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  • Review Article
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Altering the course of schizophrenia: progress and perspectives

Key Points

  • Schizophrenia is a debilitating and chronic disorder that is accompanied by psychosis and a broad spectrum of behavioural, cognitive and social deficits. It usually strikes in young adulthood. Currently, treatment is exclusively symptomatic, and medication has no direct, lasting influence on causal pathophysiology.

  • Improved knowledge of the developmental anomalies provoked by genetic, epigenetic and environmental triggers of schizophrenia has fostered interest in potential 'disease-modifying' strategies for either slowing its progression or preventing its appearance in vulnerable young adults.

  • Although awaiting further confirmation, clinical studies of pharmacotherapeutic and psychosocial and/or cognitive-behavioural interventions in young, high-risk individuals seeking help have collectively yielded evidence for a reduction in the transition to psychosis.

  • Nonetheless, only a third or so of clinically high-risk individuals convert, so it is important to improve the prediction of transition at the level of individuals by the use of biomarkers. Multi-modal approaches combining, for example, circulating biomarkers, sensory/cognitive deficits and brain imaging hold particular promise.

  • Although animal models for schizophrenia have limitations, diverse pharmacological treatments applied during adolescence preclude the appearance of a schizophrenia-like phenotype in adult rodents.

  • Studies exploiting these in vivo models, as well as novel cellular paradigms such as human induced pluripotent stem cells, are refining our understanding of the cellular substrates leading to schizophrenia, and hence unveiling potentially novel targets for medication.

  • In conclusion, though much work still remains to be undertaken, recent progress is raising the hope that it may eventually be possible to interrupt the course of schizophrenia, as well as other disorders characterized by psychosis. Of particular interest would be hybrid strategies that both relieve distress in young, at-risk individuals and reduce their conversion.

Abstract

Despite a lack of recent progress in the treatment of schizophrenia, our understanding of its genetic and environmental causes has considerably improved, and their relationship to aberrant patterns of neurodevelopment has become clearer. This raises the possibility that 'disease-modifying' strategies could alter the course to — and of — this debilitating disorder, rather than simply alleviating symptoms. A promising window for course-altering intervention is around the time of the first episode of psychosis, especially in young people at risk of transition to schizophrenia. Indeed, studies performed in both individuals at risk of developing schizophrenia and rodent models for schizophrenia suggest that pre-diagnostic pharmacotherapy and psychosocial or cognitive-behavioural interventions can delay or moderate the emergence of psychosis. Of particular interest are 'hybrid' strategies that both relieve presenting symptoms and reduce the risk of transition to schizophrenia or another psychiatric disorder. This Review aims to provide a broad-based consideration of the challenges and opportunities inherent in efforts to alter the course of schizophrenia.

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Figure 1: Onset and progression of schizophrenia in relation to risk factors and developmental processes affected by the disorder.
Figure 2: Course alteration and disease modification: core facets.
Figure 3: Clinical trajectories of young individuals seeking help who are at high risk for developing schizophrenia: diverse strategies for their detection.
Figure 4: Overview of core pathophysiological mechanisms implicated in the genesis of schizophrenia: potential targets for course-altering intervention.
Figure 5: Schematic representation of a 'hybrid' strategy as compared to other therapeutic approaches for treating schizophrenia and its genesis.

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Acknowledgements

The authors thank M. Soubeyran and J.-M. Rivet for logistical support. They would also like to thank the referees for helpful comments that strengthened the article. This paper has its origins in a small, focused meeting that took place in France in 2013, sponsored by 'Advances in Neuroscience for Medical Innovation'. Sadly, two participants at that meeting recently passed away, G. Bartzokis and P. Patterson, and the authors would like to take this opportunity to remember and pay tribute to them.

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Correspondence to Mark J. Millan.

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Competing interests

M.J.M. is a full-time employee of the Institut de Recherche Servier. J.G. has received research funding from the German Federal Ministry of Education and Research, the German Science Foundation and AstraZeneca, as well as speaker fees and congress support from Janssen-Cilag and Otsuka. D.A.L. currently receives investigator-initiated research support from Pfizer. In 2013–2015, he served as a consultant in the areas of target identification and validation and new compound development to Autifony, Bristol-Myers Squibb, Concert Pharmaceuticals and Sunovion.

