Negative symptoms of schizophrenia Clinical ... · schizophrenia Negative symptoms prominent: Figure 1 Negative symptoms throughout the lifespan of schizophrenia. Schizophrenia, which

European Neuropsychopharmacology (2014) 24, 645–692

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Abbreviations: BTTherapy; DA, dopamEvent Related PotenMRI, Magnetic Resonpositive Allosteric MEmission TomographComputerised Tomog

nCorresponding auE-mail address: m

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Negative symptoms of schizophrenia:Clinical characteristics, pathophysiologicalsubstrates, experimental modelsand prospects for improved treatment

Mark J. Millana,n, Kevin Foneb, Thomas Stecklerc,William P. Horand

aPole of Innovation in Neuropsychiatry, Institut de Recherche Servier, 125 Chemin de Ronde,78290 Croissy-sur-Seine, Paris, FrancebSchool of Biomedical Sciences, Medical School, Queen's Medical Centre, Nottingham University,Nottingham NG72UH, UKcJanssen Research and Development, Turnhoutseweg 30, 2340 Beerse, BelgiumdVA Greater Los Angeles Healthcare System, University of California, Los Angeles, MIRECC 210A, Bldg. 210,11301 Wilshire Blvd., Los Angeles, CA 90073, USA

Received 19 March 2014; accepted 19 March 2014

KEYWORDSPrefrontal cortex;Striatum;Motivation;Social cognition;Social interaction;Oxytocin

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BR, Black and Taine; DLPFC, Dorsotial; fMRI, functionance Imaging; NIModulator; PANSS,y; PFC, prefrontraphy; USV, Ultrathor. Tel.: +33 1 [email protected]

AbstractSchizophrenia is a complex and multifactorial disorder generally diagnosed in young adults atthe time of the first psychotic episode of delusions and hallucinations. These positive symptomscan be controlled in most patients by currently-available antipsychotics. Conversely, theyare poorly effective against concomitant neurocognitive dysfunction, deficits in social cognitionand negative symptoms (NS), which strongly contribute to poor functional outcome. The precisenotion of NS has evolved over the past century, with recent studies – underpinned by novelrating methods – suggesting two major sub-domains: “decreased emotional expression”, incor-porating blunted affect and poverty of speech, and “avolition”, which embraces amotivation,asociality and “anhedonia” (inability to anticipate pleasure). Recent studies implicate adysfunction of frontocortico-temporal networks in the aetiology of NS, together with a

o.2014.03.008CNP. This is an open access article under the CC BY-NC-ND license/by-nc-nd/3.0/).

n Brachyury; CB, Cannibinoid; CBT, Cognitive-Behavioural Therapy; CRT, Cognitive Remediationlateral Prefrontal Cortex; DSM, Diagnostic and Statistical Manual; EEG, electroencephalography; ERP,al Magnetic Resonance Imaging; LSD, Lysergic-diethylamide; MHC, Major Histocompatability Complex;H, National Institute of Mental Health; NMDA, N-Methyl-D-Aspartate; OFC, orbitofrontal cortex; PAM,Positive and Negative Symptom Scale; PCP, Phencyclidine; NS, negative symptoms; PET, Positronal cortex; rTMS, repetitive Transcranial Magnetic Stimulation; SPECT, Single Photon Emissionsonic Vocalisation; VHL, ventral hippocampus lesion572 2425; fax: +33 1 5572 2082.tgrs.com (M.J. Millan).

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M.J. Millan et al.646

disruption of cortico-striatal circuits, though other structures are also involved, like the insularand parietal cortices, amygdala and thalamus. At the cellular level, a disruption of GABAergic–glutamatergic balance, dopaminergic signalling and, possibly, oxytocinergic and cannibinoider-gic transmission may be involved. Several agents are currently under clinical investigation forthe potentially improved control of NS, including oxytocin itself, N-Methyl-D-Aspartate receptormodulators and minocycline. Further, magnetic-electrical “stimulation” strategies to recruitcortical circuits and “cognitive–behavioural–psychosocial” therapies likewise hold promise. Toacquire novel insights into the causes and treatment of NS, experimental study is crucial, andopportunities are emerging for improved genetic, pharmacological and developmental model-ling, together with more refined readouts related to deficits in reward, sociality and“expression”. The present article comprises an integrative overview of the above issues as aplatform for this Special Issue of European Neuropsychopharmacology in which five clinical andfive preclinical articles treat individual themes in greater detail. This Volume provides, then, aframework for progress in the understanding – and ultimately control – of the debilitating NS ofschizophrenia.& 2014 Elsevier B.V. and ECNP. This is an open access article under the CC BY-NC-ND license(http://creativecommons.org/licenses/by-nc-nd/3.0/).

1. Introduction

1.1. Schizophrenia: core characteristics andinadequate current management

Schizophrenia is a chronic, life-long and debilitating disorderwhich is triggered in a complex, heterogeneous and multi-factorial fashion by a diverse palette of genetic, epigenetic,developmental and environmental risk factors (Figure 1)(Millan, 2013; Sullivan et al., 2012; Rapoport et al., 2012).It occurs with an incidence of at least 0.7% of the populationand, quite apart from personal distress, schizophrenia has ahuge socioeconomic burden, mostly in terms of indirect costslike loss of employment and social support (Wittchen et al.,2011). Diagnosis generally occurs in the young adult (or in lateadolescence) with the advent of the first frank psychoticepisode, often in the wake of a high-risk, prodromal period inwhich occasional and/or attenuated psychotic symptoms mayoccur – though such high risk individuals may eventually transitto another psychiatric disorder like depression (Fusar-Poliet al., 2013a, 2014; Sabbag et al., 2011).

Psychosis corresponds to the most familiar cluster of cardinalsymptoms, termed positive, and including delusions and hallu-cinations (Buchanan et al., 2010; Huxley and Fonseca, 2014;Leucht et al., 2013; Tandon et al., 2013). Positive symptomshave long been treated by “first-generation” neuroleptics likehaloperidol and chlorpromazine; by clozapine; and by a rangeof more recently-developed “second-generation” antipsycho-tics including risperidone, olanzapine and aripiprazole (Asenjo-Lobos et al., 2010; Citrome, 2013; Hartling et al., 2012; Leuchtet al., 2009, 2013; Naber and Lambert, 2009). Nonetheless,control is often incomplete and some 20–30% of patients areconsidered refractory (not responsive to at least two differenttreatments). Despite decades of effort to find successor agentsof improved efficacy, clozapine remains the most effectiveagent in otherwise non-responsive patients. However, as out-lined below, clozapine shares the comparative inactivity ofother classes of antipsychotic for the management of neuro-cognitive dysfunction, impaired social cognition and negativesymptoms (NS) (Asenjo-Lobos et al., 2010; Leucht et al., 2009,2013).

Deficits in multiple domains of “neurocognition” are marked,ranging from attention to working memory to executivefunction, and they are little improved by medication, thoughCognitive Remediation Therapy (Section 4.7) is attractinginterest as an alternative therapeutic approach (Buchananet al., 2010; Carter and Barch, 2007; Kalkstein et al., 2010;Leucht et al., 2009, 2013; Millan et al., 2012; Naber andLambert, 2009; Wykes et al., 2011). The poor response toantipsychotics is hardly surprising since blockade of dopamineD2 receptors, muscarinic M1 receptors, histamine H1 receptorsand α1-adrenoceptors will compromise mnemonic performanceand overwhelm any potentially beneficial influence on cogni-tion, such as that afforded by antagonism of frontocortical D3receptors or α2-adrenoceptors (Brosda et al., 2014; Citrome,2013; Millan et al., 2000, 2012; Nakajima et al., 2013). Thismay at least partially explain why numerous mechanismsevaluated as “add-on” therapies to antipsychotics have dis-appointed for improving neurocognition (Buchanan et al.,2011a, 2011b; Millan et al., 2012).

A further domain of poorly-treated impairment in schizo-phrenia is social cognition which refers to mechanisms forunderstanding and interpreting the mental states, gestures,behaviours and facial expressions of others, and which alsoembraces the understanding of verbal and non-verbal modesof communication (Section 2.3) (Adolphs, 2009; Bora et al.,2009; Brown et al., 2012; Brüne, 2005; Fitch et al., 2010;Frith and Frith, 2012; Kalkstein et al., 2010; Millan andBales, 2013; Rushworth et al., 2013). By analogy to “neu-rocognitive impairment”, deficits in social cognition areessentially refractory to existing antipsychotics yet, withthe exception of some preliminary trials with oxytocin(Section 4.8), there have been comparatively few effortsto specifically redress the compromised social cognition ofschizophrenia (Green et al., 2012; Meyer-Lindenberg et al.,2011; Millan et al., 2012). This is unfortunate since impairedsocial cognition has grave repercussions for functional out-come and may drive other symptoms, including NS (Section2.2) (Brüne, 2005; Foussias et al., 2014; Green et al., 2008,2012; Hoe et al., 2012; Millan et al., 2012).

The NS of schizophrenia, which encompass blunted affect,poverty of speech (alogia), amotivation, anticipatory anhedonia

Adolescence

Psychotic Crises

Min

Max

Sym

ptom

Inte

nsity

Diagnosis (First Psychotic Episode)

Birth

Early-life infection/trauma

10 15 20 25 Years0 5 30 35 40 45

Isolation, StressDrug abuse

Pregnancy

Genes/DNA

Persistent negative symptoms

1st Wave hits "Booster" Hits2nd Wave hits

Infancy Adulthood

Dia

gnos

ticSu

b-th

resh

old

Epigenetic misprogramming

At risk mental state: Negative symptoms linked to poor social

integration and educationaldifficulties

Negative symptomspronounced, and not improved even when

psychosis well treated

“Deficit syndrome?“

Childhood

Pre-adolescentschizophrenia

Negative symptomsprominent

:

Figure 1 Negative symptoms throughout the lifespan of schizophrenia. Schizophrenia, which is triggered by a complex patternof genetic, epigenetic, developmental and environmental factors, is recognised at the moment of the first well-defined psychoticepisode (corresponding to positive symptoms). This usually occurs in late adolescence/young adulthood, but there are rare cases of“early-onset” schizophrenia (13–18 years) and even childhood-onset schizophrenia (under the age of 13) (Masi et al., 2006; Rapado-Castro et al., 2010). Once established, remission is rare (perhaps 10–15% of subjects recover after the first episode), and the diseasefollows a fluctuating course punctuated by psychotic crises. Even when positive symptoms are well treated, NS resist control andmany patients display predominantly NS from the first episode on. The term “deficit syndrome” has been used for subjects whomanifest predominantly NS (perhaps up to a third in the chronic phase): however, it is not universally accepted and lack of psychosisat first admission suggests that the disorder would not be schizophrenia. In addition to transient and sub-diagnostic psychoticsymptoms in many (though not all) high-risk subjects, the prodromal phase is accompanied by prominent NS, as well as impairedsocial cognition, neurocognitive and mood deficits. Finally, NS like blunted affect predominate in childhood and early-onsetschizophrenia. Thus, NS are a poorly-treated and disabling feature throughout the lifespan of schizophrenia.

647Negative symptoms of schizophrenia

and asociality, are likewise poorly-treated and severely inter-fere with the functional status of patients (Table 1) (Blanchardand Cohen, 2006; Boonstra et al., 2012; Kaiser et al., 2010;Kirkpatrick et al., 2006; Kring and Elis, 2014; Konstantakopouloset al., 2011; Messinger et al., 2011). They comprise the subjectof this Special Issue of European Neuropsychopharmacologywhich is, to the best of our knowledge, the first of its kind – atleast in recent years – and embraces both clinical andpreclinical facets of NS.

1.2. Organisation of the Special Volume, and aimsof this introductory article

Research and drug development in schizophrenia is at some-thing of a watershed with the recognition that second-generation antipsychotics do not offer any major advantagesin terms of efficacy and breadth of therapeutic activity overpreviously-available agents – and certainly not over clozapinefor refractory patients (Section 1.1).

This would seem, then, an opportune moment to devote aSpecial Volume to incapacitating NS. As reflected in the 800or so Hits generated by PubMed for “schizophrenia and NS”in 2013, there has been a recent resurgence of interestreflecting: improved insights into the interrelationship of NSwith other symptoms of schizophrenia; characterisationof two inter-related but distinguishable sub-domains ofdysfunction, “decreased emotional expression” and “avoli-tion”; the introduction of improved methods of clinical

evaluation; the imminent impact of Diagnostic and Statis-tical Manual (DSM)-5; increasing awareness of “NS-like”changes in other psychiatric and neurological disorders;attempts to better couple NS to underlying neural patho-physiology – if necessary transgressing nosological bound-aries; ongoing pivotal trials of potentially novel medication;and efforts to refine and diversify the experimental study ofNS. Further, in the spate of disappointing results of mainlyadd-on studies of new drugs for restoring neurocognition inschizophrenia (Millan et al., 2012), there is an emergingfeeling that comparable efforts might better be invested innovel pharmacotherapeutic and “alternative” strategies forcountering poorly treated NS – and interrelated deficits insocial cognition – in view of their mutually detrimentalimpact on the real-world function of patients (Section 2.3).

It would be difficult to cover every single facet of NS in asingle tome, yet the majority of core issues are discussed in thisSpecial Volume which, in addition to this introductory synthesis,contains a balanced selection of papers focussing on comple-mentary clinical and preclinical aspects of NS, their character-isation, pathophysiological substrates, potential treatment andexperimental study. The clinical section embraces 5 paperswhich: focus on the core features and significance of NS inschizophrenia compared to other disorders (Foussias et al.,2014); provide a historical perspective on NS (Malaspina et al.,2014); describe established and novel procedures used tomeasure NS in humans, including clinical trials (Marder andKirkpatrick, 2014); analyse mechanisms underlying the disrup-tion of motivation and anticipatory pleasure (Kring and Barch,

Table 1 Characteristics of the five major sub-domains of negative symptom.

