Cognitive impairment in schizophrenia: aetiology, pathophysiology, and treatment

Abstract

Cognitive deficits are a core feature of schizophrenia, account for much of the impaired functioning associated with the disorder and are not responsive to existing treatments. In this review, we first describe the clinical presentation and natural history of these deficits. We then consider aetiological factors, highlighting how a range of similar genetic and environmental factors are associated with both cognitive function and schizophrenia. We then review the pathophysiological mechanisms thought to underlie cognitive symptoms, including the role of dopamine, cholinergic signalling and the balance between GABAergic interneurons and glutamatergic pyramidal cells. Finally, we review the clinical management of cognitive impairments and candidate novel treatments.

Fig. 1. Increasing interest in cognitive impairment in schizophrenia.

The graph illustrates the proportion of PubMed articles on schizophrenia that include ‘cognitive impairment’ in the title.

Fig. 2. Variability of cognitive function in schizophrenia.

Examining the population distribution of cognitive ability can help to determine whether impairments reflect a generalised deficit or are greater in magnitude in some patients than others. Recent data indicate that the distribution is more like that shown in (B) than (A), with more variability in the patient than the control sample. This suggests in psychosis, rather than there being a constant effect on cognition, in some individuals, there is a large impairment, but in others relatively little. It is also valuable to look at intra-individual variability, unlike (A) and (B) which represent data from many individuals, (C) and (D) represent data from a single individual. From this perspective variability again appears greater in schizophrenia and those at risk with the data resembling the distribution in (D) more than that in (C).

Fig. 3. Aetiological factors and time course of cognitive impairments in schizophrenia.

Cognitive deficits in individuals who develop schizophrenia are apparent in childhood and do not appear to increase markedly in the initial phase of the illness. While CHR individuals as a group score higher than FEP individuals, longitudinal studies do not provide clear evidence for a decline over the period of transition to psychosis. The decline in cognitive function that occurs in later life in healthy individuals is evident at an earlier age in individuals with schizophrenia, potentially related to neurovascular factors.

Fig. 4. E/I balance as a common pathway to cognitive dysfunction in schizophrenia.

A Muscarinic, dopaminergic, glutamatergic, and GABAergic influences on E/I balance in healthy controls and mechanisms of disruption in schizophrenia. B E/I balance and cognition. In healthy individuals, interactions between excitatory pyramidal cells and inhibitory interneurons generate gamma oscillations, which are associated with functional brain networks observable using fMRI, with all levels showing links to healthy cognitive function. In individuals with schizophrenia, disruptions to muscarinic and dopaminergic signalling, an intrinsic interneuron deficits may underlie a state of cortical disinhibition. This disinhibition would account for the aberrant gamma activity and functional networks observed in the disorder and contribute to cognitive impairments.