(PSYCHIATRIC TIMES) - 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.
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