# Cognitive dysfunction in psychiatric disorders: characteristics, causes and the quest for improved therapy

## Key Points

• Deficits in cognitive function — ranging from decreased attention and working memory to disrupted social cognition and language — are common in psychiatric disorders.

• They severely compromise quality of life, yet are currently poorly treated.

• Recent research has identified numerous interacting causes — genetic, epigenetic, developmental and environmental — that collectively disrupt the cerebral and cellular networks integrating and modulating cognition.

• Several pharmacotherapeutic strategies for the restoration of cognition are under investigation but most drugs have only been evaluated in rodents, and there is limited positive feedback from the clinic.

• The successful development of improved agents necessitates rigorous validation both in animals and in humans. In this regard, a broad palette of techniques, ranging from behavioural testing to brain imaging, is available for the exploration of innovative concepts and the characterization of new drugs.

• Despite the key importance of pharmacotherapy, the relevance of alternative strategies should not be neglected. The association of both approaches may emerge to be particularly effective for realizing the goal of enhanced cognitive performance and, accordingly, improved quality of life in patients suffering from psychiatric disorders.

## Abstract

Studies of psychiatric disorders have traditionally focused on emotional symptoms such as depression, anxiety and hallucinations. However, poorly controlled cognitive deficits are equally prominent and severely compromise quality of life, including social and professional integration. Consequently, intensive efforts are being made to characterize the cellular and cerebral circuits underpinning cognitive function, define the nature and causes of cognitive impairment in psychiatric disorders and identify more effective treatments. Successful development will depend on rigorous validation in animal models as well as in patients, including measures of real-world cognitive functioning. This article critically discusses these issues, highlighting the challenges and opportunities for improving cognition in individuals suffering from psychiatric disorders.

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Millan. ## Ethics declarations ### Competing interests Mark J. Millan is a full-time employee of the Institut de Recherche Servier. Yves Agid carried out a consultancy at the department of neuroscience of Servier. Martin Brüne declares no competing financial interests. Edward T. Bullmore is employed half-time by GlaxoSmithKline (GSK) and holds shares in GSK. Cameron S. Carter has received a research grant from GlaxoSmithKline (GSK) and is an advisory board consultant at Pfizer. Nicola S. Clayton declares no competing financial interests. Richard Connor declares no competing financial interests. Sabrina Davis declares no competing financial interests. Bill Deakin has carried out consultancy and speaking engagements for Bristol-Myers Squibb, AstraZeneca, Eli Lilly, Schering Plough, Janssen-Cilag and Servier. All fees are paid to the University of Manchester to reimburse them for the time taken. He has share options in P1vital. Robert J. DeRubeis declares no competing financial interests. Bruno Dubois declares no competing financial interests. Mark A. Geyer has received consulting compensation from Abbott, Acadia, Addex, Cerca, Medivation, Merck, Omeros, Takeda and Teva, and holds an equity interest in San Diego Instruments. In the past 3 years, Guy M. Goodwin has had grants from Servier; received honoraria for speaking or chairing educational meetings from AstraZeneca, Bristol-Myers Squibb, Eisai, Lundbeck, Sanofi-Aventis and Servier; and advised AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Janssen-Cilag, Lilly, Lundbeck, P1vital, Roche, Sanofi-Aventis and Servier. He holds shares in P1vital and acted as an expert witness for Lilly. During the past 5 years, Philip Gorwood received research grants from Eli Lilly and Servier, and fees for presentations at congresses or participation in scientific boards from AstraZeneca, Bristol-Myers Squibb, Janssen, Lilly, Lundbeck, Roche and Servier. Thérèse M. Jay has received grant support from the Institut de Recherche Servier. Marian Joëls declares no competing financial interests. Isabelle M. Mansuy declares no competing financial interests. Andreas Meyer-Lindenberg declares no competing financial interests. Declan Murphy declares no competing financial interests. Edmund Rolls declares no competing financial interests. Bernd Saletu has received research support from Abiogen Pharma, Actelion, AstraZeneca, Cephalon, GlaxoSmithKline, Sanofi-Aventis, Schwarz Pharma, Servier and Takeda; he has received honoraria (not exceeding US$10,000 per year) for serving on the scientific advisory boards of Nycomed, Servier, Takeda, UCB and Sanofi-Aventis, for being a consultant for Merck and XenoPort and for being a speaker for AstraZeneca, Cephalon, IXICO, Janssen and Lundbeck. He is a shareholder of The Siesta Group Schlafanalyse GmbH, Austria.

Michael Spedding is employed by Les Laboratoires Servier.

John Sweeney declares no competing financial interests.

Miles Whittington declares no competing financial interests.

Larry J. Young declares no competing financial interests.

