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Neurological soft signs in schizophrenia and mood disorders: investigating a potential endophenotype

(2005) Boks, Marco Paul Maria

With these studies we investigated the meaning of NSS and its potential as an endophenotype for schizophrenia. We looked at the three requirements for a good endophenotype; measurability, reliability and specificity.
The measurability of NSS is compromised by the compositions of debatable categories of NSS. In our literature review we could not find a clear pattern of NSS based on the specificity of NSS for schizophrenia (chapter 5). However the categories of NSS we derived by means of a principle component analysis of those signs distinguishing patients from controls, revealed a pattern of NSS that was related to established abnormalities in schizophrenia but deviated from traditional categories of NSS (chapter 6).
The interrater reliability was measured by rating NSS simultaneously and calculating measures of consistency between raters, which ranged from poor to good for categories of NSS but was good for the overall score (chapter 2). The test retest reliability was studied by looking at the temporal stability of NSS at two years follow up (chapter 3) and the relationship of NSS with medication by means of a cross sectional study (chapter 4). We found no significant changes in the numbers of NSS 2-years after a first episode of psychosis. However, the number of NSS was increased in patients with an increase of medication. These findings concur with the majority of the evidence suggesting that NSS do show temporal stability, but subsets of NSS may show variation related to symptom profile and clinical outcome. The type of medication did not influence NSS insofar they did not incorporate TD signs. However they did influence the number of TD signs. It is therefore likely that NSS are independent from medication insofar the assessments do not incorporate EPS and dyskinesia signs.
We have studied the specificity of NSS by means of a literature review (chapter 5) and case-control study in two diagnostic groups (chapter 6). In our review we found that NSS are also apparent in mood disorders, at intermediate level between schizophrenia and controls. By means of a principle component analysis we did find a subset of NSS that did show specificity for schizophrenia compared to mood disorders (chapter 6) but these findings need to be interpreted with caution. We included eye movement disorders in that group and the measurability of these signs is likely to have been poor in the absence of suitable equipment. Moreover the findings await replication in a new dataset before any firm conclusions can be drawn regarding their specificity. In analogy with the poor specificity of the majority of findings in schizophrenia we therefore conclude that generally NSS do not show specificity for schizophrenia although the number of NSS or categories of NSS may differ between diagnostic groups. The overall conclusion should therefore be that NSS continue to show some potential as an endophenotype and further research into a standardised automated measurement of a combination of movement and eye-movement abnormalities seem warranted. However the evidence listed here suggests that it is unlikely to provide an endophenotype for schizophrenia.
In an attempt to illuminate a potential aetiological environmental influence on NSS we studied the relationship between NSS and obstetric complications (chapter 7). We found the number of neurological signs to be dependent on the number of obstetric complications (chapter 7). Another environmental influence may be reflected in changes in the number of NSS in those patients that had a medication increase at two years follow up. These finding could be the result of a gene-environment interaction and further research in NSS could also focus on NSS as a GEI. As such NSS may provide a tool for the further study of the complex interplay between genes and environment. Considering the parallels and relationships with movement disorders they could thus contribute to the illumination of the role and pathology of movement disorders in schizophrenia and mood disorders.