Sub-domain (alternative terms) Core characteristics

Blunted affect (affective flattening,blunted expression)

Reduced intensity and range of emotional expression as manifested via vocal andnon-verbal modes of communication including intonation (prosody), facialexpression, hand-gestures and body movements.

Alogia (poverty of speech) Decreased quantity of speech, reduced spontaneous speech and loss ofconversational fluency.

Amotivation (loss of volition) Deficits in the initiation and maintenance of goal-directed behaviours like work,study, sport, personal hygiene and daily tasks, especially when requiring an effort(cognitive or physical) and significant organisation. Also deficits in desire toundertake such activities. Related to apathy and lack of energy.

Anhedonia (reduced ability toexperience or anticipate pleasure)

The looking forward to a reward, recreational or other pleasurable experience(“wanting”) is more markedly and consistently impaired (anticipatory anhedonia)than the appreciation (“liking”) of the experience itself (consummatoryanhedonia).

Asociality (social withdrawal) Diminished interest in, motivation for, and appreciation of social interactions withothers, like family and friends. Also, loss of interest in intimate (sexual)relationships independent of any somatic problems. For children, may correspondto loss of interest in playing together.

Deficits indicated are mainly based on a NIMH consensus document (Kirkpatrick et al., 2006) which has been highly influential inorienting research and diagnosis over recent years. As outlined in the text and discussed in detail in this Special Volume (Foussiaset al., in press; Malaspina et al., in press; Marder and Kirkpatrick, in press), there is an emerging consensus, tacitly recognised in DSM-5 and supported by factor analysis, of two sub-clusters of negative symptoms. They comprise: (1) Diminished emotional expression(incorporating blunted affect and – though not explicitly mentioned in DSM-5 – alogia) and (2) avolition (encompassing amotivation,anticipatory anhedonia and asociality). Note that, as compared to poverty of speech itself, impoverished content of speech is nowusually integrated into disorganisation, another core domain of schizophrenia specified in DSM-5 (Figure 3). There is a certain degreeof overlap and interplay between the five domains: for example, asociality is partially attributable to low social motivation. Further,certain facets of blunted affect, like loss of appropriate speech intonation (prosody) and deficits in non-verbal communication, arealso inherent to an impairment of social cognition (Section 2.3).


2014); and discuss the influence on NS of currently-availableantipsychotics and newer agents under clinical exploration(Davis et al., 2014). The preclinical section is subdivided intotwo subsections. First, readouts for evaluating NS: namely,measures of motivation and reward (Barnes et al., 2014), andprocedures related to social interaction (Wilson and Koenig,2014). Second, rodents models for (not of) schizophrenia inwhich NS-like behaviours have been described, includingpharmacological (Neill et al., 2014), genetic (O’Tuathaighet al., 2014) and developmental (Moser, 2014) paradigms.

As regards this integrative and introductory paper, it hasseveral objectives. First, to set the scene in summarizingthe general features of schizophrenia and its currentmanagement, to provide a global overview of the corefacets of NS, and to emphasise challenges and opportunitiesfor their improved understanding and control. Second, tospecifically review one major theme that intersects with allother chapters yet which is not the topic for any singlearticle. That is, the cerebral circuits and neurochemicalsubstrates underling discrete sub-domains of NS as char-acterised by structural and functional imaging in humans,as well as electrophysiological and other analytic technol-ogies (Section 3). Third, to interlink the separate contribu-tions of this Volume via a mechanistic framework in which adisruption of frontocortico-temporal and frontocortico-striatal networks, as well as glutamatergic, GABAergic,dopaminergic and oxytocinergic transmission, provides aunifying theme. Fourth, to highlight a number of key topics

evoked in the separate articles, and to present someadditional aspects not covered elsewhere. Fifth, to discussprospects for the improved management of NS, with aspecial emphasis on: (1) Novel pharmacotherapeuticmechanisms, (2) alternative “stimulation” and “cognitive-behavioural-psychosocial” strategies, and (3) the morerefined, innovative and broader exploitation of experimen-tal models and readouts for the study of NS. Finally, thepresent paper incorporates some very recently-publishedarticles (up to March 2014) not otherwise cited in thisSpecial Volume.

2. Clinical studies of negative symptoms:characteristics, prevalence and measurement

2.1. Historical background and core features ofnegative symptoms up to and including DSM-5

As discussed herein by Malaspina et al. (2014), NS have along pedigree in schizophrenia stretching back to the Ger-man pioneers of Kraepelin and Bleuler, 19th/early 20thCentury English, French and American schools of thoughtand ultimately perhaps – through Avicenna – to the Hippo-cratic canon and the father of brain and mind, Alcmaeon ofKroton (Doty, 2007). In discussing “dementia praecox” (theforerunner term for schizophrenia), Kraepelin was particu-larly struck by NS-like features of indifference, emotional


deficits and, in particular, a lack of volition (Zec, 1995).Somewhat later, Bleuler (who coined the term schizophre-nia) asserted the ability to feel emotion was intact despite alack of will to seek it out – reminiscent of “anticipatoryanhedonia” (Section 3.3) (Heckers, 2011). He felt that thesechanges were driven by a core, fundamental and pathophy-siological process of disconnectivity (poor associations) ofthought and language (Heckers, 2011; Malaspina et al.,2014). Nonetheless, probably unbeknown to Kraepelin andBleuler, the notion of “NS” (and positive symptoms) hadbeen foreshadowed by the 19th English neurologist, Rey-nolds, who, in reference to epilepsy, distinguished symp-toms like anaesthesia (loss) from others like spasms (gain)(Messinger et al., 2011).

By analogy, and some 150 years later, in contrast to thepositive symptoms of schizophrenia (where delusions andhallucinations etc. are “added”), the term “negative”implies the loss of behaviours, interests, motivation anddesires as incarnated by avolition, and “diminished expres-sion” (Table 1). As originally conceptualised by Carpenteret al. (1988), it is desirable (though not always easy) todifferentiate primary NS inherent to the disease processitself from secondary NS which may be a consequenceof social exclusion, lack of environmental stimulation, atreatment-provoked extrapyramidal syndrome or co-morbiddepression etc. (Figure 2) (Foussias et al., 2014; Kaiseret al., 2010; Kirkpatrick et al., 2006). It has been suggestedthat a “deficit syndrome” associated with a particularlypoor outcome and comprising predominately NS can befound in certain drug-naïve patients at the time of admis-sion, and in perhaps a third of chronic schizophrenics

(Primary)Negative

Symptoms*(Secondary)

Neurocognitivedeficits

PsychomotorAbnormalities*

Depression,Anxietyd

Social/Environmental

deprivation

Disorganisation ,b

PositiveSymptoms ,a

Impairedsocial

cognition

ExtrapyramidalSyndromec

aHallucinations/Delusions*cAntipsychotic-induced

bSpeech*, language, thought, behaviourdEspecially social

*DSM-5

*

*

Figure 2 Induction and aggravation of negative symptomsby diverse factors related to schizophrenia. Primary NS areinherent to the pathophysiology of schizophrenia, in much thesame way as positive symptoms. However, positive symptomsthemselves (suspiciousness and paranoia) – as well as othercardinal feature of schizophrenia – may exacerbate NS. Further,secondary NS – or a phenotype resembling primary NS – can beprovoked by auxiliary factors like the extrapyramidal side-effects of neuroleptics, co-morbid depression or even a lackof environmental stimulation. Thus, NS in patients may actuallyreflect multiple causes and comprise a composite of primaryand secondary forms which are hard to differentiate.

(Figures 1 and 2). Though the status of this “deficit” entityremains somewhat contentious, it is not disputed that manypatients display enduring and predominant NS: their inclu-sion into clinical studies of NS has proven fruitful in theexploration of neurobiological substrates and potentialcontrol (Sections 3 and 4) (Beck et al., 2013; Buchanan,2007; Carpenter et al., 1988, 1999; Kaiser et al., 2010;Kanahara et al., 2013; Kirkpatrick et al., 2001; Nakaya andOhmori, 2008; Peralta and Cuesta, 2004; Peralta et al.,2014).

While NS are firmly established in the firmament ofschizophrenia as a core domain of dysfunction (Blanchardand Cohen, 2006; Blanchard et al., 2011; Buchanan, 2007;Messinger et al., 2011), their composition has evolvedsignificantly, and not always consistently, over the last 30–40 years or so. One important landmark was the NationalInstitute of Mental Health (NIMH), treatment-oriented con-sensus statement of 2005 (Kirkpatrick et al., 2006). Thisdocument enshrined the following core domains, four ofwhich are prefixed by “a/an”, underpinning the above-mentioned notion of “loss”: anhedonia, asociality, avolition,alogia, and blunted affect (Table 1) (Messinger et al., 2011).It is worth noting that the additional facet of impairedattention (Andreasen, 1982, 1989) was shunted to thesphere of neurocognition where it has become the focusof a complementary NIMH-coordinated initiative to improveneurocognitive deficits and impaired social cognition inschizophrenia (Buchanan et al., 2011b; Carter and Barch,2007; Millan and Bales, 2013). While DSM-III tended toneglect negative vs positive symptoms (except for povertyof speech), both avolition and flat affect made theirentrance in the revised version DSM-IIIR. Later on, aroundthe turn of the millennium, DSM-IV placed NS on centrestage of the agenda with the recognition of avolition, alogiaand blunted affect.

The latter points are thoughtfully discussed by Malaspinaet al. (2014) in this volume, who also emphasise that thediagnostic goalposts appear to be moving again with theadvent of DSM-5 (Figure 3) (Blanchard et al., 2011; Barchet al., 2013; Heckers et al., 2013; Tandon et al., 2013). In thisrecently-released tome, NS comprise one of the five “defin-ing” domains of schizophrenia (or schizophrenia spectrumdisorder) together with hallucinations (auditory and othersensory sensations not rooted in the outside world), delusions(beliefs detached from reality), disorganised speech (incoher-ent verbal language) and abnormal psychomotor function(bizarre behaviours and catatonia). In addition to three further(though not “defining”) diagnostic dimensions (depression,mania and cognition), NS and the other four core domains ofschizophrenia are semi-quantifiable on a scale of 0–4, whichshould facilitate their assessment and comparison. In the DSM-5 canon, NS are considered to be (1) avolition, embracingdecreased motivation, asociality and anticipatory anhedoniaand (2) diminished emotional expression, incorporatingblunted affect and – implicitly – alogia (poverty of speech)(Table 1). Avolition would be apparent from, for example,a lack of goal-directed and self-initiated behaviours whilerestricted emotional expression would be revealed by apoverty of speech and non-verbal (paralinguistic) communica-tion like facial expressions and hand gestures (Blanchardet al., 2011; Barch et al., 2013; Heckers et al., 2013;Tandon et al., 2013).

Psychomotordisfunction

Depressedmood

Delusions

Negativesymptoms

Disorganisationa

ImpairedCognitionb

Mania

Hallucinations

b embracessocial cognition

« Defining »symptoms

DSM-5 diagnosisof schizophrenia

Other relevant symptoms

a in particularof speech

Figure 3 Negative symptoms as one of the five diagnosticpillars of schizophrenia in DSM-5. DSM-5 has identified five“defining” symptoms for the diagnosis of schizophrenia, whichshould become apparent in the course of appropriate observa-tion and interviews. One of these is NS, together with halluci-nations and delusions (positive symptoms), psychomotordysfunction (agitation, retardation, catatonia) and disorganisa-tion. Depressed mood, mania and cognitive impairment (whichsubsumes impaired social cognition) are additional criteria tobe considered, but they are not diagnostic per se. Note thatneurocognitive dysfunction usually requires the use of specifictests for its characterisation as opposed to impairment in socialcognition and NS which should be apparent during the course ofthe interview and from other forms of interaction.


Importantly, this lack of non-verbal expression, togetherwith impaired prosody (intonation in speech), intersectswith deficits in social cognition (Section 2.3). On the otherhand, the “anhedonia” of NS does not, in contrast todepression (a separable domain), principally reflect anability to experience pleasure (“liking”). Rather, it conformsto deficient anticipation of pleasure (“wanting”) asreflected in a lack of coordinated behaviour and effortdedicated to its attainment (Section 3.3) (Berridge et al.,2009; Berridge and Kringelbach, 2013; Der-Avakian andMarkou, 2012; Strauss et al., 2014) – evocative of theKraepelian notion of impaired volition (Foussias et al.,2014; Gard et al., 2007; Huxley and Fonseca, 2014; Kaiseret al., 2010; Zec, 1995; Kring and Barch, 2014; Kring andElis, 2014; Wynn et al., 2010 – but see Konstantakopouloset al., 2011). Anticipatory anhedonia is medication-independent and apparent both at first episode and in thechronic phase of the disorder (Nielsen et al., 2012; Yeeet al., 2010). This issue is carefully analysed by Foussiaset al. (2014), and by the complementary article of Kring andBarch (2014), in this Special Volume.

These authors likewise discuss the reasoning underlyingthe growing (and DSM-5 reinforced) conviction of twointerrelated yet distinguishable sub-clusters of NS: avolitionand diminished emotional expression. This notion harks backto the NIMH consensus document evoked above (Kirkpatricket al., 2006) and to the analysis made around this time ofBlanchard and Cohen, 2006. Then, and in many subsequentstudies (Foussias et al., 2014; Mehta et al., 2011), the five

negative symptom domains summarised in Table 1 couldmostly be accounted for by the robust and independentfactors of decreased emotional expression and avolition.