## Supplementary information

### Supplementary information S1 (figure)

Cellular substrates and susceptibility genes influencing synaptic plasticity and cognitive processes in psychiatric disorders. (PDF 1364 kb)

### Supplementary information S2 (figure)

Cellular networks underpinning cognitive processes, potential targets for countering the cognitive impairment of psychiatric disorders. (PDF 953 kb)

### Supplementary information S3 (box)

Complex social alliances in dolphins and other cetaceans: relevance to human social cognition (PDF 192 kb)

### Supplementary information S4 (box)

Prairie voles, social cognition and the key pro-social role of oxytocin. (PDF 146 kb)

### Supplementary information S5 (box)

Complex cognitive capacities of birds: focus on temporal and social dimensions. (PDF 195 kb)

## Glossary

Cognition

A suite of interrelated conscious (and unconscious) mental activities, including: pre-attentional sensory gating; attention; learning and memory; problem solving, planning, reasoning and judgment; understanding, knowing and representing; creativity, intuition and insight; 'spontaneous' thought; introspection; as well as mental time travel, self-awareness and meta-cognition (thinking and knowledge about cognition).

Learning

The active, experience- and/or training-driven acquisition of information or behaviour. The term 'conditioning' is usually used in an experimental context of associative learning. Learning necessitates complementary and distinct processes of encoding and acquisition that can be perturbed and modulated independently.

Memory

Partly separate mechanisms permitting consolidation, retention and retrieval of information from various sensory domains. Short-term memory relates to immediately available information maintained for 30 seconds. Information retained for longer periods must be consolidated into mechanistically different long-term memory; in principle, this relates to the unlimited (in quantity and in time) capacity to store information.

Extinction

The progressive reduction of a response to a stimulus — for example, owing to discontinuation of reinforcement or loss of association between an unconditioned and conditioned stimulus. Extinction does not just refer to forgetting (a loss or weakening of memory) or 'un-learning' (a decay of the processes involved in retention and recall); rather, it refers to a special form of learning that involves active processes of suppression. The extinguished response may reappear following a change of context or exposure to stress.

Attention

The awareness and attendance to a stimulus or set of stimuli. It depends on the perception, selection and filtering of sensory input and information. Sustained attention (vigilance) is the capacity to maintain attention over an extended period. Selective (focused) attention is the ability to preferentially attend to a subset of stimuli, thus avoiding distraction. Divided attention is the capacity to respond to multiple stimuli simultaneously, and may involve executive shifts in focused attention according to the demands of the situation.

Processing speed

The rapidity with which a cognitive operation is undertaken successfully. Although this is usually related to the speed of information processing, it may also apply to the speed of retrieval. Processing speed affects performance in many tasks and is operationally related to reaction time.

Working memory

Permits the transient 'online' evaluation, manipulation and synthesis of newly acquired and/or stored information. Working memory operates in short-term memory but the two terms are not synonymous. Working memory is closely interrelated to, and interacts with, attention and executive function.

Top-down cortical cognitive control

Related to executive function. Refers to cortically integrated (in the prefrontal cortex, cingulate cortex and parietal cortex) top-down processes that favour goal-directed behaviours by flexibly investing resources (such as sustained attention) that are needed for goal accomplishment. It also involves the suppression of interference from irrelevant information, habitual actions, negative emotions, and so on.

Procedural learning

The progressive assimilation (learnt association between a stimulus and a response), by practice, of an appropriate behaviour generally involving a motor skill, such as driving a car, which may become an automatic habit. It is closely related to non-declarative (implicit) memory — a form of long-term memory that involves non-conscious recollection of skills, behaviours, habits and preferences such as cycling or one's favourite colour.

Executive function

A purposeful, goal-directed operation such as planning, decision making, problem solving, reasoning, concept formation, self-monitoring or cognitive flexibility (adaptive alternation between different strategies, responses and behaviours). Executive function reciprocally interacts with attention and working memory. It includes both initiation of appropriate and suppression of inappropriate responses.

Declarative memory

A form of long-term memory that demands conscious learning. It is divided into episodic and semantic memory.

Semantic memory

A form of long-term memory that involves the learning and storing of immutable facts, information, ideas, and so on. In contrast to episodic memory, semantic memory cannot — in principle — be modified by questions and alternative accounts.

Episodic memory

The conscious recollection of experiences linked to times and places in the past — what happened, where and when. It may involve mental time-travel back into a situation (known as autobiographical re-experiencing), mirrored by projection into an imagined future (prospective envisioning). As such, it is related to the theory of mind ('travel into' or simulation of other minds). Fully-fledged episodic memory may be a uniquely human trait, but there is evidence for its presence in primates, corvids and even some rodents.

Prosody

The use (and interpretation) of features such as stress, intonation and rhythm that lend additional meaning and emotion to speech.

Pragmatics

The appropriate social use of spoken language.

Verbal fluency

The ability to use written and spoken language, to choose the right word at the right time and to make appropriate associations.

Semantics

The meaning of what is said, written, read or heard.

Epigenetic control

A somatic and/or germline modification of chromatin (DNA plus nuclear proteins) that leads to long-lasting alterations in gene expression but not in the DNA sequence. DNA methylation silences genes and occurs mainly in CpG-rich promoter islands. Histone tails are subject to interacting processes of methylation (lysine and/or arginine residues), acetylation (lysine residues), phosphorylation, sumoylation, ubiquitylation and ADP ribosylation. Acetylation causes decondensation (unwinding), increased access for transcription factors and enhanced gene expression.

