recreational Ketamine Users
Narendran et al.
Am. J. Psychiatry 2005;162:2352-2359.
ABSTRACT | FULL TEXT  

Elaboration on Premorbid Intellectual Performance in Schizophrenia: Premorbid Intellectual Decline and Risk for Schizophrenia
Reichenberg et al.
Arch Gen Psychiatry 2005;62:1297-1304.
ABSTRACT | FULL TEXT  

Neurobiology of early psychosis
KESHAVAN et al.
Br. J. Psychiatry 2005;187:s8-s18.
ABSTRACT | FULL TEXT  

First-Episode Psychosis: Psychopathology, Quality of Life, and Functional Outcome
Malla and Payne
Schizophr Bull 2005;31:650-671.
ABSTRACT | FULL TEXT  

Structural Brain Imaging Evidence for Multiple Pathological Processes at Different Stages of Brain Development in Schizophrenia
Pantelis et al.
Schizophr Bull 2005;31:672-696.
ABSTRACT | FULL TEXT  

Pathogenesis of schizophrenia: a psychopathological perspective
Owens et al.
Br. J. Psychiatry 2005;186:386-393.
ABSTRACT | FULL TEXT  

Neuropsychological Impairment and Its Neurological Correlates in Adult Offspring With Heightened Risk for Schizophrenia and Affective Psychosis
Schubert and McNeil
Am. J. Psychiatry 2005;162:758-766.
ABSTRACT | FULL TEXT  

Regionally Specific Disturbance of Dorsolateral Prefrontal-Hippocampal Functional Connectivity in Schizophrenia
Meyer-Lindenberg et al.
Arch Gen Psychiatry 2005;62:379-386.
ABSTRACT | FULL TEXT  

Effects of Psychotic State and Task Demand on Prefrontal Function in Schizophrenia: An fMRI Study of Overt Verbal Fluency
Fu et al.
Am. J. Psychiatry 2005;162:485-494.
ABSTRACT | FULL TEXT  

Imaging Frontostriatal Function in Ultra-High-Risk, Early, and Chronic Schizophrenia During Executive Processing
Morey et al.
Arch Gen Psychiatry 2005;62:254-262.
ABSTRACT | FULL TEXT  

Schizophrenia: a genetic disorder of the synapse?
Owen et al.
BMJ 2005;330:158-159.
FULL TEXT  

Partial agonism and schizophrenia
Bolonna and Kerwin
Br. J. Psychiatry 2005;186:7-10.
FULL TEXT  

Interaction of COMT Val108/158 Met Genotype and Olanzapine Treatment on Prefrontal Cortical Function in Patients With Schizophrenia
Bertolino et al.
Am. J. Psychiatry 2004;161:1798-1805.
ABSTRACT | FULL TEXT  

Basal Ganglia High-Energy Phosphate Metabolism in Neuroleptic-Naive Patients With Schizophrenia: A 31-Phosphorus Magnetic Resonance Spectroscopic Study
Gangadhar et al.
Am. J. Psychiatry 2004;161:1304-1306.
ABSTRACT | FULL TEXT  

Predictors of antipsychotic treatment response in patients with first-episode schizophrenia, schizoaffective and schizophreniform disorders
Perkins et al.
Br. J. Psychiatry 2004;185:18-24.
ABSTRACT | FULL TEXT  

Prospective Study of Neurological Abnormalities in Offspring of Women With Psychosis: Birth to Adulthood
Schubert and McNeil
Am. J. Psychiatry 2004;161:1030-1037.
ABSTRACT | FULL TEXT  

Criminal Offending in Schizophrenia Over a 25-Year Period Marked by Deinstitutionalization and Increasing Prevalence of Comorbid Substance Use Disorders
Wallace et al.
Am. J. Psychiatry 2004;161:716-727.
ABSTRACT | FULL TEXT  

Prefrontal Broadband Noise, Working Memory, and Genetic Risk for Schizophrenia
Winterer et al.
Am. J. Psychiatry 2004;161:490-500.
ABSTRACT | FULL TEXT  

Genotype-environment interaction in schizophrenia-spectrum disorder: Long-term follow-up study of Finnish adoptees
Tienari et al.
Br. J. Psychiatry 2004;184:216-222.
ABSTRACT | FULL TEXT  

Reward-Predicting Activity of Dopamine and Caudate Neurons--A Possible Mechanism of Motivational Control of Saccadic Eye Movement
Kawagoe et al.
J. Neurophysiol. 2004;91:1013-1024.
ABSTRACT | FULL TEXT  

Presynaptic Dopaminergic Dysfunction in Schizophrenia: A Positron Emission Tomographic [18F]Fluorodopa Study
McGowan et al.
Arch Gen Psychiatry 2004;61:134-142.
ABSTRACT | FULL TEXT  

Cavum Septum Pellucidum and Its Increased Prevalence in Schizophrenia: A Neuroembryological Classification
Galarza et al.
J. Neuropsychiatry Clin. Neurosi. 2004;16:41-46.
ABSTRACT | FULL TEXT  

A Modeling Study Suggests Complementary Roles for GABAA and NMDA Receptors and the SK Channel in Regulating the Firing Pattern in Midbrain Dopamine Neurons
Komendantov et al.
J. Neurophysiol. 2004;91:346-357.
ABSTRACT | FULL TEXT  

Smaller Anterior Hippocampal Formation Volume in Antipsychotic-Naive Patients With First-Episode Schizophrenia
Szeszko et al.
Am. J. Psychiatry 2003;160:2190-2197.
ABSTRACT | FULL TEXT  

Prefrontal DA Transmission at D1 Receptors and the Pathology of Schizophrenia
Abi-Dargham and Moore
Neuroscientist 2003;9:404-416.
ABSTRACT  

Magnetic Resonance Imaging of Mediodorsal, Pulvinar, and Centromedian Nuclei of the Thalamus in Patients With Schizophrenia
Kemether et al.
Arch Gen Psychiatry 2003;60:983-991.
ABSTRACT | FULL TEXT  

Elucidating the pathogenesis of schizophrenia
Sawa and Kamiya
BMJ 2003;327:632-633.
FULL TEXT  

The Schizophrenia Phenotype in 22q11 Deletion Syndrome
Bassett et al.
Am. J. Psychiatry 2003;160:1580-1586.
ABSTRACT | FULL TEXT