2.2. Measurement of NS: established and novelrating scales

The above-mentioned distinction has been further rein-forced by recent work and, as articulated by Malaspinaet al. (2014) and Marder and Kirkpatrick (2014) in thisSpecial Volume, finds expression in the recent developmentof new rating scales for identification, characterisation andquantification of NS – both in the context of diagnosis and,importantly, of clinical trials. Deserving of special mentionare the NIMH-linked CAINS (Clinical Assessment Interviewfor Negative Symptoms) and the somewhat shorter (time tocomplete) and already-translated BNSS (Brief NegativeSymptom Scale) which: (1) share similar organisation,(2) display excellent test/re-test reliability and (3) providesupport for the two-factor concept of deficits in motivationvs blunted affect. These new instruments represent signifi-cant advances compared to older scales like the compositeand widely-used: (1) Positive and Negative Symptoms Scale(PANSS), of which the relevant subscale fails to fully coverthe whole gamut of NS and (2) Scale for Assessment ofNegative Symptoms (SANS) which, like the PANNS, incorpo-rates attentional deficits, and conflates observations over aone month period limiting its sensitivity to detect rapidchange (Harvey et al., 2006; Horan et al., 2011; Kirkpatricket al., 2011; Kring et al., 2013; Malaspina et al., 2014;Marder and Kirkpatrick, 2014). The respective merits – andlimitations – of these innovative scales will become clearerin the course of their broader utilisation. In any event, theyshould permit the more sensitive and rigorous characterisa-tion of NS, with the differentiation of the two above-evokedsub-domains likely related to contrasting neurobiogicalsubstrates (Section 3). This should, in turn, facilitate theclinical evaluation of new and potentially-improved medi-cation for NS (Section 4). Supporting this contention,Strauss et al., 2012, 2013, for example, recently reportedtwo subpopulations that showed contrasting profiles ofimpaired avolition yet essentially intact expression and viceversa.

Three final yet important points – not enitrely resolved todate by any particular scale per se – should briefly beevoked. These are the issues of, first, differentiatingprimary NS inherent to the disorder from secondary NS(vide supra). Though reducing NS by avoiding motor side-effects and alleviating co-morbid depression is obviouslydesirable, novel medication should be designed to specifi-cally relieve debilitating, primary NS. The second andrelated issue is distinguishing a symptom from a cause andfrom an outcome. Social withdrawal, for example, is anexpression of asociality and decreased (social) motivation,yet also a consequence of impaired social cognition and acontributory factor to depressed mood. This leads to a thirdand interrelated remark that NS may have several, conver-ging causes: in the case of social withdrawal, a lack of socialmotivation, deficits in social cognition and social anxiety.This multiple causation is reflected in the implication ofdiverse neural substrates discussed in Section 3.


2.3. Relationship of negative symptoms toimpaired social cognition

The concluding point of the previous paragraph brings upthe more general, complex and incompletely resolvedmatter of the interplay between NS and other core domainsof dysfunction in schizophrenia in terms of patient pheno-type, underlying neurobiological substrates and potentialtreatment strategies (Figure 4).

Though normal neurocognitive performance is beneficial forappropriate social cognition, these are distinct domains offunction, both of which are impaired in schizophrenia (Blikstedet al., 2014; Brown et al., 2012; Bora et al., 2009; Brüne, 2005;Fanning et al., 2012; Green et al., 2008, 2012; Hoe et al., 2012;Mehta et al., 2013; Millan et al., 2012). In fact, rather thanimpaired neurocognition, it is the interface between deficits insocial cognition and NS that is the most noteworthy andcomplex to comprehend since, while distinct, they interact.NS are driven by impaired social cognition which, at leastpartially, intervenes in its deleterious impact on functionaloutcome (Figure 4) (Foussias et al., 2014; Harvey et al., 2006;Kaiser et al., 2010; Lincoln et al., 2011; Mehta et al., 2013;Sergi et al., 2007).

As briefly mentioned above, social cognition refers to thesuite of cerebral mechanisms and mental operations used to

NeurCognidefic

Depression/Social anxiety

Negatsympto

Impairedsocial

cognition

DiminishedExpression

Alogia

EmotionalProcessing

Theory of Mind

Executive function

Working memory

Figure 4 The “compass” of schizophrenia: interrelationshipdisorder. In this particular depiction, all roads lead South – to NS, w(blunted affect and alogia) and avolition (amotivation, asocialitthemselves may feedback to aggravate other facets of schizophrenmay drive, NS. For example, social withdrawal is both a feature ofhand, a lack of motivation to engage in social contact will reinfoparticular the higher level operations indicated, will aggravate NSparanoia of positive symptoms may also provoke (secondary) NS. Anby positive symptoms and impending treatment, and may aggravespecially social withdrawal. Depression is associated with deficits infurther deteriorate motivation. These observations suggest that NSother symptoms into poor functional outcome with which NS are staggravate (provoke) positive symptoms (paranoia and delusions) duthe actions and intentions of others. Abbreviation not in the text:

monitor social signals from others, and to decipher theiremotional status and intentions. It embraces “Theory ofMind”, the internal representation of the mental state ofothers in relation to ones own mental state, allowing for theinference of others beliefs, desires, needs, knowledge andfuture behaviour (Adolphs, 2009; Byrne and Bates, 2010;Frith and Frith, 2012; Millan et al., 2012; Millan and Bales,2013; Rushworth et al., 2013). Theory of mind is stronglyrelated to empathy and trust. In humans, social cognition isintegrated with culture and verbal language, and necessi-tates appropriate knowledge of prosody and pragmatics(context-related behaviour and speech) (Fitch et al.,2010; Frith and Frith, 2012; Millan et al., 2012). Ultimately,effective social cognition is indispensable for appropriatesocial engagement, social integration, and the setting-upand maintenance of normal social relationships.

As currently conceived, impaired social cognition showssignificant overlap with – and may contribute to – NS, so it isnot surprising that they involve the anomalous operation ofseveral common neural circuits: notably, the temporalcortex (including the superior temporal gyrus) and theprefrontal cortex (PFC) (Adolphs, 2009; Frith and Frith,2012; Hovington and Lepage, 2012; Millan et al., 2012;Rushworth et al., 2013). Two examples may be given. First,social withdrawal is a consequence both of NS and of faulty

o-tiveits

General anxiety

ivems

Positivesymptoms

AmotivationAsociabilityAnhedonia

Delusions

Hallucinations

« Top-down »Cognitive control*

Episodic memory

*PFC/PAR.CX

between negative symptoms and other core facets of thehich are comprised of two sub-domains, diminished expression

y and anticipatory anhedonia), respectively. Reciprocally, NSia. Impaired social cognition is strongly interrelated with, andNS and a consequence of faulty social cognition. On the otherrce deficits in social cognition. Deficits in neurocognition, in, such as mechanisms required for acquisition of reward. Thexiety is often co-morbid with schizophrenia: it is also provokedate NS. Further, social anxiety will more directly impact NS,effort-related behaviours which, together with anhedonia, willmay, to a certain extent, channel the deleterious influence ofrongly correlated. Note that impaired social cognition may alsoe to faulty and hasty (jumping to conclusions) interpretation ofPAR.CX, Parietal cortex.


social cognition – in addition to social anxiety (Pallantiet al., 2004; Romm et al., 2011; Voges and Addington,2005). Second, reduced facial expression, body movementsand hand gestures are core elements of NS (diminishedemotional expression), yet the enactment of these modes ofnon-verbal communication, just as much as their interpre-tation, are usually taken as fundamental components ofsocial cognition (Frith and Frith, 2012; Millan et al., 2012).

One approach to resolving this paradox might be toconsider social cognition as purely concerned with thereception and interpretation as opposed to the perfor-mance and emission of social signals. For the presentpurposes, the critical point is that impaired social cognitionnot only aggravates positive symptoms like paranoia, suspi-ciousness and delusional thinking, but also contributes toand drives NS (Figure 4). This is important since NS andimpaired social cognition collectively have the most seriousimpact upon the functional status of patients: correspond-ingly, they are correlated with poor outcome throughout theentire course of schizophrenia (Figure 1) (Corcoran et al.,2011; Foussias et al., 2014; Lincoln et al., 2011; Maat et al.,2012; Mehta et al., 2013; Sergi et al., 2007).

2.4. Relationship of negative symptoms to otherclasses of symptom

The consummatory anhedonia of depression is, as men-tioned above, distinct to the anticipatory anhedonia seen inschizophrenia. Nonetheless, co-morbid depression may wellexacerbate NS by directly compromising hedonic states, andfurther delimiting effort-linked cognitive and motor perfor-mance aimed at acquiring reward (Harvey et al., 2009;Huxley and Fonseca, 2014; Kaiser et al., 2010; Millan et al.,2012; Salamone et al., 2012). In a broad sense, anxiety isvery prevalent in schizophrenia: in addition to co-morbidanxious states, anxiety can be provoked by psychoticepisodes and aversion to medication. Social anxiety isparticularly common: it may specifically contribute to socialwithdrawal, or itself be provoked and aggravated by a lackof social motivation (Figure 4) (Pallanti et al., 2004; Rommet al., 2011; Voges and Addington, 2005).

As pointed out elsewhere (e.g., Messinger et al., 2011),positive symptoms may drive asociality and other facets ofNS due to extreme suspiciousness and paranoia. As forneurocognitive deficits, many authors have discussed theirinterrelationship with NS, and Foussias et al. (2014) con-sidered the possibility that their impact on functionaloutcome is mainly mediated via NS – and impairment ofsocial cognition (Figure 4) (Harvey et al., 2006; Hoe et al.,2012; Lin et al., 2013; Nakagami et al., 2008; Ventura et al.,2009). Moreover, Kring and Barch (2014) and Barnes et al.(2014) evoked the significance of compromised executivefunction and top-down cognitive control (Lesh et al., 2011;Millan et al., 2012) to the defective goal-directed acquisi-tion of reward seen in schizophrenia (Section 3.3). Whileattentional deficits have, as mentioned above, beendetached from NS, this should not detract from the pointthat impaired attention will deleteriously impact mechanismssustaining the attainment of reward and social engagement(Figure 4) (Der-Avakian and Markou, 2012; Harvey et al.,2006). In addition, intact episodic memory (remembering,

recall, and prospective cognition) (Schacter et al., 2007;Millan et al., 2012) is required for appropriate social inter-action and estimation of future reward values (Section 3.3).Reciprocally, avolition can impact multiple domains of neu-rocognition – not least the performance of cognitive testsduring clinical trials (Nakagami et al., 2008; Millan et al.,2012).

Finally, it is hard to imagine that the poor content ofspeech and loss of verbal fluency in schizophrenia (a featureof disorganisation) (Figure 3) is entirely unrelated to thepoverty of speech, itself a sub-domain of NS (Table 1) (Fitchet al., 2010; Frith and Frith, 2012; Millan et al., 2012).

In light of the above remarks, it is instructive to considerNS not in isolation, but rather in relation to other prominentand interacting symptoms of schizophrenia (Figure 4).

2.5. Relationship of negative symptoms tofunctional impairment throughout the lifespanof schizophrenia

In view of the deleterious impact of NS on real worldfunction, it is important to note their occurrence through-out the disorder, not just in medicated, chronic, remitting-relapsing subjects, but around the first episode and even inthe prodrome (Figure 1) (Boonstra et al., 2012; Corcoranet al., 2011; Demjaha et al., 2012; Fusar-Poli et al., 2013a;Green et al., 2012; Hovington et al., 2012). Together withimpaired social cognition, co-morbid depression and disor-ganisation, NS are prominent and disabling in at-risk,prodromal adolescents and young adults (Corcoran et al.,2011; Fulford et al., 2013; Fusar-Poli et al., 2013a, 2014;Piskutic et al., 2012). The sub-domains of NS that mostdisrupt for normal life, social integration and academicachievements in at-risk subjects are uncertain, but intui-tively a lack of social motivation is likely to be especiallyincapacitating.

The presence of NS during the prodrome supports thenotion of their primary nature and suggests that NS andtheir neural substrates may even be a driver (like impairedsocial cognition) of transition to psychosis (Figure 4).Correspondingly, it may be hypothesised that treatmentsalleviating NS – and impaired social cognition/neurocogni-tion – in high-risk young subjects would both alleviatesuffering and reduce the risk of transition to schizophrenia– and other serious psychiatric disorders (Fusar-Poli et al.,2013a; Lewis, 2012; Miyamoto et al., 2012; Millan et al.,2012; Sabbag et al., 2011).

2.6. Negative-like symptoms in other psychiatricand neurological disorders

The present issue focuses exclusively on schizophrenia but itis worth accentuating, as exemplified in the article ofFoussias et al., 2014, that NS-like symptoms are present inseveral other psychiatric and neurological disorders. Thismirrors the occurrence of deficits in social cognition across abroad range of psychiatric and neurological conditions(Millan et al., 2012) and emphasises that NS alone cannotper se be considered as diagnostic for schizophrenia(Figure 3) (Barch et al., 2013; Tandon et al., 2013). It hasbeen claimed that NS (including apathy) are manifest in


about a third of subjects with major depression, and thatthey are distinct from consummatory pleasure (anhedonia)(Bottlender et al., 2003; Huxley and Fonseca, 2014). Apathyis also prominent in Parkinson's and Alzheimer's disease and,in the latter case, correlates with the magnitude ofdementia (Chase, 2011; Levy and Dubois, 2006; Millan,2010; Mitchell et al., 2011; Starkstein et al., 2009). Mirror-ing schizophrenia, the presence of NS in these disorders isassociated with poor functional status, and conventionalmedication is largely ineffective (op. cit).

