Prospective longitudinal studies of birth cohorts and genetic high-risk samples have elucidated the following risk factors and predisposing signs of schizophrenia: family history, obstetric complications (OCs), urban residence, season of birth, low IQ, and delayed developmental milestones.1
Retrospective studies suggest that subjects with a first episode of schizophrenia typically have passed through 3 successive prodromal stages2,3
: (1) a nonspecific phase with affective and anxiety symptoms, (2) an early prodromal phase with prominent negative symptoms (mean duration of 5 years), and (3) a late prodromal phase with subthreshold psychotic symptoms (1.1 years on average).
The ultra-high-risk (UHR) criteria outlined by Yung and McGorry4
correspond to the late prodromal phase, which is characterized by attenuated positive symptoms (APS) or brief limited intermittent psychotic symptoms (BLIPS). Patients meeting the UHR criteria have a transition rate to psychosis of approximately 30%–35% within a follow-up period of 1–3 years.5–7
The work of Huber, Gross, and Klosterkötter suggests that some cognitive basic symptoms allow the identification of subjects in an even earlier prodromal state.8,9
Basic symptoms describe subtle, self-experienced, and self-reported deficits in thought and perception. In a clinical sample, Huber’s basic symptoms had high positive predictive values (0.71–0.91) and high specificity. Seventy percent of individuals who showed basic symptoms at baseline developed schizophrenic psychosis in a mean time of 5.6 years.10
Thus, Huber’s basic symptoms are manifested during the early prodromal phase of psychosis.
Neurocognitive investigations have provided further evidence about the developmental course of the disease. Neurocognitive deficits, considered an integral part of the illness,11
are present at the beginning of the first psychotic episode in patients with schizophrenia.12
They are stable over time,13–16
largely independent of positive symptomatology,17,18
and partly independent of medication treatment.19–21
Furthermore, neurocognitive deficits are present in patients before the presence of psychotic symptoms. Prospective birth cohort studies22–25
and genetic high-risk studies26–32
have found specific deficits in measures of verbal memory, working memory, executive function, and attentional functioning in individuals who developed schizophrenia.
Therefore, neurodevelopmental models have become the dominant hypotheses used to explain the pathogenesis of schizophrenia,33,34
which indicate that neuromotor deficits, cognitive abnormalities, and physiological alterations are already present early in life and vary qualitatively and quantitatively with brain development and disease progression.
The aim of the German Research Network on Schizophrenia (GRNS) is to study in depth the appearance of deficits and symptoms in the early course of the illness. It has aimed to replace the established pragmatic (treatment-oriented) definition of subjects at UHR with definitions of an early prodromal state (EPS) and a late prodromal state (LPS), respectively, thereby integrating the basic symptom and the UHR approaches.
The present study focuses on the neurocognitive profiles of these 2 groups. Previous studies of clinical high-risk subjects indicated that they perform at an intermediate level between healthy controls and first-episode psychosis patients in multiple cognitive functional domains.35–39
In particular, patients who fulfilled UHR criteria have shown impairments in tasks involving executive control, verbal learning/memory, motor control, and general intellectual functioning.36,40–43
However, the generalizability of the results and the ability to draw conclusions about specific deficits were limited because of several methodological issues. Most studies used healthy control groups that were not comparable with regard to premorbid intellectual functioning, educational level, or demographical characteristics,37,40,42,43
whereas others used population norms of individual tests obtained from different normative samples.36,41
Furthermore, some used small and selective test batteries38,42,43
or compared data of single tests35,36,40,42
or composite scores with unconfirmed factor structures.38,41
In addition, sample sizes were small and consisted mainly of patients with APS. Possible differences between patients with APS and those with BLIPS and the effects of psychotropic medication on neuropsychological functioning were not generally addressed in previous studies. Finally, the issue of specific and generalized impairments has received little attention so far in UHR studies. Lencz et al44
addressed many of the above-mentioned criticisms in their study. They found lower current estimated IQ scores than predicted from premorbid IQ scores in UHR individuals. In addition, they reported generalized deficits across cognitive domains and specific deficits in verbal learning and executive functions, whereas visual–spatial functions were relatively spared in UHR patients compared with individuals in a healthy control group, who were comparable with regard to years of education and demographical characteristics. Verbal memory deficits in UHR patients predicted psychosis within a mean follow-up time of 2 years.
To summarize, previous studies with subjects fulfilling UHR criteria provide clear evidence for cognitive dysfunction; however, the time point at which the generalized or specific deficit emerges is unclear. Only 2 recent studies considered neuropsychological functioning of subjects in a putatively earlier prodromal state and compared their performances with UHR subjects in an LPS.37,45
Both failed to find substantial differences between high-risk groups. Pukrop et al37
reported significant impairments in the EPS compared with controls in measures of verbal learning and verbal fluency; however, Simon et al45
did not find neurocognitive impairments compared with help-seeking patient controls. Small sample sizes and small effect sizes might account for these conflicting results.
Thus, it is not clear whether high-risk individuals in an EPS have any cognitive deficits at all and, if so, whether these deficits are qualitatively similar to those found in UHR individuals in an LPS. This study expands the scope of previous investigations by addressing the neurocognitive functions of 2 different high-risk groups in comparison to a healthy control group (comparable with respect to demographical data and general intellectual ability) and by investigating whether generalized or specific cognitive deficits exist and whether these deficits are related to current medication treatment, current (negative, positive, or depressive) symptoms, and general functioning in everyday life.
Our hypotheses are as follows:
- High-risk subjects in an EPS and those in an LPS have generalized neurocognitive deficits compared with subjects in the healthy control group.
- Measures of executive function and verbal memory are more impaired than those of other domains in the LPS.
- Individuals in an EPS of psychosis perform intermediate between the subjects in the healthy control group and individuals in the LPS of psychosis.