Cognitive dysfunction as an endophenotype

Cognitive deficits are widely regarded as a core feature of schizophrenia and not an epiphenomenon of the illness.^{251, 252, 253} There is remarkable agreement in the literature that deficits in multiple cognitive domains predate the onset of clinical symptoms;^{254, 255, 256, 257, 258} are not attributable to antipsychotic medications;²⁵⁹ persist over the course of the illness; are unrelated to its duration;^{260, 261, 262} and behave like a stable trait.^{233, 263, 264} Pervasive cognitive dysfunction has been reported in >50% of schizophrenia patients in a community-based survey in Scotland,²⁶⁵ and there is compelling evidence that cognitive deficits are significantly correlated with impairments in activities of daily living (ADL) in patients with schizophrenia,^{266, 267, 268, 269, 270} but only weakly associated with psychotic symptoms.²⁷¹ Patients with paranoid schizophrenia and pronounced positive symptoms tend to show better cognitive functioning compared to patients with undifferentiated or disorganized schizophrenia.^{272, 273, 274}

Population-based, longitudinal cohort studies^{254, 275, 276} have found that compromised general cognitive ability in late adolescence is a strong predictor of subsequent schizophrenia risk. Family studies indicate that a proportion of the unaffected first-degree relatives of index cases of schizophrenia display similar patterns of deficit in an attenuated form,^{234, 235, 277, 278, 279} and an epidemiologically-based study of 111 DZ and MZ twin pairs discordant for schizophrenia²⁸⁰ found that deficits in working memory, attention, reaction time and word recall intrusions were highly heritable. Thus, the balance of the evidence suggests that cognitive dysfunction meets most of the criteria¹⁹⁸ of an endophenotype in schizophrenia. This conclusion is underscored by the meta-analysis by Heinrichs and Zakzanis²⁸¹ of 204 studies published between 1980 and 1994 (a total of 7420 schizophrenia patients and 5865 controls), in which effect sizes (Cohen's d) and the U statistic (degree of nonoverlap) were calculated for 22 neurocognitive test variables ranging from IQ, verbal memory, and attention to executive function, and language. Neurocognitive deficit was found to be a reliable and well replicated finding in schizophrenia, although no single test or cognitive construct was capable of separating perfectly schizophrenia patients from normal controls. Seven widely used measures achieved effect sizes greater than 1.0 (60–70% nonoverlap between the cases and controls): global verbal memory (1.41), bilateral motor skills (1.30), performance IQ (1.26), the continuous performance task (1.16), word fluency (1.15), the Stroop task (1.11), and WAIS-R IQ (1.10). Although a subset of 50% of patients had nearly normal performance, significant cognitive impairment was common in schizophrenia and exceeded the deficits found in some neurological disorders, justifying the view that 'schizophrenia is a neurological disorder that manifests itself in behaviour'.²⁸¹

Date: 2016-04-22; view: 801