Certain mechanisms underlying NS may be similarbetween schizophrenia and other disorders, such as theanomalous operation of cortico-striatal mechanisms ofreward, yet others will inevitably differ (Berridge andKringelbach, 2013; Gradin et al., 2011; Kring and Barch,2014; Simon et al., 2010). For example, the implication ofanomalous dopaminergic signalling in the apathy of bothschizophrenia and Parkinson's disease deserves mention, aswell as a role for dysfunctional circuits linking the PFC andthe basal ganglia (Section 3) (Chase, 2011; Levy and Dubois,2006; Starkstein et al., 2009). Conversely, as regardsanhedonia, the perturbation of mesolimbic dopaminergictransmission in major depression can be differentiated fromits deregulation in schizophrenia (Section 3.3) (Millan, 2006;Remington et al., 2011). Further, despite the fact thataberrant function of the PFC is incriminated in the apathy ofschizophrenia and Alzheimer's disease (Section 3.2), thefunctional breakdown of frontocortico-temporal coupling inschizophrenia (Section 3.1) can be distinguished from theprogressive β-amyloid and tau-driven processes of neuronalneurodegeneration that damage the temporal lobe andentorhinal cortex in Alzheimer's disease (Chase, 2011;Mitchell et al., 2011; Stella et al., 2014).

Importantly, common patterns of NS-like symptoms – andpathophysiological substrates – amongst schizophrenia andother diseases accentuate the relevance of a trans-nosological perspective in the study and ultimately controlof multi-factorial and heterogeneous disorders like schizo-phrenia (Cuthbert, 2014; Millan et al., 2012). An agentfound to alleviate NS in schizophrenia might emerge to havebroader utility in the treatment of NS-like symptoms inother psychiatric and neurological disorders.

3. Neural and neurochemical substrates ofnegative symptoms

3.1. Cortico-subcortical circuits implicated in NS:general considerations

By analogy to Alzheimer's disease, there has been somedebate as to whether schizophrenia might, at least partially,be a neurodegenerative-like disorder, with “neurotoxic”repercussions of the disease process itself progressivelydamaging the brain in a manner, either inhibited by,resistant to, or even exacerbated by antipsychotics(Archer, 2010; Fusar-Poli et al., 2013b; Rund, 2009). None-theless, there is overwhelming evidence that schizophreniais principally a disorder of neurodevelopment triggered by apanoply of genetic, epigenetic and environmental factors,providing a the foundation for animal models discussed in

Section 5 (Archer, 2010; Fatemi and Folsom, 2009; Millan,2013; Puri, 2010; Rapoport et al., 2012).

Regardless of causation, as described below, like otherfacets of schizophrenia, NS likely reflect anomalies ofdistributed neural networks rather than the disruption ofany discrete brain region (Figure 5). The correspondingstructural and functional changes are well-established atthe time of the first psychotic episode, and they actuallyanticipate diagnosis bring prominent in high-risks subjectsprior to transition (Section 2.5): further, they continue toprogress throughout the course of the disorder, notably asregards changes in the frontal and temporal lobes (Fusar-Poli et al., 2012, 2013b; Nakamura et al., 2013; Puri, 2010;Vita et al., 2012).

Many investigations have compared patients displayingpersistent and predominant NS to those without them, orstudied patients with a “deficit syndrome” (Section 2.1)(Carpenter et al., 1988, 1999; Buchanan, 2007; Kaiser et al.,2010; Kirkpatrick et al., 2001), in order to pinpoint the keycircuits impacted. As regards techniques exploited, structuralMagnetic Resonance Imaging (MRI) imaging permits visualisa-tion of alterations in the grey matter volume of specific brainstructures, Diffusion Tensor Imaging has been employed toexamine the disruption of white matter tracts, and functionalneuroimaging – mainly functional MRI (fMRI), but also SinglePhoton Emission Computerised Tomography (SPECT) – has beenapplied to probe the alterations in neuronal activity ofdiscrete brain regions in relation to NS.

Several studies of schizophrenia outlined below havefocussed on the resting and self-referential “default modenetwork”, which deactivates during goal-directed activity –

such as the organised acquisition of a reward (Broyd et al.,2009; Mazza et al., 2013; Orliac et al., 2013; Park et al.,2009; Whitfield-Gabrieli and Ford, 2012). Nonetheless, mostfMRI work has been undertaken employing cognitive tasks,of which certain – like executive function – are coordinatedby cortico-subcortical networks dysfunctional in NS. Inaddition, studies of blunted affect have tended to exploitemotionally-charged (and erroneously interpreted) stimulito determine the sites of anomalous cerebral activity inschizophrenia (Barch and Dowd, 2010; Dowd and Barch,2010; Goghari et al., 2010; Hovington and Lepage, 2012).

For all studies, despite an increasing tendency to performwork early in the disorder and in subjects with predominant NS,it is still difficult to isolate changes directly related to NS vsthose coupled to other symptoms, in particular as regardsimpaired social cognition (Section 2.3). Studies have beenundertaken in drug-naïve subjects, but medication remains anobvious confound: in this case, an attractive option is toexamine its potential reversal of putative anomalies (Barchand Dowd, 2010; Benoit et al., 2012; Filippi et al., 2014;Goghari et al., 2010; Hovington and Lepage, 2012; Kring andBarch, 2014; Stip et al., 2005; Strauss et al., 2014).

As regards the interpretation of data, it should notautomatically be assumed that alterations are causal toNS: changes may be merely correlated (epiphenomon) oreven provoked by NS themselves. Alternatively, they may becompensatory in an effort to counter the deleterious impactof NS, as suggested for cannibinoids (Section 3.7) (Ceccariniet al., 2013) and exemplified by observations in schizo-phrenics that certain brain regions are over-activated incognitive, emotion-processing and motor procedures in an

*Overlaps withventromedial PFC

DLPFC

OFC*

ACC

Amygdala VentralStriatum

SNpc

DA perikarya:

GPPrefrontalCortex

VTA

DLPFC - Dorsal striatum: Goal-directed and organised planning for reward acquisitionOFC - Ventral striatum: Value of reward, prediction, timing, delay-discounting (value vs delay) ACC - Ventral striatum: Cost of obtaining reward, monitoring of effort invested, competition

Also consummatorypleasure (“liking”)

Temporal cortex

GlutamateDopamine

Anticipatory pleasure/reward (“wanting”)

Nucleus Accumbens

Thalamus

Insularcortex

5-HTGlu

CB

DAOpioidOT

GABA

VP

Caudate

Dorsal Striatum

PallidumN.Acc

Reward/motivation

Figure 5 Schematic representation of cerebral circuits impacted in NS, in particular in relation to deficits in anticipatoryreward. As discussed in the text, a perturbation of frontocortico-temporal networks has been consistently related to NS, while adisruption of cortico-striatal loops is strongly implicated in amotivation and anticipatory anhedonia. As depicted, these sub-domainsof NS reflect the impaired operation of several, anatomically- and functionally-distinct (yet interdependent and interacting)pathways running from the prefrontal cortex (PFC) to the dorsal or ventral striatum. From the latter regions, pathways project tosub-regions of the pallidum which, via the thalamus and dopaminergic nuclei of the ventrotegmental area (VTA), close the loops inprojecting back to the PFC. The nucleus accumbens, itself also under the influence of the amygdala, is a core region for modulationof reward and emotional processing. Several other cerebral regions implicated in NS are not shown for reasons of space (see text),and the thalamus has been anatomically relocated for better visibility. Glutamatergic fibres interconnecting the various territoriesof the PFC are not shown for reasons of clarity, nor projections from the PFC to the VTA. Many neurotransmitters are implicated inNS, as highlighted for amotivation/anticipatory anhedonia in the inset. Abbreviations not in the text: ACC, anterior cingulate cortex;STG; superior temporal gyrus; GP, Globus pallidus; VP, Ventral pallidum; SNpc, Substantia nigra, pars compacta; OT, Oxytocin andGlu, glutamate CB.


attempt to offset the failure of structures that fail torespond (Bracht et al., 2014; Koike et al., 2013; Tayloret al., 2012; Unschuld et al., 2014). Moreover, from a trans-nosological perspective, it is still unclear which cerebralmechanisms implicated in the NS of schizophrenia areentirely distinct from those incriminated in the NS-likedysfunction of other disorders (Section 2.5). Finally, patho-physiological mechanisms incriminated in the genesis of NSare not necessarily synonymous with those that maintainthem once established.

Despite these caveats, and sometimes marked variabilitybetween the findings of specific studies, data from com-plementary structural, imaging and electrophysiologicalapproaches have converged in incriminating several pivotalnetworks and cerebral structures in NS. Further, the con-clusions of studies in patients are globally in line withexperimental work discussed below, despite the – to date– limited application of imaging to rodents (Section 5).As outlined below, fronto-temporal and frontocortico-striatalcircuits are the most consistently and robustly implicated inNS – though not exclusively – but the roles of their specificsub-regions differ amongst distinct sub-domains of NS.

It is instructive to initially summarise overall findings forthe temporal and frontocortical lobes before focussing on

structures more specifically implicated in the different sub-domains of NS. The dysfunction of neural networks involvedin anticipatory anhedonia is particularly complex andauthoritively analysed by Kring and Barch (2014) in thisSpecial Volume. Consequently, this rich and specialised bodyof the literature is only succinctly summarised below.

3.2. Anomalies of cerebral structures implicatedin NS: structural and functional characterisation

3.2.1. Temporal lobes: structural imagingA decrease in the grey matter volume of the temporal lobe,in particular the superior temporal gyrus, has been asso-ciated with NS with striking consistency (Benoit et al., 2012;Cascella et al., 2010; Fischer et al., 2012; Fusar-Poli et al.,2012, 2013b; Galderisi et al., 2008; Hovington and Lepage,2012; Sanfilipo et al., 2000; Vita et al., 2012; Yamasueet al., 2004). Interestingly, the temporal gyri lie at theheart of circuits involved in social cognition, includingfacial/gaze processing and, for the superior temporal gyrus,Theory of Mind – and this region is also integral to networksintegrating language (Adolphs, 2009; Carrington and Bailey,2009; Millan et al., 2012; Millan and Bales, 2013; Rushworth


et al., 2013). These observations are consistent with thereduced verbal expression (alogia) of NS and underscore theinterrelationship of NS with impaired social cognition, thoughtemporal lobe anomalies are also related to other features ofschizophrenia, like positive symptoms and disorganisation(Goghari et al., 2010).

The temporal lobe is strongly interconnected with thefrontal lobes, and both structural studies of white matter –and electrophysiological recordings (Section 3.2.4) (Kimet al., 2014, Thoma et al., 2005) – suggest that thedisruption of this connection is related to the genesis ofNS. For example, the uncinate fasiculus links the temporallobe to the orbitofrontal cortex (OFC), and its disturbancein schizophrenia has been related to NS, perhaps due tointerrupted exchange of information concerning rewardvalue and history (Kitis et al., 2012; S.H. Lee et al., 2013;Nestor et al., 2013; Voineskos et al., 2013; Von Der Heideet al., 2013).

There is, then, a compelling set of observations linkingdysfunction of the temporal lobe to NS, most likely asregards asociality and blunted affect (especially alogia) andperhaps also as concerns the elements of time and memoryfor predicting reward, though this remains to be directlydemonstrated.

3.2.2. Frontal lobes: structural imagingAs for the frontal lobes themselves, a rather disparatepattern of grey matter reductions has been found in varioussub-regions (Hovington and Lepage, 2012).

Regions where deceases in grey matter have been reportedinclude the inferior frontal gyrus – a core component of socialcognition (Adolphs, 2009; Millan et al., 2012) – and both theOFC and anterior cingulate, with a probable link to aberrantmechanisms of reward (Bergé et al., 2011; Filippi et al., 2014;Galderisi et al., 2008; Nakamura et al., 2013; Nestor et al.,2013; Sanfilipo et al., 2000; Schobel et al., 2009; Stip et al.,2005; Takayanagi et al., 2010, 2013; Yamasue et al., 2004).Conversely and counter-intuitively, despite its implication indeficient goal-directed behaviour required for reward acquisi-tion (Kring and Barch, 2014), the dorsolateral PFC (DLPFC) hasshown only modest and variable changes in volume: moreover,putative changes are not necessarily correlated with NS,rather to cognitive dysfunction (Baaré et al., 1999; Behere,2013; Benoit et al., 2012; Fischer et al., 2012; Galderisi et al.,2008; Hovington and Lepage, 2012; Schobel et al., 2009; Stipet al., 2005; Takayanagi et al., 2010; Volpe et al., 2012).

A rather robust observation is a reduction of whitematter, correlated with the severity of NS and suggestingreduced connectivity: (1) amongst sub-territories of thePFC, (2) between the PFC and other cortical regions like thetemporal, insular and occipital cortices (see above) and (3)to sub-cortical structures like the striatum (see below)(Bracht et al., 2014; Cascella et al., 2010; Galderisi et al.,2008; Hoe et al., 2012; S.H. Lee et al., 2013; Voineskoset al., 2013; Zetzsche et al., 2008).

3.2.3. Temporal and frontal lobes: functional imagingReinforcing structural data presented above, functionalimaging has visualised temporal lobe anomalies linked toNS, including hypoactivity and a greater rightward symmetry:aberrant operation of the temporal lobe is also suggested by

the poor performance of schizophrenics in neuropsychologi-cal tests involving the temporal cortex. In addition, NS arecorrelated with reduced connectivity of the superior tem-poral gyrus to frontocortical regions like the anterior cingu-late (Benoit et al., 2012; Cohen et al., 2007; Ke et al., 2010;Millan et al., 2012; Potkin et al., 2002).

As concerns the PFC itself, several studies suggest that adysfunction of the default mode network involving theventromedial PFC is correlated with NS (Mazza et al.,2013; Orliac et al., 2013; Park et al., 2009), and possiblydefective verbal expression (Bluhm et al., 2007; Whitfield-Gabrieli and Ford, 2012). Further, there are reports ofabnormal activity in the OFC and anterior cingulate,changes blunted by antipsychotics (Kanahara et al., 2013;Stip et al., 2005). Similar alterations have been seen in theinsula, and its interaction with the anterior cingulateappears to be disrupted in schizophrenia (Figure 5)(Gradin et al., 2013; Manoliu et al., 2013).

