Schizophrenia is a devastating psychiatric disorder that affects 1% of the population worldwide. Patients often suffer their first psychotic outbreak in their late teens or early 20s. Despite advances in neuroleptic drugs, many patients' symptoms remain refractory to treatment, with recurrent episodes of auditory and visual hallucinations, bizarre delusions, depression, and social withdrawal that can last an entire lifetime. Neuroimaging studies now suggest that schizophrenia is a disorder of brain development, with anatomic abnormalities present at disease onset. Teen-agers with a severe, early-onset form of schizophrenia also exhibit a dynamically spreading wave of cortical gray matter loss, detectable in sequential magnetic resonance imaging scans. The tissue loss begins in a small region of the parietal cortex and moves forward to engulf frontal and temporal systems. These deficits correlate with psychotic symptom severity and may link with cortical dopamine or serotonin dysfunction. The shifting pattern of deficits is distinct from the neurodegeneration observed in the dementias and may be an exaggeration or derailment of the neuronal remodeling that normally occurs in late teen-age brain development. Computerized tracking of these cortical deficits will help understand how neuroleptic drugs decelerate or block the disease process. Cortical deficits are also detectable in patients' first-degree relatives, who are at greatly increased genetic risk for schizophrenia (10% lifetime risk). In the future, these dynamic and genetic brain maps may predict imminent onset of the disease, identifying pre-symptomatic brain changes in family members who are candidates for early interventions.
One of the greatest enigmas in contemporary psychiatry is why schizophrenia strikes in the late teen-age years or young adulthood, often without warning. With an average age of onset around 20 to 25 in men and 25 to 30 in women, psychotic outbreaks in schizophrenia may include delusions, hallucinations and bizarre thoughts (i.e., positive symptoms). Negative symptoms include chronic depression, flattened affect, poverty of speech, loss of motivation and social decline. If these symptoms are untreated, the active phase of florid psychotic symptoms may last forever; however, they may be controlled to a degree by antipsychotics. Even when medications are effective, psychotic outbreaks are often replaced by a residual phase of poverty of thought or blunted affect. Around 20% of patients have a single psychotic outbreak, and 35% have multiple episodes without severe functional or personality impairments (Green, 1999). The remainder of patients has relatively static (10%) or progressive (35%) functional impairments between psychotic episodes.
Unlike Alzheimer's disease, where amyloid plaques, neurofibrillary tangles and neuronal loss are pervasive in the brain at autopsy, there are no widely accepted pathologic hallmarks of schizophrenia. This is frustrating, as a biochemical marker could provide the basis for a diagnostic test and a target for drug action or disease prevention. Nonetheless, multiple lines of evidence suggest that cortical neurotransmitter function is disturbed in schizophrenia. Abnormalities in cortical dopamine, serotonin, glutamate, -aminobutyric acid (GABA) and norepinephrine have been intensively investigated. Classical antipsychotics (e.g., haloperidol [Haldol]) alleviate positive symptoms by blocking dopamine (D2-type) receptors in the limbic and prefrontal cortices of the brain, systems that regulate emotion and executive function. Newer atypical antipsychotics, including clozapine (Clozaril) and olanzapine (Zyprexa), powerfully block the 5-HT2 serotonin and D4 dopamine receptors and tend to outperform haloperidol in reducing negative symptoms (Bilder et al., 2002). Intriguingly, genetic studies suggest that 2% of patients with schizophrenia exhibit a chromosomal deletion in region 22q11, which harbors the gene encoding catechol-O-methyltransferase (COMT), a powerful inactivator of dopamine. Mice with targeted deletion of this gene have excess dopamine in the prefrontal cortex. This is consistent with the notion that patients with this deletion (which confers a 25% to 30% lifetime risk of schizophrenia) may suffer from a functional excess of cortical dopamine, and this may be responsible for their positive symptoms.
Advances in neuroimaging, and structural MRI in particular, have empowered the search for biological markers of schizophrenia. Reduced cortical and hippocampal volume are found consistently in patients with schizophrenia, and the ventricular and sulcal cerebral spinal fluid spaces are often enlarged. Diffuse gray matter deficits are observed on MRI even in first-episode patients, where the confounding effects of medication on brain structure are ruled out. There is great interest in identifying when these anatomical deficits first appear. If their origins were identified, it may be possible to pinpoint precisely where, and when, an active pathological process begins. This could allow earlier disease detection and targeted interventions.
Abnormal Brain Development
Over 20 years of studies suggest that the origins of schizophrenia, as well as multiple risk factors, may lie in childhood or embryonic brain development. Obstetric risk factors, which confer a later risk for schizophrenia, include fetal malnutrition, extreme prematurity, hypoxia and ischemia (Cannon et al., 2002b). People born in winter months (Kirch, 1993) or exposed to the influenza virus in the second trimester (Mednick et al., 1988) may also have an increased incidence of schizophrenia. Some studies have contested this association, but others suggest that early viral exposure may increase risk for other psychiatric disorders as well (Akil and Weinberger, 2000). Given the array of proposed risk factors, disrupted brain development may play a causative role in schizophrenia. If this is the case, a key puzzle is why there is a long gap between an early cerebral insult and the emergence of symptoms 20 or more years later. To explain this, some theorists favor a two-hit (or diathesis-stress) model, in which an early developmental or genetic anomaly must be compounded by psychological trauma, viral infection or some currently unknown trigger later in life for the disease to be expressed.