Supplementary information

Supplementary information S1 (figure)

'Conventional' and 'revised' R&D working paradigms for improving symptomatic control of schizophrenia. (PDF 524 kb)

Supplementary information S2 (box)

Genetics of schizophrenia: insights into identification of clinically high-risk subjects and potential course-altering therapeutics (PDF 175 kb)

Supplementary information S3 (box)

Anomalous control of mRNA translation by miRNA: a potential substrate for intervention (PDF 218 kb)

Supplementary information S4 (box)

Promotion of microtubule dynamics underpinning axonal-dendritic organisation (PDF 157 kb)

Supplementary information S5 (box)

A potential role for retroviruses in the pathogenesis of schizophrenia (PDF 175 kb)

Supplementary information S6 (figure)

A 'triad' of interacting risk factors favouring transition to schizophrenia in young, vulnerable individuals. (PDF 1317 kb)

Supplementary information S7 (box)

Significance of placebo effects, gender and culture for CHR subject stratification and clinical trials (PDF 123 kb)

Supplementary information S8 (figure)

Impaired social cognition/processing as a potential driver of schizophrenia and a target for course-altering strategies. (PDF 1253 kb)

Supplementary information S9 (box)

Minimising a theoretical risk of accelerated onset of psychosis following treatment (PDF 122 kb)

PowerPoint slides

Glossary

Psychosis

A cluster of clinical signs related to, but not identical to, positive symptoms of schizophrenia: detachment from reality; compromised insight; hallucinations and delusions; psychomotor anomalies, such as catatonia or agitation; and disorganized thought, speech and behaviour. Psychosis is generally used as the operational definition of transition to schizophrenia, despite its (less systematic) occurrence in other disorders.

Positive symptoms

Include delusional thinking, hallucinations, false beliefs, bizarre thoughts, suspiciousness and paranoia. Although usually mild and transient during the prodrome, full-blown positive symptoms during the first episode of psychosis are a diagnostic pillar of schizophrenia. Positive symptoms are reduced in most patients by antipsychotics, but remission may be incomplete, relapses occur and about 20–30% of patients are refractory.

Negative symptoms

Prominent from the pre-diagnostic to the chronic phase of schizophrenia, negative symptoms are poorly controlled by antipsychotics and linked to poor real-world function. There are two sub-clusters: decreased expression (poverty of speech and blunted affect) and avolition (amotivation, asociality and loss of anticipatory pleasure for normally rewarding activities).

Neurocognitive deficits

Deficits in a range of cognitive domains, including those dependent on frontocortico-striato and frontocortico-parietal circuits: attention; working memory (handling of new and stored information); executive function (planning, decision making and flexible shifting of goals); speed of processing and procedural memory (learning motor tasks); and verbal learning and memory.

Social processing and cognition

Processes used to decode social cues, interpret and predict the mental state, beliefs, desires and intentions of others and hence behave in a socially appropriate, adaptive manner. Signals include facial expression, body posture and hand gestures. Impaired social cognition is seen in the prodrome, interrelated with negative symptoms and linked to poor functional outcome. Deficits are irresponsive to antipsychotics.

Disease modification

Interventions that directly interrupt, decelerate or even reverse the core pathophysiological processes causing a disorder, with the goal of preventing or delaying its onset and/or moderating its severity once it evolves. Effects should, in principal, persist even after treatment has been discontinued and are not necessarily apparent at the onset of, or even during, administration.

Prodromal period

A high-risk state that precedes the transition to schizophrenia or another psychotic disorder by weeks to years. It is characterized by attenuated and/or brief self-limiting psychotic symptoms, negative, neurocognitive and social cognitive symptoms, depressed mood and other psychological and behavioural abnormalities. Not all individuals showing a prodrome transition to a psychotic disorder, so the term is somewhat misleading.

Neurological soft signs

A cluster of minor developmental anomalies in motor and sensory integration, motor coordination and motor sequencing. They are present in high-risk individuals before transition to schizophrenia, for whom they represent a useful warning sign.

Neurexin 1

A presynaptically localized adhesion molecule that interacts with the postsynaptic protein neuroligin 1. Neurexin 1 is abundant in inhibitory GABAergic synapses where it controls transmitter release, as well as synaptic formation and transmission. Deletions of the neurexin 1 gene (de novo and inherited) are consistently associated with schizophrenia.

MicroRNA

(miRNA). A short stretch of non-coding RNA (22–24 nucleotides long) that neutralizes and destabilizes matching mRNAs (in some cases matching hundreds of different mRNAs). When the match is perfect the matched mRNA is degraded. Hundreds of different miRNAs exist in the brain. Many interact with developmentally important proteins, and cerebral levels of diverse classes of miRNA are altered in schizophrenia.

Default mode network

Interconnected cerebral regions in humans that are active in fMRI studies under resting conditions, for example, during introspection and rumination. Conversely, they are deactivated by goal-directed actions such as the performance of a working-memory test. An equivalent network seems to exist in rodents.

Event-related potentials

Negative and positive shifts in the voltage of electroencephalogram recordings triggered by external stimuli, usually auditory but also visual.

P300

A positive deflection peaking ~300 milliseconds after a deviant ('oddball') stimulus that differs in frequency, duration and strength to a previous sequence.

Mismatch-negativity

A pre-attentional negative response peaking ~100–150 milliseconds after a deviant stimulus.

Machine learning

A mode of multivariate analysis which uses so-called 'support vector machine' algorithms to detect otherwise-invisible patterns in large data arrays and to inter-link the different variables recorded. Its application to combined genetic, imaging, clinical and other readouts from high-risk individuals increases the sensitivity and specificity of prediction of transition to psychosis, even at the individual level.