Mirroring findings with structural studies evoked above,and in contrast to the ventromedial PFC (Figure 5), fMRIstudies have not invariably found an association between NSand decreased operation of the DLPFC: disruption of thisregion and its interaction with the striatum seems morestrongly linked to disorganisation and cognitive impairment,notably of executive function (Ehrlich et al., 2012; Goghariet al., 2010; Lesh et al., 2011; Van Veelen et al., 2010).Goghari et al. (2010) carefully discussed these findings, andsuggested that putative deficits in DLPFC activity may havebeen normalised by antipsychotics in certain studies –

analogous to above-mentioned findings for the OFC andanterior cingulate (Stip et al., 2005). Interestingly, disrup-tion of DLPFC activity (and frontal lobe dysfunction ingeneral) was claimed to be predictive of the induction ofNS by ketamine (Honey et al., 2008). Clearly, the questionof how the apparent dysfunction of the DLPFC in schizo-phrenia relates to NS awaits more refined evaluation.

It should also be pointed out that alterations in the activityand connectivity of the parietal cortex, including the pre-cuneus – part of the default mode network (Whitfield-Gabrieliand Ford, 2012) – have been linked to the induction of NS(Bluhm et al., 2007; Broyd et al., 2009; Goghari et al., 2010).It is possible that these observations relate to the importantrole of this region in social cognition (Adolphs, 2009; Millanet al., 2012; Guo et al., 2014; Rushworth et al., 2013).

Thus, the interplay between NS on the one hand andneurocognition-social cognition on the other can be hard todetermine. Nonetheless, structural and functional datacollectively indicate that a disruption of diverse sub-territories of the temporal lobe and PFC, and of commu-nication between the PFC, temporal and probably insular,parietal and occipital lobes, is related to NS. As indicatedbelow, this is not to neglect the significance of PFC couplingto the basal ganglia, and the possible implication of otherstructures like the thalamus and cerebellum (Ehrlich et al.,2012; Goghari et al., 2010; Hovington and Lepage, 2012;Pinault, 2011; Potkin et al., 2002).

3.2.4. Cortical and sub-cortical circuits,electrophysiological studiesThough perhaps less glamourous than imaging, non-invasive electrophysiological (EEG) tools are invaluable for


characterising the interrelationship between the activity ofspecific cerebral circuits and functional domains perturbed inschizophrenia like information-processing, mood andcognition, (Boutros et al., 2013; Millan et al., 2012; Wang,2010).

It was suggested that an impairment in the synchronousoperation of local vs global cortical circuits, including a lossof gamma power, is specifically linked to NS (Noh et al.,2013). This is interesting since the coordination of PFC-driven glutamatergic networks by GABAergic interneuronescan be picked up in the gamma range (30–80 Hz): theirdisruption in schizophrenia is related to abnormal, PFC-integrated executive function and “top-down control”which indirectly impacts NS (Figures 4 and 5) (Kring andBarch, 2014; Stan and Lewis, 2012; Lesh et al., 2011; Millanet al., 2012; Wang, 2010). Likewise of pertinence arestudies using spectral EEG that related increases in slowerrhythms, including episodic memory-related, frontocortico-hippocampal theta (4–7 Hz), to the intensity of NS (Boutroset al., 2013). Further, a decrease in delta slow wave sleephas repeatedly been found to correlate with NS severity; itappears to involve perturbation of thalamic projections tothe frontal lobes, emphasising that aberrant input to thecortex from this key gating structure may participate in theinduction of NS (Pinault, 2011; Sekimoto et al., 2011).

The monitoring of Event Related Potentials (ERP) can alsoyield insights into the integrity of cortical circuits in relationto NS and to the risk of transition during the prodromalphase (Boutros et al., 2013; Fusar-Poli et al., 2013a; Horanet al., 2010). For example, several – though not all – studiesindicate that interference with the P300 “oddball” (unex-pected stimulus) response is linked to NS: further, the mostmarked reduction is seen over the parietal region inpatients with predominantly NS, as opposed to the temporallobe for those with less pronounced NS (Boutros et al., 2013;Oribe et al., 2013; Ozgürdal et al., 2008). The P300 signal isalready aberrant in subjects at high risk for conversion(Boutros et al., 2013; Fusar-Poli et al., 2013a). As anotherexample, studies of ERP have supported the above-evokedrelationship between fronto-temporal decoupling and NS(Kim et al., 2014; Thoma et al., 2005).

The precise mechanistic foundations of links betweenelectrophysiological readouts on the one hand, and NS onthe other, is still uncertain, but these findings reinforce thesignificance of disruption of cortical and cortico-subcorticalnetworks to their genesis.

3.3. Dysfunctional neural circuits related toamotivation and anticipatory anhedonia

As emphasised in this Special Volume (Foussias et al., 2014;Kring and Barch, 2014; Malaspina et al., 2014), the appre-ciation of pleasure per se does not seem to be greatlyaffected in schizophrenia, and consummatory anhedonia(“liking”) appears to be dissociable from NS which arecoupled to compromised “wanting” (anticipatory anhedo-nia) (Berridge et al., 2009; Berridge and Kringelbach, 2013;Huxley and Fonseca, 2014). Imaging studies support thisinterpretation, despite the fact that some variable changeshave been seen in fMRI studies of the response of thecortex, striatum, cerebellum and amygdala to rewarding

stimuli (Dowd and Barch, 2010; Barch and Dowd, 2010;Goghari et al., 2010; Kring and Barch, 2014; Simon et al.,2010).

By contrast to consummatory pleasure per se, imagingstudies in schizophrenics have consistently revealed anoma-lies in processes related to the anticipation of reward(anticipatory anhedonia), and to the motivation, effort,approach behaviour and goal-directed actions requisite foracquisition: they can primarily be attributed to abnormaloperation of the ventral striatum (nucleus accumbens) anddorsal striatum (mainly the caudate) in interaction with thePFC (Figure 5). For example, cues signalling reward are lessefficient in activating the ventral striatum – and ventrome-dial PFC/OFC – in schizophrenics (Dowd and Barch, 2012;Juckel et al., 2006; Harvey et al., 2009; Nielsen et al., 2012;Simon et al., 2010; Strauss et al., 2014; Waltz et al., 2009).Other interlinked structures also appear to be involved, likethe anterior insular cortex which projects to the OFC andventral striatum and which is reciprocally interconnectedwith the amygdala: it plays an important role in socialcognition, emotional processing, mood and reward, andboth its volume and functional activity is compromised inschizophrenia (Section 3.1) (Millan et al., 2012; Manoliuet al., 2013; Waltz et al., 2009; Yamasue et al., 2004), witha specific link to the reward deficits of NS (Croxson et al.,2009; Dowd and Barch, 2010; Gradin et al., 2011).

Since the article of Kring and Barch (2014) in this SpecialVolume (Section 5.6) critically analyses this sub-domain ofNS in detail, the core observations are only briefly recapi-tulated below and, for ease of comprehension, the majorcircuits implicated are graphically presented in Figure 5.See also Barnes et al. (2014) in this Special Volume for anexperimental perspective on this issue, and note thatanatomical and functional observations are not entirelytransposable across species.

The motivational deficits accounting for anticipatoryanhedonia – or impaired anticipatory pleasure (desire) –

can be parsed into several, interrelated functions known tobe compromised in schizophrenia (Croxson et al., 2009;Fervaha et al., 2013; Gold et al., 2013, Strauss et al., 2014;Ward et al., 2012), and mediated by contrasting territoriesof the PFC and striatum (Figure 5).

First, a core element of motivation is the perceived valueof the reward in relation to desires/needs. This may need tobe updated in the light of recent experience, and valuecalculated in light of the delay to receipt (“delay discount-ing”). The OFC – which plays a key role with the nucleusaccumbens in pleasure (Berridge and Kringelbach, 2013;Kringelbach, 2005) – acts in interaction with the nucleusaccumbens and dopaminergic mechanisms to underpin thesefunctions (Deserno et al., 2013; Padoa-Schioppa and Cai,2011). Both the function of the OFC and its interconnectionwith the nucleus accumbens, as well as value computationof reward, are perturbed in schizophrenia (Bracht et al.,2014, Diekhof et al., 2012; Harvey et al., 2009; Levy andDubois, 2006; Morris et al., 2012; Strauss et al., 2014).Faulty encoding of expected reward in schizophrenia (impli-cated in apathy) involves, then, dysfunction of an OFC-striatal network, though other DA-rich regions may also beinvolved, like the insular cortex, amgydala and hippocam-pus (Gradin et al., 2011; Kring and Barch, 2014; Levy andDubois, 2006).


Second, acquiring a reward necessitates effort and willincur a (cognitive and/or physical) cost, the computation ofwhich is assumed by the anterior cingulate together with(dopaminergic signalling in) the nucleus accumbens. Theirfunctional integrity is essential for a decision to opt for agreater reward coupled to supplementary effort, andpatients with schizophrenia show both a disruption of theanterior cingulate (Section 3.2) and of this function(Botvinick et al., 2009; Croxson et al., 2009; Fervahaet al., 2013; Gold et al., 2013, Strauss et al., 2013;Treadway et al., 2009, 2012; Ward et al., 2012). Interest-ingly, in a social environment, it may be necessary tocompete for reward, coupled to additional effort, and theanterior cingulate likewise appears to be involved in optionselection in this context, one likely to be flawed in schizo-phrenia (Hillman and Bilkey, 2012). It should also bementioned that dysfunctional coupling between the ante-rior cingulate and the insular cortex (“salience network”)has been linked to the failure to appropriately processreward in schizophrenia (Gradin et al., 2013).

Third, in the context of exploratory behaviour, a goal-directed action must be engaged in order to obtain thereward, This function appears to depend on the DLPFCwhich, reflecting intrinsic dopaminergic, adrenergic andother mechanisms related to executive function, exerts atop-down control to enhance reward oriented behaviour(Lesh et al., 2011; Levy and Dubois, 2006; Millan et al.,2012). The abnormal activity of the DLPFC in schizophrenia(Section 3.2) relates, then, in conjunction with impairedexecutive function (coordination, planning, organisation),to deficits in the initiation and maintenance of goal-directed, reward-seeking behaviour and its appropriatelinking to affect (Goghari et al., 2010; Kring and Barch,2014; Millan et al., 2012; Strauss et al., 2013; Unschuldet al., 2014; Ursu et al., 2011; Van Veelen et al., 2010).

The above observations collectively provide a frameworkfor conceptualising the amotivation and anticipatory anhe-donia of NS not as a loss of hedonic state and rewardappreciation as such, but rather in terms of defectivecortico-striatal integrated processes indispensable forreward acquisition and anticipatory pleasure. These deficitsare interlinked with anomalies in emotional processing andneurocognitive operations related to executive function andepisodic memory (recalling previous positive experiencesand prospective imaging of future pleasure), in line with theinvolvement of other structures like the temporal lobe,insular cortex, amygdala and hippocampal complex (Gradinet al., 2011; Schacter et al., 2007; Millan et al., 2012; Ursuet al., 2011).

In a nutshell, schizophrenic patients are unable toassemble, get motivated by and exploit information aboutprevious pleasurable experiences in the service of goal-directed and effort-requiring attainment of a future reward(Burbridge and Barch, 2007; Deserno et al., 2013; Kring andBarch, 2014; Strauss et al., 2014).

3.4. Dysfunctional neural circuits related toasociality

As regards a further sub-domain of NS, asociality, therelevant structures disrupted in schizophrenia are less well

delineated than those underpinning anticipatory anhedonia,and it is hard to tease them apart from those implicated inimpaired social cognition. Nonetheless, inasmuch as asoci-ality is, at least partially, driven by a lack of (anticipatory)social motivation, asociality presumably involves mechan-isms and substrates outlined in the previous paragraphs.Indeed, a role of the nucleus accumbens (striatum) in socialanhedonia has been evoked (Dowd and Barch, 2010).Additional neural structures are also likely to be incrimi-nated as deduced by studies in humans, by experimentalwork in rodents and, in both cases, by studies of the “pro-social” neuropeptide, oxytocin (Sections 3.6 and 4.8).

Thus, the disruption of an oxytocin-modulated networkincorporating the superior temporal gyrus, inferior frontalgyrus, PFC and insula cortex, may contribute to socialwithdrawal in schizophrenia (Churchland and Winkielman,2012; Millan et al., 2012; Millan and Bales, 2013; Meyer-Lindenberg et al., 2011). Further, oxytocin promotes socialbehaviour and social motivation via actions in the nucleusaccumbens and amygdala (Dolen et al., 2013; Gordon et al.,2011; Lee et al., 2005 Rosenfeld et al., 2011), andanomalous cannibinoidergic signalling in these regions, ininteraction with the PFC, may also be involved in the loss ofsociality in schizophrenia (Seillier et al., 2010, 2013; Trezzaet al., 2011a, 2011b). These neurochemical observations,further evoked below (Section 3.6), support a role foranomalous operation of frontocortico-subcortical circuitsin the asociality of schizophrenia.

In addition, it might be speculated that a failure of thedefault mode network to properly deactivate when switch-ing from a self-referential to a social context, may con-tribute to impaired social engagement in schizophrenia(Bluhm et al., 2007; Broyd et al., 2009; Whitfield-Gabrieliand Ford, 2012; Mazza et al., 2013; Orliac et al., 2013).

3.5. Dysfunctional neural circuits related todiminished emotional expression

By analogy to asociality, information on the precise neuralsubstrates underlying diminished emotional expression alsoremains fragmentary though loss of the expressive use ofnon-verbal signals like hand gestures likely involves struc-tures common to impaired social cognition (vide supra).

