Ideally, an endophenotype should be a stable, state-independent parameter. An endophenotype should be an enduring characteristic of an individual, and should be present prior to the onset of illness. Thus, increased rates of an endophenotype for schizophrenia should be detectable when studying the young adult children of schizophrenic persons. The same statement cannot be made regarding an endophenotypic study of the prepubertal children of schizophrenic individuals because it is entirely possible that the endophenotype may not be manifest until after puberty. This is particularly relevant because schizophrenia is uncommon among prepubertal children, but becomes common in young adults.
Increased rates of an endophenotype for schizophrenia should be detectable when studying the individuals who are acutely psychotic, as well as those in partial remission. Similarly, an endophenotype for bipolar disorder should be observable in the depressed, euthymic, or manic states.
These qualities render the endophenotype more easily demonstrable.
Consider one outstanding example of an endophenotype, the P50 abnormality in schizophrenia. An abnormality of the P50 auditory evoked potential
is considered an endophenotype for schizophrenia.21
The P50 wave is a positive deflection (recorded by scalp electrodes) occurring 50 ms after an auditory stimulus, typically a single click. When two such clicks are presented, with the second click occurring ~ 200 ms after the first, the amplitude of the P50 wave after the second click is reduced in comparison to the amplitude of the wave after the first click (
This is considered to be an electrophysiological signature of sensory gating. In some individuals with schizophrenia, the amplitude of the p50 wave for the second click is similar to the amplitude after the first click. This is interpreted as a failure of sensory gating. This is shown in graphic form in Figure 1.
Figure 1 The P50 abnormality in schizophrenia. In studying the P50 wave, two clicks (~70 db) ~200 ms apart are used. Usually the response to the second click is reduced in amplitude, in comparison to the response to the first click. In some persons with schizophrenia, (more ...)
The P50 abnormality is found more often among individuals with schizophrenia, compared with controls,22,23
although this is not universally confirmed.24,25
The P50 abnormality is found more frequently among the relatives of persons with schizophrenia, compared to controls.26,27
It is a heritable characteristic, based on twin studies.28,29
Heritability is also implied by the reports that DNA sequence polymorphisms in and near the α7
-nicotinic receptor subunit gene on chromosome 15 explain some of the variance in the P50 abnormality30-32
The chromosome 15 location is a confirmed linkage region for schizophrenia,33-36
thereby lending added confidence to this line of investigation.
While there is ample evidence that the P50 is partially under genetic control,28-32
there is also substantial evidence that P50 parameters are influenced by environmental forces. For example, smoking or administration of nicotine may “normalize” an abnormal P50 test.37,38
The finding becomes more intriguing when it is recalled that ~80% of individuals with schizophrenia are daily smokers.37
Additionally, there is evidence that atypical antipsychotic medications can “normalize” abnormal P50 testing.39-42
These results indicate a critical point when considering endophenotypes: environmental influences must be considered, not only as sources of variance (eg, experimental error, circadian variation, influence of personal habits such as nicotine and caffeine intake), but also as clues to mechanisms that may provide pathways from gene variants to endophenotypes, or from endophenotypes to key symptom clusters or subtypes of disorders.
To summarize the P50 endophenotype literature, there is substantial evidence that the P50 abnormality in schizophrenia fulfills generally accepted criteria for an endophenotype. Variation in or near the α7-nicotinic receptor subunit gene may explain some of the genetic variance in the P50 measurement, and additional research with this endophenotype can be expected to yield new insights into this subtype of schizophrenia.