Renewed interest in the developmental hypothesis comes from recent brain imaging studies. These identify a drastic remodeling of brain structure in the teen-age years and beyond. Well into adolescence, there are growth spurts in myelination (Thompson et al., 2000), and dramatic waves of gray matter loss (Giedd et al., 1999a; Sowell et al., 1999). In a landmark paper based on MRIs of healthy subjects, Giedd et al. (1999b) built quadratic growth curves between the ages of 4 and 20 for gray matter volumes in each lobe of the brain. Perhaps surprisingly, the overall volume of gray matter declined sharply after the age of 12, especially in frontal and parietal cortices. This process continued through adolescence and beyond, with the latest decrements occurring in the frontal cortex (Sowell et al., 1999). Since schizophrenia typically strikes at a time when these developmental changes are still occurring, an intriguing hypothesis is that a normal teen-age process of dendritic remodeling and synapse elimination (sometimes called pruning) may be accelerated or otherwise derailed in schizophrenia (Feinberg, 1982). This excessive pruning may reach a threshold level where cortical information processing is disrupted. It may also account for the increased neuronal packing density seen in some cortical layers in postmortem studies of patients with schizophrenia (Selemon et al., 1995).
In a large-scale effort to map the trajectory of brain changes during development, Judith Rapoport, M.D., and her colleagues at the National Institute of Mental Health have scanned over 1,000 children and teen-agers with high-resolution MRIs (Rapoport et al., 1999). Most of these children have been scanned every two years since 1992, producing a remarkable time-lapse movie showing their brain development. Among those patients scanned at NIMH were 50 adolescents (30 boys, 20 girls) with early-onset schizophrenia (EOS). These patients satisfied DSM-III-R/DSM-IV criteria for diagnosis of schizophrenia before age 13. Rigorous clinical and cognitive evaluations revealed their symptoms were continuous with the adult disorder; many patients resemble poor-outcome adult cases (Rapoport and Inoff-Germain, 2000).
1. Akil M, Weinberger DR (2000), Neuropathology and the neurodevelopmental model. In: The Neuropathology of Schizophrenia: Progress and Interpretation, Harrison PJ, Roberts GW, eds. New York: Oxford University Press, pp189-212.
2. Bilder RM, Goldman RS, Volavka J et al. (2002), Neurocognitive effects of clozapine, olanzapine, risperidone, and haloperidol in patients with chronic schizophrenia or schizoaffective disorder. Am J Psychiatry 159(6):1018-1028 [see comment].
3. Cannon TD, Thompson PM, van Erp TG et al. (2002a), Cortex mapping reveals regionally specific patterns of genetic and disease-specific gray-matter deficits in twins discordant for schizophrenia. Proc Natl Acad Sci U S A 99(5):3228-3233.
4. Cannon TD, van Erp TG, Rosso IM et al. (2002b), Fetal hypoxia and structural brain abnormalities in schizophrenic patients, their siblings, and controls. Arch Gen Psychiatry 59(1):35-41.
5. Feinberg I (1982), Schizophrenia: caused by a fault in programmed synaptic elimination during adolescence? J Psychiatr Res 17(4):319-334.
6. Giedd JN, Blumenthal J, Jeffries NO et al. (1999a), Brain development during childhood and adolescence: a longitudinal MRI study. Nat Neurosci 2(10):861-863 [letter].
7. Giedd JN, Jeffries NO, Blumenthal J et al. (1999b), Childhood-onset schizophrenia: progressive brain changes during adolescence. Biol Psychiatry 46(7):892-898 [see comment].
8. Green B (1999), A review of schizophrenia. Psychiatry Online. Available at: www.pol-it.org/schizo.htm. Accessed February 18, 2003.
9. Kirch DG (1993), Infection and autoimmunity as etiologic factors in schizophrenia: a review and reappraisal. Schizophr Bull 19(2):355-370.
10. Mednick SA, Machon RA, Huttunen MO, Bonett D (1988), Adult schizophrenia following prenatal exposure to an influenza epidemic. Arch Gen Psychiatry 45(2):189-192.
11. Rapoport JL, Giedd JN, Blumenthal J et al. (1999), Progressive cortical change during adolescence in childhood-onset schizophrenia. A longitudinal magnetic resonance imaging study. Arch Gen Psychiatry 56(7):649-654.
12. Rapoport JL, Inoff-Germain G (2000), Update on childhood-onset schizophrenia. Curr Psychiatry Rep 2(5):410-415.
13. Selemon LD, Rajkowska G, Goldman-Rakic PS (1995), Abnormally high neuronal density in the schizophrenic cortex. A morphometric analysis of prefrontal area 9 and occipital area 17. Arch Gen Psychiatry 52(10):805-818.
14. Sowell ER, Thompson PM, Holmes CJ et al. (1999), In vivo evidence for post-adolescent brain maturation in frontal and striatal regions. Nat Neurosci 2(10):859-861 [letter].
15. Thompson PM, Giedd JN, Woods RP et al. (2000), Growth patterns in the developing human brain detected using continuum mechanical tensor mapping. Nature 404(6774):190-193.
16. Thompson PM, Hayashi KM, de Zubicaray G et al. (2003), Dynamics of gray matter loss in Alzheimer's disease. J Neurosci 23(3):994-1005.
17. Thompson PM, Vidal C, Giedd JN et al. (2001), Mapping adolescent brain change reveals dynamic wave of accelerated gray matter loss in very early-onset schizophrenia. Proc Natl Acad Sciences U S A 98(20):11650-11655.