Nicotineresponsive Elementary Phenotypes In Schizophrenia

Schizophrenia is a complex genetic disorder; i.e., the illness does not have a pattern of inheritance resulting from a single genetic abnormality.10 Two nicotine-responsive neurophysiological abnormalities, one in auditory sensory gating and the other in smooth pursuit eye movements, are currently under investigation as potential elementary phenotypes representing gene effects that, in combination with other specific gene effects, may result in the development of schizophrenic illness.1112 These neurophysiological abnormalities appear to be transmitted as autosomal dominant characteristics in some families with high occurrence rates for schizophrenia, and they are both normalized by nicotine administration. The subjective experience of this normalization may contribute to the drive to smoke among patients with schizophrenia.

11.2.1 Auditory Sensory Gating Abnormalities

In nearly all neuronal systems, when stimuli are repeated, the electroencephalo-graphic response to the second stimulus is less than that to the first. The first stimulus activates not only the initial response, but also inhibitory circuits that reduce the response to the second stimulus. When presented with two-click stimuli 500 msec apart, patients with schizophrenia do not inhibit one aspect of their response (the P50 wave of the auditory evoked potential) to the second click as much as normal individuals do. After these patients smoke as much as they wish, this deficit in auditory sensory gating disappears and the responses to the second stimulus are decreased, as occurs in normal individuals, for 15 to 30 minutes before again returning to the abnormal pattern as nicotine effects dissipate. Fifty percent of the nonafflicted, first-degree relatives of patients with schizophrenia who have this auditory sensory gating deficit also demonstrate the deficit. Chewing nicotine gum corrects the deficit in these nonafflicted, nonsmoking relatives as well.

Linkage analysis of P50 auditory sensory gating abnormalities in families that display this trait has provided evidence for linkage in the chromosome 15 q 14 region, a site later shown to code for the alpha-7 nicotine receptor subunit.13

11.2.2 Smooth Pursuit Eye Movement Abnormalities

Patients with schizophrenia have significantly more frequent intrusions of small anticipatory saccades into their smooth pursuit eye movements than do normal individuals. Like the auditory sensory gating abnormalities, these intrusions can be conceptualized as deficits in inhibition. The eye movement abnormalities can be dispelled temporarily by high doses of nicotine, such as those delivered by the heavy smoking of patients with schizophrenia. The eye-tracking abnormalities also appear to be transmitted as an autosomal dominant characteristic, and can be demonstrated in 50% of the offspring of a parent with schizophrenia. Linkage studies suggest a locus on chromosome 6.12

Childhood onset schizophrenia is a rare, severe form of the illness with early onset and poor prognosis. A study of ten proband/both parent trios revealed bilineal transmission of sensory gating and/or eye movement abnormalities to these probands, in contrast to the more common transmission of one of these traits down one parental line that characterizes most patients with adult-onset schizophrenia.12

Currently, ongoing research is exploring whether individuals with these potential elementary phenotypes can be consistently discriminated from individuals without the phenotypes, and whether these potential elementary phenotypes reflect single genetic phenomena. Comorbidity appears to be the rule rather than the exception in psychiatric disorders, and potential nicotinic mechanisms involved in highly comor-bid disorders (e.g., substance use disorders) must be distinguished from those involved specifically in schizophrenia. Several genetic disorders involving the long arm of chromosome 15 are associated with increased incidence of schizophrenialike psychosis, lending validation to the auditory sensory gating/alpha-7 nicotine receptor linkage with schizophrenia. The ultimate goal of such work is to understand how genotypes associated with elementary phenotypes contribute to risk for schizo-phrenia.11

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