Polyunsaturated fatty acids

(PUFAs). Major components of cell membranes that are derived from dietary linoleic and α-linolenic acid, which are transformed in the liver into omega-6 and omega-3 derivatives, respectively (numbers refer to location of the first double-bond at the methyl end). They are essential for brain function and development perinatally and in childhood. Precursor intake is often poor in Western diets and a risk factor for schizophrenia.

Cognitive-behavioural therapy

(CBT). A form of psychotherapy that helps individuals disengage from negative and self-defeating thoughts about themselves, their lives and environment and hence to think, feel and behave in a more adaptive and positive fashion. It may embrace stress management. Both therapist and computerized modes are available for various psychiatric disorders, including people at high risk of developing schizophrenia.

Minocycline

A tetracycline-like antibiotic with anti-inflammatory and antioxidant properties that easily enters the brain. It is under investigation for a number of central nervous system disorders, including adjunctive therapy with antipsychotics for the treatment of schizophrenia, especially negative symptoms soon after diagnosis.

N-acetylcysteine

An analogue of l-cysteine that is rapidly oxidised into cystine in the brain. Cystine is a substrate of glial cystine–glutamate antiporters, so N-acetylcysteine elevates extracellular levels of glutamate. In cells, cystine is reduced into cysteine, the rate-limiting component of the antioxidant, glutathione. Hence, N-acetylcysteine enhances glutathione activity. N-acetylcysteine also exerts anti-inflammatory properties.

Kalirin 7

A member of a family of brain-specific guanine-nucleotide exchange factors for RAC-like GTPases such as RAC1. Kalirin 7 is located in the postsynaptic density, where it interacts with the actin cytoskeleton to regulate the formation, maturation and stability of dendritic spines, and hence influence synaptic plasticity.

Synaptic pruning

Processes for developmental elimination of 'excess' synaptic connections that are especially prominent during adolescence. Axo-dendritic synapses not stabilized by neural activity in frontocortical, temporocortical and hippocampal regions are particularly affected. Appropriate synaptic pruning optimizes the operation of neural networks, whereas both excessive (schizophrenia) and defective (autism) pruning are deleterious.

Graph theory

The mathematical analysis of networks of proteins, cells, brain regions or individuals in social groups. These elements are considered as 'nodes' connected by 'edges' (vectors). Brain organization is modular and non-random, incorporating features that enhance integration such as highly connected hubs and a short path length between nodes (a 'small world'). In schizophrenia, this organization is disrupted.

Frontocortical GABAergic interneurons

A subset of fast-firing (gamma frequency, 40–100 Hz), parvalbumin- positive basket (and chandelier) GABAergic interneurons in the prefrontal cortex that synchronises the activity of local, intra-cortical and cortico-subcortical networks of glutamatergic pyramidal neurons. Their dysfunction, which leads to a disruption of the excitation–inhibition balance, network synchrony, cognition and mood, is implicated in events leading to schizophrenia.

Extracellular matrix

Contains proteins such as astrocyte-derived chondroitin sulfate proteoglycans, hyaluronans, neuregulins and reelin. It fills the space between cells in the brain, including the synaptic cleft. 'Perineuronal nets' appear postnatally, are localized perisynaptically, and stabilize neural connections. Their developmental disruption has been related to abnormal plasticity and the genesis of schizophrenia.

The Na–K–Cl co-transporter

Transports Cl into neurons in the ratio of two Cl to one each of N+ and K+. Accumulation of excess Cl is prevented by extrusion through the K–Cl co-transporter KCC2. In early life, Na–K–Cl co-transporter levels are elevated versus KCC2 so internal Cl increases and GABAA receptors mediate depolarisation not hyperpolarisation. Owing to lack of a developmental switch, this may persist in autism and schizophrenia.

Reelin

A developmentally regulated glycoprotein that controls neuronal migration, corticogenesis and synaptic plasticity. Reelin is enriched in and secreted by GABAergic interneurons in adult prefrontal cortex where it is co-regulated with GABA by epigenetic mechanisms. It is a component of the extracellular matrix.

Human endogenous retroviruses

Viral elements within the genome that encode a protein envelope, reverse transcriptase and other proteins needed for replication. They are relics of ancient infections that survived by integration into the genome where multiple gene copies occur owing to amplification and re-infection. They comprise ~8–10% of the human genome, mostly in non-coding regions. Revival may trigger disorders like multiple sclerosis and, possibly, schizophrenia.

RAISE

A National Institute of Mental Health initiative to alter the course and prognosis of the first episode of psychosis. A well-trained, multidisciplinary team offers up to two years of pharmacotherapeutic and psychosocial treatments together with family education, resiliency training and supported employment in a patient-centric and real-world fashion to improve function and promote recovery.

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Millan, M., Andrieux, A., Bartzokis, G. et al. Altering the course of schizophrenia: progress and perspectives. Nat Rev Drug Discov 15, 485–515 (2016). https://doi.org/10.1038/nrd.2016.28

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