Furthermore, a complete dissociation of neural sub-strates implicated in avolition compared to those involvedin blunted affect would seem improbable. In addition toroles for the ventromedial PFC, DLPFC, anterior cingulateand temporal cortex, impaired emotional processing andexpression in response to positive and negative emotionalstimuli may be related to anomalous activation of theamygdala, and to changes in the dorsal striatum andhippocampus/parahippocampal gyrus (Dowd and Barch,2010; Kring and Elis, 2014; Fahim et al., 2005; Goghariet al., 2010; Gur et al., 2007; Lepage et al., 2011; Rosenfeldet al., 2011; Taylor et al., 2012; Ursu et al., 2011). A linkbetween dysfunctional language-speech networks incorpor-ating the PFC, temporal, parietal and occipital cortices andpoor content of speech appears probable (Makris et al.,2010; Millan et al., 2012; Poeppel, 2012), but the specificneural foundations of alogia (decreased verbal fluency) are


not well understood (Fischer et al., 2012; Hovington andLepage, 2012; Potkin et al., 2002).

Finally, alterations in default mode activity and connec-tivity of the ventromedial PFC and parietal cortex may belinked to decreased verbal expression (Bluhm et al., 2007;Orliac et al., 2013; Whitfield-Gabrieli and Ford, 2012).

Further work remains to be undertaken to better definethe specific neural substrates implicated in the diminishedemotional expression of schizophrenia.

3.6. Onset of anomalies related to NS in at-riskpatients prior to diagnosis

To summarise, while many questions persist, anomalousoperation of a complex suite of partially-overlapping andinteracting cortico-subcortical circuits is implicated in thevarious sub-domains of NS, and certain are common toimpaired social cognition. A broad role of the PFC ininteraction with the temporal cortex, striatum and amyg-dala can be recognised, yet distinct sub-territories fulfildifferential roles, accounting for the contrasting functionalimpact of their dysfunction. In addition, the significance ofinteracting regions like the insular and parietal cortices,as well as the thalamus and cerebellum, should not beneglected.

The earliest circuit irregularity antecedent to schizophre-nia – assuming it exists – is not currently known, nor whetherit might act as a trigger for the complex pattern ofdisruption related to NS. In this light, the increasingapplication of imaging early in the disorder, during theprodrome, and in young subjects with identified risk factors,should progressively clarify the comparative time of emer-gence of diverse neural anomalies linked to NS sub-domains.

Importantly, mirroring NS themselves, the underlyingstructural, functional and electrophysiological changes aremanifest in at-risk and prodromal subjects and henceanticipate the first psychotic episode (Section 2.5). Notably,even before diagnosis, grey matter volume reductions,white matter changes and network disruption are seen instructures like the PFC, temporal and insular cortices(Fusar-Poli et al., 2012, 2013b; Smieskova et al., 2012),together with perturbation of ERP depending upon fronto-temporal-parietal circuits (Boutros et al., 2013; Kim et al.,2014; Oribe et al., 2013; Ozgürdal et al., 2008). Thesepoints are of significance with respect to the developmentof potential biomarkers for predicting transition of vulner-able individuals to schizophrenia.

3.7. From neural substrates to cellular andneurochemical bases of NS

Another important question – which bears on the chronologyof pathophysiological changes triggering NS – concernsthe molecular substrates of neural circuit dysfunction inschizophrenia.

Various sub-domains of NS may be independently pro-voked by contrasting cellular anomalies, such as aberrantoxytocinergic transmission for asociality, or anomalouscannabinoid/DA signalling for anticipatory anhedonia.On the other hand, abnormal expression of proteins likeReelin or Neuregulin-1 would impact a broad community of

GABAergic interneurons and cortical pyramidal neuronesdispersed across multiple regions of the PFC implicated inNS: furthermore, the induction of an immune-inflammatoryresponse upon perinatal infection would likewise have awidespread impact on the developing brain (Fatemi andFolsom, 2009; Lewis, 2012; Millan, 2013; Moser, 2014;Piontkewitz et al., 2012; Rapoport et al., 2012).It remains then to be clarified just how the various patternsof neuronal and circuit dysfunction linked to sub-domains ofNS are interrelated in terms of their causes, interplay andonset, and whether there exists a unifying and commonprecipitating mechanism.

To determine the succession of events that ultimatelyresult in NS and schizophrenia itself, it will be necessary toconsiderably improve our knowledge at the cellular level.Compared to the rich pattern of data generated concerningneural circuits, little is known at the neurotransmitter levelregarding NS since it is technically far more challenging toundertake such studies on humans as compared to theconventional imaging. Nevertheless, the following findings– generally supported by experimental observations (Section5) – justify mention.

Magnetic Resonance Spectroscopy data has provideddirect evidence that a disruption of GABA-glutamatergicdialogue in the PFC and striatum is correlated with NS,though a disequilibrium of the inhibitory-excitatory balanceis also related to neurocognitive and positive symptoms(Poels et al., 2014; Reid et al., 2010; Rowland et al., 2013).The endogenous antioxidant, glutathione, interacts withNMDA receptors and may protect against the induction ofschizophrenia (Yao and Keshavan, 2011), so it is of note thatdecreases in its levels correlate with the severity of NS(Matsuzawa et al., 2008).

Positron Emission Tomography (PET) and SPECT permitthe characterisation of dopaminergic transmission in termsof DA release and receptor occupation (Mugnaini et al.,2013) and, as outlined by Kring and Barch (2014) and Barneset al. (2014), convergent clinical and preclinical evidencesupport the core significance of aberrant striatal andprefrontal dopaminergic signalling in the motivational def-icits of schizophrenia (Section 3.2). An interesting varianton these data, and an approach that could be more widelyused to examine neurochemical substrates of NS, is pro-vided by the finding that repetitive Transcranial MagneticStimulation (TMS) of the PFC – which can relieve NS (Section5.5) – elicits DA release in the human caudate (Stratellaet al., 2001). It should also be mentioned that a compara-tively early deficit in mesocortical dopaminergic transmis-sion related to NS and cognitive impairment – itselfdownstream of aberrant GABA-glutamate coupling – maysecondarily provoke the hyperactivity/hyper-responsivenessof mesolimbic dopaminergic pathways manifested in posi-tive symptoms at the time of the first psychotic episode(Lewis, 2012; Millan et al., 2012; Remington et al., 2011).

Especially intriguing are data pertaining to endogenouscannabinoids in view of their role in reward mechanismsexpressed in the mesolimbic system in interaction withdopamine (Der-Avakian and Markou, 2012; Leweke, 2012;Leweke et al., 2012). Cerebrospinal fluid levels of theendogenous ligand, anandamide, are elevated in schizo-phrenia. Similarly, the density of Cannibinoid (CB) 1 recep-tors is higher in post-mortem tissue, and several studies


have found comparable increases in CB1 receptor number inthe nucleus accumbens and PFC using highly-selective PETligands. Importantly, increases in CB1 receptor signalling inthe nucleus accumbens (and other structures) are nega-tively correlated with NS. Accordingly, even though canna-bis abuse is a risk factor for psychosis, it has beenspeculated that endogenous cannibinoidergic mechanismsplay a counter-adaptive and protective role in the suppres-sion of NS (Ceccarini et al., 2013; Coulston et al., 2011;Leweke et al., 2012). This line of thinking will be of interestto pursue.

Finally, to reiterate a point outlined above, decreasedoxytocinergic transmission appears to be implicated notonly in impaired social cognition but also in the genesis ofNS, including a loss of social motivation and interaction(Churchland and Winkielman, 2012; Goodson and Thompson,2010; Gordon et al., 2011; Meyer-Lindenberg et al., 2011).That oxytocinergic signalling is defective in schizophrenia issuggested by the modest correlation between reducedcerebrospinal fluid and plasma levels of oxytocin and themagnitude of NS (Goodson and Thompson, 2010; Meyer-Lindenberg et al., 2011; Rosenfeld et al., 2011; Rubin et al.,2010; Sasayama et al., 2012). Though this relationshipwould benefit from confirmation, a significant associationshas been reported between Single Nucleotide Polymorph-isms in the Oxytocin receptor gene and NS (Montag et al.,2013). There is experimental evidence that an interactionwith serotonergic transmission in the nucleus accumbensparticipates in the facilitation of social behaviour andreward by oxytocin (Dolen et al., 2013), while oxytocin alsoacts in the amygdala to favour social behaviour andmotivation (Gordon et al., 2011; Lee et al., 2005Rosenfeld et al., 2011). Hence, deficient oxytocinergictransmission in these regions, and in cortico-subcorticalcircuits underpinning social cognition and processing(Section 3.3) (Meyer-Lindenberg et al., 2011). may berelated to the asociality of schizophrenia.

Other mechanisms potentially defective in schizophreniashould also be briefly evoked. These include mu-opioidreceptors which in the nucleus accumbens and in interac-tion with DA, facilitate social and other mode of reward,while kappa-opioid receptors act oppositely: further, like-wise acting in this region, adenosine regulates reward-related effort (Chartoff et al., 2012; Salamone et al.,2012; Scholsburg et al., 2013; Trezza et al., 2011a, 2011b).

3.8. Implications of insights into neural andneurochemical substrates of NS for novel modes oftreatment

As summarised in the preceding section, our knowledge ofneurochemical substrates underpinning NS remains patchy,and this restricted knowledge base continues to handicapthe elaboration of novel medication (Section 4). It isdifficult to imagine that neuronal and (poorly understood)glial mechanisms relevant to NS are limited to the handfulof examples evoked above – which themselves pose chal-lenges for therapeutic utilisation, such as the contrastingimplication of dopamine (DA) D2 receptors in NS vs positivesymptoms, and the widespread and heterogeneous role ofglutamatergic transmission throughout the brain (Remington

et al., 2011; Schobel et al., 2013; Poels et al., 2014).Furthermore, it is not necessarily cellular processes impli-cated in the genesis of NS that are the key issue – they maybe developmentally decoupled in time from treatment.Rather, it is those processes involved in the maintenanceand counter-regulation of NS that best provide a potentialfoundation for improved pharmacotherapy. The optimalentrance point, as opposed to a susceptibility gene, wouldbe a modulatory mechanism (facilitatory or inhibitory)upstream, downstream or in parallel to causal processesand still accessible to manipulation. As an analogy, andirrespective of whether 5-HT levels are genuinely deficientin major depression, SSRIs act by interfering with 5-HTreuptake, yet a dysfunction of 5-HT transporters is notincriminated in the aetiology of this disorder (Millan, 2006).

Concerning neural structures circuits related to NS, againwe have the problem of establishing their precise roles inthe maintenance and modulation of NS and, over and abovethis, cerebral regions are not in themselves targets forpharmacotherapy. Drugs acts at molecules, not on Brod-mann areas. Nonetheless, such insights are instructive inseveral ways. First, they provide potentially useful para-meters for clinical development: either imaging biomarkersfor NS and patient stratification, or surrogate measures ofmedication efficacy and target engagement during clinicaltrials. Second, in the context of drug discovery, they suggestwhich large-scale structures should best be modulated andraise the possibility of the back-translation of imaging andEEG findings into animal models for schizophrenia. EEGprocedures are pretty well characterised and, though stillchallenging, progress is rapidly been made into structural(white and grey matter) imaging in rodents, as well as fMRIof neural activity – for example a default mode network hasrecently been described (Bertrand et al., 2010; Broberget al., 2013; Chin et al., 2011; Dodero et al., 2013; Ellegoodet al., 2013; Schobel et al., 2013). This corresponds to the“MATRICS” mantra of identifying comparable and transla-table behavioural, electrophysiological and other readoutsacross animals in order to facilitate drug discovery. Third,cortical neural circuits can be directly recruited for therelief of NS by stimulation strategies and, in a differentfashion, by cognitive-behavioural/psycho-social modes oftherapy likewise evoked below (Section 4.7).

4. Current and prospective therapy ofnegative symptoms: clinical investigations

4.1. Studies of potentially improved treatment ofnegative symptoms: general considerations

In view of their disabling nature and high prevalence, anespecially important topic addressed in this volume is thecurrent treatment of NS and prospects for improved control(Arango et al., 2013;. Miyamoto et al., 2012). In this light,the article by Davis et al. (2014) surveys the effects ofcurrently-available pharmacotherapy, and discusses on-going clinical trials of potential new medication. The articleconsiders several complementary facets of the actions ofdrugs for the management of NS including; methodologicalissues and trial design – for which a consensus is emerging asto how studies should best be performed (Marder and


Kirkpatrick, 2014); efficacy against primary compared tosecondary NS; and the actions of antipsychotics themselves,antidepressants and diverse other classes of agent.

In this respect, it is worth pointing out that: (1) manyolder monotherapy studies of antipsychotics were under-taken with positive rather than NS as the primary readout,and often in acute psychosis and (2) many recent studies of“novel” mechanisms of action were designed for restoringneurocognition in association with antipsychotics, withmeasures of NS essentially “tagged on”, and the effects ofthe drugs alone not always examined (Arango et al., 2013;Davis et al., 2014; Hanson et al., 2010; Hartling et al., 2012;Miyamoto et al., 2012; Murphy et al., 2006; Zhang et al.,2013). Neither of these designs is optimal to detect animpact of a drug (novel mechanism of action) againstprimary NS. Indeed, clinical studies focussing on the influ-ence of monotherapy with innovative agents on primary NSare still rare, but should become more frequent with: pro-active Federal Drug and European Medicines Agency sup-port, improved rating scales (Section 2.1) and agreement oncore criteria like the duration of trial (12 and 26 weeks forPhase II and III respectively), exclusion of comorbid depres-sion, and prior clinical stability for around 4–6 months(Marder and Kirkpatrick, 2014).

