In an effort to reveal susceptibility genes, schizophrenia research has turned to the endophenotype strategy. Endophenotypes are characteristics that reflect the actions of genes predisposing an individual to a disorder, even in the absence of diagnosable pathology. Individual endophenotypes are presumably determined by fewer genes than the more complex phenotype of schizophrenia and would, therefore, reduce the complexity of genetic analyses. Unfortunately, despite there being rational criteria to define a viable endophenotype, the term is sometimes applied indiscriminately to characteristics that are deviant in affected individuals. Schizophrenia patients exhibit deficits in several neurophysiological measures of information processing that have been proposed as candidate endophenotypes. Successful processing of sensory inputs requires the ability to inhibit intrinsic responses to redundant stimuli and, reciprocally, to facilitate responses to less frequent salient stimuli. There is evidence to suggest that both these processes are “impaired” in schizophrenia. Measures of inhibitory failure include prepulse inhibition of the startle reflex, P50 auditory evoked potential suppression, and antisaccade eye movements. Measures of impaired deviance detection include mismatch negativity and the P300 event-related potential. The purpose of this review is to systematically evaluate the endophenotype candidacy of these key neurophysiological abilities. For each candidate, we describe typical experimental procedures, the current understanding of the underlying neurobiology, the nature of the abnormality in schizophrenia, the reliability, stability and heritability of the measure, and any reported gene associations. We conclude with a discussion of the few studies thus far that have employed a multivariate approach with these candidates.

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Neurophysiological Endophenotypes of Schizophrenia: The Viability of Selected Candidate Measures

Smoking, nicotine and neuropsychiatric disorders

Endophenotypes in schizophrenia: a selective review.

http://www.fss.uu.nl/psn/web/people/personal/stigchel/rommelsereview.pdf

A review on eye movement studies in childhood and adolescent psychiatry

The tell-tale tasks: A review of saccadic research in psychiatric patient populations

Smooth pursuit and antisaccade eye-tracking abnormalities have been proposed as endophenotypes for schizophrenia. However, it is not clear whether these tasks measure the same underlying abnormality. We hypothesised that these measures would be correlated. The association between smooth pursuit and antisaccade task performance was assessed in 50 schizophrenic patients, 80 unaffected first-degree relatives and 40 unaffected controls. Smooth pursuit measures included gain, number of saccades and a qualitative measure of smooth pursuit. The antisaccade distractibility error (ADE) score was the only measure of the antisaccade task. A significant correlation was found between reduced gain and an increased ADE score for all the subjects in the three groups combined. The total number of saccades was negatively correlated with the ADE score in the schizophrenic group, but positively in the relative group. Qualitative ratings of smooth pursuit correlated with the ADE score. Our results suggest that the antisaccade distractibility error score is related to gain and qualitative measures of smooth pursuit, although the relationship with number of saccades did not conform to this pattern. The finding may reflect a shared genetic liability, that affects both eye-tracking phenotypes. It is likely that both measures reflect frontal cortical dysfunction.

Eye tracking in schizophrenia: Does the antisaccade task measure anything that the smooth pursuit task does not?

Background. Saccadic distractibility, as measured by the antisaccade task, has attracted attentionas a putative endophenotypic marker for schizophrenia. Some studies have suggested that thismeasure is elevated in the unaﬀected relatives of schizophrenia patients. However, recent studieshave called this into question and the topic remains controversial.Method. Saccadic distractibility was measured in 53 patients with DSM-IV schizophrenia, 80unaﬀected ﬁrst-degree relatives and 41 unaﬀected controls.Results. Schizophrenia patients performed worse than relatives and controls combined (p<0.00001), but relatives did not diﬀer signiﬁcantly from controls. Performance in multiply aﬀectedfamilies was no worse than that in singly aﬀected families. Relatives with a high presumed geneticrisk for schizophrenia performed no worse than other relatives. The performance of the patientsdid not predict that of their relatives.Conclusions. These results demonstrate that saccadic distractibility is strongly associated withdisease status but not with genetic loading for schizophrenia. We conclude that saccadic distract-ibility is unlikely to be useful as an endophenotypic marker in schizophrenia.INTRODUCTIONFamily, twin and adoption studies have indi-cated that operationally deﬁned schizophreniahas a heritability of over 0.8 (Cardno et al.1999). However, the non-Mendelian segregationwithin families and the disparate linkage ﬁnd-ings suggest that schizophrenia is a complex,polygenicdisorder(Gottesman&Shields,1982).Genetic transmission in schizophrenia is likelyto be further complicated by epistasis (Wade,2001) (non-additive interactionsbetween genes),pleiotropy (Hodgkin, 1998) (a single gene deter-mining two or more characteristics), incompletepenetrance (Levinson et al. 1996), interactionswith environmental factors (Van Os & Sham,2002), and the probable aetiological hetero-geneity of the clinically deﬁned disorder(Cardno & Gottesman, 2000).One approach to overcoming these problemsis the use of intermediate phenotypes, or bio-logical markers. These are anatomical, physio-logical or biochemical variables that segregatewith genetic risk for the disorder, and whichare assumed to have a simpler genetic architec-ture than the disorder itself (Weinberger, 2002),with a more proximal relationship to theunderlying genes. It is hoped that the use ofbiological markers will identify more homo-geneous groups of subjects within the broaderclinically deﬁned phenotype, and thus lead toimproved success in the search for susceptibilitygenes.The necessary criteria for a biological markerwere set out by Wickham & Murray (1997).

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Helen Simon

Papers

Eye tracking in schizophrenia: Does the antisaccade task measure anything that the smooth pursuit task does not?

Saccadic distractibility is elevated in schizophrenia patients, but not in their unaffected relatives.

Using speech-to-text technology to empower young writers with special educational needs.