Default-mode network

A functionally interconnected network of cortical regions that is active under wakeful, resting conditions in functional magnetic resonance imaging paradigms, yet is consistently deactivated by goal-directed activity such as cognitive tasks. It includes the posterior cingulate cortex, precuneus, medial prefrontal cortex and inferior parietal cortex, and is characterized by synchronised, low-frequency oscillations of less than 1.0 Hz.

Neurogenesis

The continuous generation of new neurons from neural precursor cells in humans and other mammals. It is seen mainly in two regions. First, the subventricular zone of the lateral ventricle gives rise to neurons that migrate to become granule neurons and periglomerular neurons mainly in the olfactory bulb. Second, neurogenesis in the subgranular zone of the hippocampal dentate gyrus yields neurons, some of which are integrated into local neural networks once they have matured.

Fragile X syndrome

A disease that is usually caused by the expansion of a trinucleotide sequence in the 5′-untranslated region of the fragile X mental retardation 1 (FMR1) gene. This leads to FMR1 promoter hypermethylation, transcriptional silencing and loss of the RNA-binding protein FMR1. Abnormal translation of mRNAs, including those regulated by metabotropic glutamate receptor 5, results in excessive long-term depression. Affected individuals have defects in speech, language, attention, working memory and social cognition.

Tuberous sclerosis

An autosomal dominant disorder, usually caused by sporadic mutations, leading to inactivation of the tumour suppressor genes tuberous sclerosis 1 (TSC1; also known as hamartin) and TSC2 (also known as tuberin), which normally inhibit RHEB (a GTPase that is an activator of mammalian target of rapamycin). Loss of TSC1 or TSC2 leads to disinhibition of cell growth, cortical tubers and giant astrocytomas in the brain. Patients have deficits in attention, executive function and memory, as well as symptoms resembling autism spectrum disorder and attention deficit hyperactivity disorder.

Rett's syndrome

An X-linked developmental disorder, mainly seen in females, caused by de novo mutations in the gene encoding methyl CpG binding protein 2 (MECP2). MECP2 normally binds to methylated DNA to transcriptionally repress genes, although some are activated. MECP2 also interacts with histone deacetylases, so its loss leads to gene-dependent histone hypo- and hyperacetylation. Patients with Rett's syndrome suffer from retardation, loss of verbal learning and speech, and impaired social cognition.

Rubinstein–Taybi syndrome

A rare disorder characterized by autistic features, learning difficulties and poor attention. In approximately 50% of cases, it is caused by de novo mutations or deletions in the genes encoding CREB-binding protein or, rarely, histone acetyltransferase p300. These CREB-binding proteins and transcriptional co-activators are also histone acetylases, so patients display histone hypoacetylation and reduced gene transcription.

MicroRNAs

(miRNAs). Small, non-protein-coding sequences (22–24 nucleotides) of RNA, mostly derived from intergenic regions, although some are found in introns. An individual species of miRNA can bind to the 3′-untranslated regions of up to hundreds of different species of mRNA. Translation is usually suppressed but it is sometimes enhanced, and in certain cases mRNA may even be degraded.

Savant syndrome

A rare syndrome that is closely associated with high-functioning autism spectrum disorder but also found in other developmental disorders and following damage to or disease of the central nervous system. It alludes to 'islands of genius' in one or a few cognitive domains such as mathematics despite broader deficits in others, and is usually associated with prodigious memory. Savant-like abilities can partially be reproduced by transcranial magnetic stimulation over the cortex.

Functional magnetic resonance imaging

(fMRI). A technique that exploits the differential paramagnetic properties of oxy- and deoxyhaemoglobin to estimate local cerebral blood oxygenation level-dependent (BOLD) activity. Increased oxygen supply compensates for (and transiently exceeds) energy needs, so the BOLD signal is proportional to neuronal activity. Interpretation of data is challenging as BOLD integrates changes both in neurons and in glia, pre- and postsynaptic changes in excitability, as well as local and upstream effects of drugs. Furthermore, BOLD signals can be affected by energy balance and haemodynamic parameters.

Graph theory

A mathematical approach for modelling complex networks whereby individual elements, like cerebral regions, neurons or cellular proteins, are considered as 'nodes' linked by 'edges'. Brain graphs (derived from neuroimaging data) and cellular graphs (derived from studies of protein networks) reveal non-random topological properties such as modularity (clusters of nodes highly connected to each other) and hubs (nodes with numerous connections). These properties help to optimize network function, including cognitive processing.

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Millan, M., Agid, Y., Brüne, M. et al. Cognitive dysfunction in psychiatric disorders: characteristics, causes and the quest for improved therapy. Nat Rev Drug Discov 11, 141–168 (2012). https://doi.org/10.1038/nrd3628

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