The overview below has a very mechanistic “flavour” inhighlighting the actions of selected interventions in relationto their influence upon above-mentioned cerebral circuitsand neurotransmitters implicated in the pathogenesisof NS, with a particular focus on: the PFC, dopaminergic

Table 2 Overview of pharmacotherapeutic mechanisms for throdents.

2nd Generationantipsychotic(5-HT2A4D2)

Neuroleptic D3

antag.5-HT2C

Negativesymptoms

0/+ 0/� + +

Impaired socialcognition

0/+/� 0/� ++ 0/+

Neurocognitivesymptoms

0/+/� 0/� +/++ 0/+

Positivesymptoms

++ + + + 0/�

Otherbeneficialproperties

Low risk of EPS Marked EPSprovoke 21NS

↓ Drug-seeking

Anxiolyantidep

++, Robust activity; +, significant activity; 0, no marked effect; –patterns of data. The putative influence of mechanisms upon NSpotentially-useful actions are also indicated. The table is based mgeneration antipsychotics like olanzapine, and neuroleptics like haloupon NS is, as indicated, modest and variable: they robustly conextrapyramidal syndrome, but no other obvious common benefitsAll specific mechanisms of action refer to receptors. Although feedsymptoms uncertain, D3 antagonists appear of especial interest.facilitator, they have yielded a mixed bag of data in patients and romay be more effective, but this remains to be demonstrated. Fdocumented and await consolidation. GABA A receptor facilitation pexplore additional mechanisms for potentially improving the control ocannibinoidergic modulators and the anti-inflammatory agent, minocyAbbreviation not in text: EPS, Extrapyramidal syndrome.

transmission, N-Methyl-D-Aspartate (NMDA) receptors,GABAergic signalling, oxytocin and serotonin. The profilesof three instructive agents are highlighted in view of theattention that have attracted (and that they are stillattracting), albeit for very different reasons: amisulpride,bitopertin and oxytocin. In addition, in light of the currentinadequacies of pharmacotherapy, quite extensive consid-eration is devoted to “alternative” stimulation-based andcognitive–behavioural–psychosocial approaches which haveyielded promising data and appear to act via the modulationof cortico-subcortical networks underlying NS.

4.2. Limited efficacy of established and recently-introduced antipsychotics for controlling NS

4.2.1. Neuroleptics and second generation(5-HT2A4D2) antipsychoticsDespite their efficacy against positive symptoms in themajority of subjects, and mirroring their limited relief ofimpaired social cognition and neurocognitive deficits, NS arepoorly controlled by currently-available medication such ashaloperidol, and second-generation successors like olanza-pine and risperidone (Table 2) (Citrome, 2013; Hartlinget al., 2012; Leucht et al., 2013; Naber and Lambert,2009; Zhang et al., 2013). Further, induction of extrapyr-amidal symptoms at higher doses of neuroleptics risks theinduction of secondary NS, though this happens only rarelythese days (Remington et al., 2011). It was comparisons to

e potential control of NS as based on pre-clinical studies in

antag. 5-HT7 antag. NMDAfacilitator

GABA Afacilitator

Oxytocinfacilitator

+ + + ++

0 + 0/+ ++

0/+ +/++ + 0

0 + + 0/+

ticressant

Antidepressant ↓Conditionedfear

Anxiolytic ↓ Socialanxiety

potentially deleterious impact. 0/+, 0/� and 0/+/�, Variableis indicated in relation to other cardinal symptoms, and otherainly on findings in rodents, with the exceptions of second-

peridol. The clinical impact of second-generation antipsychoticstrol positive symptom in most patients and do not provoke ahave yet been identified in the treatment of schizophrenia.back from patients is awaited, and putative control of positiveAs regards mechanistically-diverse classes of NMDA receptordents: potentiation of endogenous D-Serine rather than Glycineor oxytocin receptors, promising therapeutic data have beenrincipally refers to the α2 subtype. There is an urgent need tof NS: in this respect, intriguing data have been reported for bothcline. See text and Davis et al. (in press) for further information.


(highish doses of) haloperidol and other agents liable toprovoke an extrapyramidal syndrome that initially impliedthe advantage of clozapine for alleviating NS, but morerecent and longer-term investigations, studies in compar-ison to antipsychotics with a lesser propensity to induce NS,and observations in patients displaying predominant NSsuggest that it is principally effective against secondaryNS, and that its ostensible effectiveness against primary NSpossibly reflects superior control of positive symptoms(Citrome, 2013; Davis et al., 2014; Hartling et al., 2012;Leucht et al., 2013). For second-generation antipsychotics,there is only inconsistent evidence for advantages vs olderagents in terms of efficacy against NS (Leucht et al., 2013;Hartling et al., 2012; Naber and Lambert, 2009; Zhanget al., 2013). This does not, at least in one sense, seem sosurprising. Notwithstanding a potpourri of pharmacologicalactivities, these agents are typified by their common andpreferential 5-HT2A over D2 receptor antagonist profileswhich, while diminishing the risk of an extrapyramidalsyndrome – and perhaps effective for moderating hallucina-tions – would not, on a mechanistic basis, be anticipated tomarkedly reinforce the control of NS (Citrome, 2013;Meltzer, 2012; Miyamoto et al., 2012; Millan et al., 2000).

4.2.2. A role for α2-adrenoceptor blockade inantipsychotic impact on NSSome recently-introduced agents have been orientedtowards the improved control of NS on the grounds of morerelevant pharmacological properties. For example, block-ade of α2-adrenoceptors reinforces frontocortical vs meso-limbic DA release and may, in theory, exert a beneficialinfluence upon certain sub-domains of NS (Brosda et al.,2014; Franberg et al., 2012; Millan et al., 2000, 2012).Asenapine shows high antagonist potency at α2-adrenoceptors compared to other second-generation agents(Franberg et al., 2012), and also behaves as a 5-HT1A and 5-HT6 receptor antagonist which should favour cognitiveperformance (Loiseau et al., 2008; Meffre et al., 2012;Millan et al., 2012). Indeed, reports of beneficial effects ofsublingual asenapine against NS (Weber and McCormack,2009; Citrome, 2013) are intriguing and over 52 – but not 26– weeks it out-performed olanzapine. Nonetheless, it hasnot been authorised for control of NS and, unless under-pinned by more robust findings, putative control of NS byasenapine seems unlikely to be of major relevance in aroutine context (Arango et al., 2013; Buchanan et al., 2012;Citrome, 2013; Potkin et al., 2013). Moreover, the contribu-tion of α2-adrenergic receptor blockade to its actionsremains to be elucidated and several other antipsychoticssimilarly elevate frontocortical release of DA by contrastingmechanisms: 5-HT1A partial agonism (ziprasidone) and 5-HT2C receptor blockade (olanzapine). As for clozapine,relative to modest D2 receptor blockade, it possesses allthree of these actions and robustly increases dialysis levelsof DA in the rodent PFC (Meltzer, 2012; Millan et al., 2000).Thus, it is uncertain how the molecular signature ofasenapine relates to any distinctive influence on NS, andto what extent increases in frontocortical release of DA maybe related to its putative relief of NS (see Section 4.3 for afurther consideration of the role of DA release in the PFC).

4.2.3. Case report: amisulpride and the potentialsignificance of 5-HT7 receptor blockadeThe benzamide derivative, amisulpride, also warrants abrief digression for several reasons, some of them para-doxical.

First, it is authorised for treating NS in several countries(including France, its homeland), despite the fact and theoverall clinical picture for efficacy still remains rathernebulous. Early studies uniformly suggested improvementof NS, yet with ambivalent efficacy against positive symp-toms, while other studies questioned its superiority toolanzapine and haloperidol at equi-effective doses vs posi-tive symptoms (Leucht, 2004; Moller, 2003). More recentwork remains ambiguous concerning any putative andspecific impact upon primary NS (Ahn et al., 2011; Leuchtet al., 2013; Nuss and Tessier, 2010; Zhang et al. 2013).

Second, reflecting its unusually poor blood brain barrierpenetration, despite potent (low nM) affinity at D2/D3 recep-tors, amisulpride has a long onset of action and necessitatesadministration of very high doses of up to 500–1000 mg. It wasproposed that doses at the lower end of this range (50–300) aremost appropriate to controlling NS since they preferentiallyoccupy extra-striatal D2 receptors whereas higher doses (400–1200) are more suitable for moderating positive symptoms inthat they block striato-accumbus populations of D2 receptor(Bressan et al., 2003; La Fougère et al., 2005; Meisenzahl et al.,2008; Moller, 2003). However, there is no obvious reason whythe former mechanism should counter NS, proposed explana-tions of preferential D3 vs D2 receptor blockade and/orantagonism of pre vs postsynaptic D2 receptors have little realfoundation, and amisulpride does indeed occupy striatal popu-lations of D2 receptor at clinically-active doses (La Fougèreet al., 2005; Meisenzahl et al., 2008). Thus, the putativeefficacy of amisulpride against NS would appear to require analternative hypothesis.

Third, while amisulpride can be distinguished from theprototypical preferential 5-HT2A4D2 receptor profile of othersecond generation antipsychotics, recent studies have shownthat it is not entirely “devoid of serotonergic actions” in that itpossesses significant antagonist properties at 5-HT7 receptors.Though other agents like olanzapine also recognise these sites,their 5-HT7 actions are swamped by their additional receptorinteractions at muscarinic receptors, histamine H1 receptorsand α1-adrenoceptors etc. (Citrome, 2013). By contrast, themore discrete antagonism of 5-HT7 receptors may be impli-cated in the actions of amisulpride in animal models related toNS (Abbas et al., 2009; Nikiforuk et al., 2013). Moreover,antagonism of 5-HT7 receptors is associated with antidepres-sant properties in rodents (Hedlund, 2009), which have alsobeen reported for amisulpride (Abbas et al., 2009). This is ofparticular relevance since its apparent relief of NS may besecondary to a reduction of depressed mood (Buchanan, 2007).

Further evaluation of the significance of 5-HT7 receptorblockade to the control of NS may be warranted.

4.3. Antidepressants and reinforcement offrontocortical dopaminergic transmission: a role for5-HT2C receptor inactivation?

As mentioned above, compromised activity of mesocorticaldopaminergic pathways has been implicated in NS, though it


cannot account for the full range of dysfunction. Essentiallyall classes of clinically-active antidepressant increase extra-cellular levels of DA in the FCX in freely-moving rodents viaa variety of mechanisms, including (1) blockade of 5-HTCreceptors and α2-adrenoceptors (mirtazepine) and (2) indir-ect recruitment of 5-HT1A autoreceptors (5-HT reuptakeinhibitors like citalopram) (Alex and Pehek, 2007; Brosdaet al., 2014; Meltzer, 2012; Millan, 2006). The beneficialinfluence of antidepressants upon social anxiety via 5-HT2Creceptor blockade or 5-HT2C receptor desensitization(uptake inhibitors) (Dekeyne et al., 2000; Millan, 2006),and the possibility that relief of depressed mood maysecondarily improve NS, has encouraged studies of the co-administration of antidepressants with antipsychotics(Hanson et al., 2010; Davis et al., 2014).

In fact, the latter point remains the crux of the issuesince, despite modest evidence that augmentation withantidepressants like mirtazapine and citalopram may befavourable in patients with prominent NS, effects aremodest and it is uncertain whether NS are directly impactedor indirectly improved via alleviation of depressed mood(Arango et al., 2013; Davis et al., 2014; Kishi and Iwata,2013; Rummel et al., 2006; Singh et al., 2010; Sommeret al., 2012). It also remains unclear whether the potentia-tion of frontocortical DA release is fundamental to theiractions, since most second generation antipsychotics like-wise promote DA release in the PFC of rodents, despiteinactivity against NS (Meltzer, 2012). Another potentialmechanism of antidepressant action would be strengtheningof reward mechanisms by an as yet poorly-understoodenhancement (not requiring DA release) of postsynapticDA signalling in the nucleus accumbens – though it is unclearwhy this action would not exacerbate psychosis (Millan,2006; Remington et al., 2011). Adrenergic and serotonergicactions mediated independently of DA transmission andaffecting reward, motivation and social behaviour maylikewise be implicated in the actions of antidepressants(Millan, 2006). These issues lie beyond the remit of thispaper yet, irrespective of mechanistic and conceptualdeliberations, an agent that both alleviates depressedaffect and NS would be attractive to patients, so furtherstudy of the clinical impact and mechanisms of action ofantidepressants against NS appears desirable (Chertkowet al., 2009; Kishi and Iwata, 2013).

It is possible that induction of frontocortical DA release isrelated to the actions of other classes of adjunctive agentunder evaluation in schizophrenia such as nicotinic α7modulators, though greater interest has been ascribed totheir putative improvement of cognition rather than NS(Jones et al., 2012; Millan et al., 2012), an issue consideredby Davis et al. (2014) in this volume.

These authors likewise discuss adjunctive use of thevigilance-promoting agent, modafinil, as well as the psy-chostimulants, methylphenidate and lis-dexamphetamine,for the treatment of NS inpatients stabilised on antipsycho-tics. However, their genuine efficacy at acceptable dosesnot risking exacerbation of psychosis remains an issue.In addition, it is unclear to what extent the increase infrontocortical DA and noradrenaline levels (related toenhanced attention) are involved in their putative actionscompared to actions on limbic-striatal pools of DA (favouringmotivation and reward (Lindenmayer et al., 2013; Remington

et al., 2011)). Other mechanisms should not be excluded formodafinil, a particularly promiscuous agent (Millan, 2006;Scoriels et al. 2013).

