Biological Indicators

During the last two decades, a considerable number of biological indices have been investigated with the aim to find measurable indicators of, and confirmatory tests for, the disorder. According to Szymanski et al [123], the most promising biological indicators are pursuit eye movement dysfunctions, abnormalities in electrodermal activity, abnormalities in event-related brain voltage potentials, deficits in attention and information processing, and abnormal findings from brain imaging procedures.

According to a review by Clementz and Sweeney [124], between two-thirds and three-quarters of patients with schizophrenia show an impairment in smooth pursuit eye movements. The impairment is significantly higher in patients with schizophrenia than in normal controls and in other psychotic or non-psychotic control subjects [125, 126]. In addition, abnormal pursuit eye movements have been found in one third to more than one half of first-degree relatives of persons with schizophrenia, in contrast to only a small proportion of relatives of persons with other psychiatric disorders. Abnormal pursuit eye movements are, however, not entirely specific for schizophrenia. In particular, they may be observed in bipolar disorder [127]. According to Matthysse et al [128] and Holzman et al [129], eye movement impairment may be one possible manifestation of a genetically determined latent trait, with schizophrenic symptoms being one of several possible phenotypic expressions of that trait. On the whole, eye movement dysfunction is ''a robust candidate in the search for a trait marker but not a confirmatory test for schizophrenia'' [123].

Measures of evoked potentials have been widely found to be abnormal in patients with schizophrenia. St Clair et al [130] have reported smaller P300 amplitudes as well as delays in latency in patients with schizophrenia versus control subjects. According to Pfefferbaum et al [131], reduced auditory-and visual-evoked P300 amplitudes may be correlated with negative symptoms, while increased auditory P300s have been associated with positive symptoms [132]. Abnormalities in P300 are, however, not specific for schizophrenia, since they have also been found in patients with other psychiatric disorders, in particular in patients with schizotypal or borderline personality disorders [133,134] and in patients with dementia [135].

Other investigations on event-related brain voltage potentials (ERPs) have found abnormalities in N100 and contingent negative variation as well as defects in sensory gating. The results of these studies are, however, conflicting and non-specific [123].

Studies on electrodermal activity have shown that 40-50% of patients with schizophrenia are non-responsive with the phasic skin conductance orienting response (SCOR) test versus 5-10% of non-psychiatric control subjects [136]. This type of response is, however, not specific for schizophrenia, since it has also been found in other psychiatric disorders, in particular in mood disorders [136]. Attempts to link non-response to positive or negative symptoms have yielded mixed results [137-140]. Recent studies on the SCOR test in patients with schizophrenia have identified two subgroups: a large subgroup of low to moderately aroused phasic SCOR non-responders; and a smaller subgroup of SCOR responders in which electrodermal tonic arousal is abnormally high [141,142]. According to Dawson et al [143], phasic SCOR non-responding may qualify as a vulnerability indicator for schizophrenia, whereas tonic electrodermal arousal qualifies as a state-sensitive indicator.

Impairment in sustained focused attention as measured by continuous performance tests (CPT) may be a strong neuropsychological risk indicator for schizophrenia. According to Erlenmeyer-Kimling and Cornblatt [144], 40-50% of patients with schizophrenia show impaired performance. According to the same authors and to Nuechterlein et al [145], more complex CPT versions show significant differences between high-risk children and control subjects. In a recent review of more than forty studies that used various versions of the CPT, Cornblatt and Keilp [146] concluded that impaired attention is detectable in patients with schizophrenia, regardless of clinical state; that the disturbance is detectable before onset of the disorder; and that it is apparently heritable. The authors concede that attentional disturbances are also found in patients with other disorders such as mood disorders and children with attention deficit disorder, but report that there are particular patterns of impairment that appear to be specific to schizophrenia. They conclude that abnormal attention as shown with different versions of the CPT is highly promising as an indicator of a biological susceptibility to schizophrenia.

Structural and functional neuroimaging studies are providing new insights into schizophrenia [147]. Computerized tomography (CT) and magnetic resonance imaging (MRI) studies have shown an enlargement of lateral cerebral ventricles in some but not all patients with schizophrenia. In a meta-analysis of CT and MRI studies, Raz and Raz [148] found convincing evidence that mean ventricular volume in patients is larger than in normal controls, but that the magnitude of the effect is relatively small. There is also evidence that the smaller cerebral tissue volumes found in patients with schizophrenia are due to deficits in the volume of grey matter, with temporal and frontal regions showing greater deficits than parietal and occipital areas [147,149,150]. The question of whether the brain abnormalities in patients with schizophrenia are static or progressive, or whether they are static in some patients and progressive in others is still being debated [151].

Functional imaging techniques, such as positron emission tomography (PET) or single photon emission computer tomography (SPECT) have recently been reviewed by Liddle [152]. According to the reviewer, functional imaging studies have provided strong evidence for widespread disturbance of brain function, especially in the association cortex of frontal and temporal lobes.

Studies on the neurochemistry of schizophrenia, in particular on potential neurotransmitter-related enzymatic activity markers, have not yielded any consistent results up to now [123,153].

In 1987, Garver [154] identified the following criteria for a trait marker to detect biological risk for psychosis: (a) it should distribute differently in patients with psychosis than in control populations; (b) it should have a greater prevalence in family members of identified patients with psychosis than in the general population and be associated with psychotic spectrum disorder in family members; (c) it should correlate with subsequent development of psychotic spectrum disorder in high-risk children and occur preceding the development of clinical manifestations of psychotic spectrum disorder; (d) it should be reliable and stable over time.

Although some biological indicators, including in particular those listed above, show promise for meeting Garver's criteria, none of them meets them completely. According to Szymanski et al [123], there are no biological indicators at present that can be employed in establishing a diagnosis of schizophrenia. According to these authors, longitudinal studies in high-risk populations utilizing multiple biological measures may, however, eventually define psychiatric syndromes with greater precision than clinical criteria or single biological markers.

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