Overall, there are arguments that strengthening compro-mised mesocortical DA transmission in schizophrenia mightfavourably influence NS, but rigorous proof is lacking, noagent has yet been described that specifically recruits thismechanism to alleviate NS, and this is unlikely to besufficient alone as exemplified by second-generation anti-psychotics which enhance DA release in the PFC of rodentsyet fail to robustly control NS. Note, moreover, thatPhencyclidine (PCP) markedly accelerates the release ofDA in the PFC of rodents (Millan et al., 1999), yet it is hardlyan efficacious treatment for NS! Interestingly, there appearsto be a bell-shaped relationship for DA release in the PFCand function either insufficient or excessive frontocorticaldopaminergic transmission is deleterious to affect, cogni-tion and behaviour, and hence might be linked to NS (Ballaet al., 2012; Millan et al., 1999; 2012; Remington et al.,2011).

Finally, it is possible that mechanisms independent ofmonoamines are involved in the actions of antidepressants,such as interactions with sigma1 receptors and ion channels(Millan, 2006) or, as recently proposed, modulation ofGABAA receptor-mediated signalling (Silver et al., 2011).

4.4. Anxiolytics and positive modulation of GABAAreceptors

As recently reviewed elsewhere (Dold et al., 2013), thoughpossibly useful for short term control of agitation andaggression (Gillies et al., 2013), there is little evidencefor the utility of adjunctive benzodiazepines in the manage-ment of NS. Despite the not unreasonable argument thatrelief of social anxiety might secondarily diminish NS, thisremains to be demonstrated. Benzodiazepines act as posi-tive allosteric modulators (PAMs) at GABAA receptors, whichretain their interest in light of the functional down-regulation of frontocortical chandelier GABAergic interneur-ones in schizophrenia. More specifically, loss of GABAα2subunit on pyramidal neurone axon initial segments maycontribute to the desynchronisation of frontocortico-subcortical glutamatergic circuits (Hines et al., 2013;Lewis, 2012; Stan and Lewis, 2012). Interestingly, a recentfMRI study related alterations in GABAA signalling in the PFCto the modulation of affect, and actions of lorazepam weremore pronounced in schizophrenic patients, perhaps reflect-ing loss of GABAergic inhibition and GABAA receptor super-sensitivity (Taylor et al., 2014). While the GABAAα2 agonist,MK 0777, exerted little benefit on cognitive symptoms inassociation with antipsychotics (Buchanan et al., 2011a), itwould be interesting to evaluate its actions as monotherapyin patients with predominant NS, and as early as possible inthe disorder (Lewis, 2012; Millan et al., 2012).

Interest in GABAA receptor modulation is supported byobservations with the neurosteroid, pregnenolone, of whichthe metabolite allopregnenolone behaves as a PAM atGABAA receptors. Both experimental and clinical datasuggest that adjunctive pregnenolone alleviates NS (andpossibly cognitive symptoms). While its precise mechanismof action awaits clarification and clinical data require


consolidation, this would appear a promising piste forfurther study (Kreinin et al., 2014; Ritsner et al., 2010,2014; Marx et al., 2011) supported by studies in animals(Wong et al., 2012).

4.5. Correcting anomalous glutamatergictransmission: metabotropic and ionotropic (NMDA)receptors

4.5.1. Positive modulation of Glycine B sites on NMDAreceptorsIn fact, there is evidence that pregnanolone itself potenti-ates transmission at NMDA receptors (Marx et al., 2011).This is of relevance since one well-established hypothesis inschizophrenia is that a hypoactivity of frontocortical NMDAreceptors results in reduced activity of chandelier GABAer-gic interneurons, leading in turn to the above-mentioneddisorganisation of neural networks linking cortical and sub-cortical structures (Coyle et al., 2012; Gilmour et al., 2012;Millan, 2005; Stan and Lewis, 2012).

Accordingly, one argument underlying the developmentof metabotropic glutamate 2/3 partial agonists/PAMs forschizophrenia was that, by virtue of their actions atmetabotropic glutamate 2 autoreceptors on glutamatergicneurones, they would “normalise” the activity of disinhib-ited glutatamatergic pathways, as shown by their bluntingof PCP-induced glutamate release in the FCX of rats.Nevertheless, despite promising initial data for both NSand positive symptoms, further clinical studies provedinconclusive (Hashimoto et al., 2013; Stauffer et al., 2013).

A direct approach to restituting the activity of NMDAreceptors surmised to be deficient in schizophrenia is torecruit their positive, modulatory Glycine B site (DeBartolomeis et al., 2012; Hashimoto et al., 2013; Javitt,2012; Millan, 2005). Though no Glycine B drug has ever beentested alone, an extensive series of small scale and larger,controlled multi-centre clinical studies has been undertakenwith: (1) the endogenous agonists, Glycine and D-Serine,(2) the synthetic partial agonist, D-Cycloserine and (3) theendogenous inhibitor of glycine reuptake, sarcosine, inassociation with antipsychotics other than clozapine – whichitself reinforces NMDA transmission, thereby compromisingstudy outcome (Millan, 2005). Briefly summarised, thesestudies have yielded a chequered pattern of data permittingno definitive conclusions (nor, of course, drug authorisations)yet with the most promising suggestion of efficacy – some-what counter-intuitively – for NS rather than for cognitive orpositive symptoms, and with greater activity associated withfull rather than partial agonism, exerted either directly orvia suppression of glycine reuptake (Buchanan, 2007; DeBartolomeis et al., 2012; Gilmour et al., 2012; Javitt, 2012;Kantrowitz and Javitt, 2010; Lane et al., 2010; Singh andSingh, 2011; Weiser et al., 2012).

4.5.2. Case report: the Glycine 1 transporter inhibitor,bitopertin – hot off the pressThese clinical observations and the above-evoked notion thatNMDA receptor hypoactivity may be pivotal to the aetiologyof schizophrenia, prompted the development of bitopertin,a highly selective ligand at Glycine 1 transporters, which arelocalised in the vicinity of neurones bearing NMDA receptors

in the PFC and other cerebral regions (Alberati et al., 2012).Guided by PET studies of target engagement, a double-blind,placebo-controlled, 8 week randomised study of subjectswith predominantly NS revealed significant effects of 10 and30 mg in the NS factor score of the PANSS and in ClinicalGlobal Improvement, whereas a higher dose of 60 (mirroringthe “inverted U” dose-response of direct ligands (DeBartolomeis et al., 2012)) did not separate from placebo(Umbricht et al., 2010).

The promising – though not overwhelming – Phase II data,coupled to an excellent safety profile, encouraged thedecision to simultaneously launch three Phase III add-ontrials in patients with persistent and predominant NS. Threefurther and large add-on trials with doses of 5–20 mg ofbitoperin were also initiated in patients with suboptimalcontrol of all symptoms, likewise over 52 weeks, and in thesame centres. The primary endpoint of the three NS trialswas the PANSS at 24 weeks.

Frustratingly, Roche have just revealed that the initialoutcome of the bitopertin studies for persistent and pre-dominant NS was negative. No other details nor analyses areas yet available, but it is important to consider why thesestudies may not have succeeded overall in view of: theirconsiderable interest; the inevitable fall-out; and potentialinsights into putatively responsive patient sub-groups andrelated therapeutic strategies.

4.5.3. From FCX pools of Glycine to D-Serine forimproved control of NSIt may be that use of newer NS metrics mentioned above(Section 2.) would have been more successful – and sensitive– and a focus on NS sub-clusters might also have been moreinsightful. As regards mechanistic explanations, stress-induced glutamate release in hippocampus is implicated inthe induction of psychotic states, so actions at NMDAreceptors in this region may be deleterious (Schobelet al., 2013). In addition, we have little idea of howfacilitating NMDA activity in other subcortical structuresimplicated in the genesis and putative control of NS, likethe dorsal striatum, nucleus accumbens and amygdala, mayaffect their expression. A further issue is the preferentiallocalisation of Glycine 1 transporters in hindbrain vs fore-brain stuctures, where they more markedly elevate extra-cellular levels of glycine than in the PFC itself (Gobertet al., 2011 and pers.comm.). Perhaps most fundamentally,however, following initiation of the bitopertin studies,evidence emerged that D-Serine rather than glycine maybe the principle endogenous ligand gating NMDA receptorscontrolling synaptic plasticity in PFC (Papouin et al., 2012;Fossat et al., 2012). Though such observations are mostobviously related to the control of cognition, they areultimately also germane to NS.

Thus, apart from the all too familiar message that apositive Phase II outcome is no guarantee of Phase IIIsuccess, there may be something of a silver lining. Ratherthan fruitlessly searching for other ligands that putativelyincrease levels of endogenous Glycine at NMDA receptors inPFC, greater success may be acquired with strategies thatpreferentially elevate extracellular levels of D-Serine.A “bitopertin-mimic” strategy aimed at increasing ambientlevels of D-Serine will depend upon further characterisation


of the transporters clearing D-Serine from the synaptic cleft(Hashimoto et al., 2013; Millan, 2005; Sacchi et al., 2013).Alternatively, D-Serine signalling may be strengthened byinhibition of the degrading enzyme, D-Amino-acid-Oxidase(Ferraris and Tsukamoto, 2011). Indeed, very recently, theD-Amino-acid-Oxidase inhibitor, benzoate, was found to beeffective in both PANSS total and NS sub-scale scores in a6 week, double-blind, placebo-controlled add-on trial ofchronic schizophrenia (Lane et al., 2013). Clearly, confirma-tion of these encouraging data in more extensive trials oflonger duration, and employing more selective inhibitors,would be desirable.

A further strategy would be to inhibit the synthesis ofkynenurenic acid, an endogenous antagonist of the GlycineB sites which likewise behaves as an antagonist of nicotinicα7 receptors, suggesting a double therapeutic advantage forcontrolling NS – and neurocognitive impairment (Alexanderet al., 2012; Jones et al., 2012; Schwarcz et al., 2012).

4.6. Recruitment of cortical networks bystimulation techniques

The traditional notion of hypofrontality per se as a causalfactor underlying NS and other non-positive facets ofschizophrenia has been superseded by a more sophisticatedand refined model of state, sub-territory and time-dependent dysfunction expressed in interaction with corti-cal and sub-cortical networks (Section 3.2). Anomalousoperation of the PFC, including hypoactive NMDA receptors,down-regulated GABAergic interneurones, desynchronisedpyramidal neurones and blunted DA release are nonethelessimplicated in the pathophysiology of schizophrenia, includ-ing NS (see above). Not least owing to the long kinetics ofnew drug development, and limited progress to date withnew classes of agents, there is increasing interest in otherstrategies for modulating the action of the PFC and furthercortical regions to therapeutic ends.

High frequency (410 Hz) rTMS of the PFC, in particular theDLPFC, enhances brain metabolism and excitability. It hasbeen reported (in several though not all studies) to beeffective in the relief of NS when applied for several weeksearly in the course of schizophrenia, with an impact on severalsubdomains of NS (except alogia), and independent of anychange in depressive symptoms (Barr et al., 2012; Prikrylet al., 2013; Prikryl and Kucerova, 2013; Shi et al., 2014).Interestingly, there is some evidence that its actions involvemodulation of NDMA receptors and striatal DA release, possiblyto favour motivation (Pell et al., 2011; Stratella et al., 2001).

Transcranial, direct current stimulation involves theapplication of a weak electric current via two electrodesto increase neuronal excitation in the underlying regions ofthe brain. Despite some conflicting observations, it holdspromise for the monotherapy of major depression (Berlimet al., 2013), can promote social cognition (when appliedover the temporo-parietal junction) (Santiesteban et al.,2012), and is currently under study for the treatment of NS(and auditory hallucinations) of schizophrenia. Electrodesare placed over the left DLPFC (anode) and temporopartie-tal junction (cathode), and recruitment of cortico-subcortical networks appear to be involved in its beneficialimpact on NS, though this awaits confirmation and the

effects of direct current stimulation depend, like those ofrTMS, upon the precise parameters of stimulation employed(Agarwal et al., 2013; Brunelin et al., 2012).

Ongoing studies should help standardise stimulation para-meters and clarify the genuine utility of these approachesfor recruitment of frontocortical mechanisms and thealleviation of NS.

4.7. Cognitive and psychosocial interventions forrelieving NS: implication of frontocortical circuits

A different approach to restore the functionality of cortico-subcortical circuits disrupted in schizophrenia consists inthe application of interrelated – and sometimes combined –

“cognitive-behavioural-psychosocial” therapies. A diversepalette has been described, certain of which are proposedfor the treatment of NS and/or impaired neurocognition anddeficits in social cognition. They are undertaken eitherindividually or as group therapy, and almost invariably ontop of antipsychotic medication to guarantee robust controlof positive symptoms (Barsaglini et al., 2014; Elis et al.,2013; Johnson et al., 2013; Valencia et al., 2013).

The behavioural training (practise) technique of CognitiveRemediation Therapy (CRT) aims to endurably rekindle keyskills related to neurocognition and social cognition, and hasbeen shown to recruit a distributed network of frontocorticalstructures including the inferior frontal gyrus, DLPFC andanterior cingulate cortex, all implicated in NS (Section 3.2)(Bor et al., 2011; Haut et al., 2010; Wykes et al., 2011). The(modest) amelioration of NS by tailored programmes of CRTincludes an decrease in avolition and may be related to anenhancement of motivation (Elis et al., 2013; Klingberg et al.,2012; Sanchez et al., 2014; Wykes et al., 2011). Thoughenhanced executive function may help improve patient out-come following CRT, its contribution remains unclear.

A rather different approach is represented by CognitiveBehavioural (or simply Cognitive) Therapy (CBT) – the first“alternative” mode of therapy to be formally endorsed bynational organisations both in the UK and US (Buchananet al., 2010; Dixon et al., 2010, Jauhar et al., 2014). Thistechnique more specifically targets poor motivation andanhedonia together with negative and defeatist beliefs, andpromotes the active engagement of patients to attaindefined goals: it can be oriented to an individual's strengthsand has as a core objective improved functional status and,if possible, recovery (Beck et al., 2013; Grant et al., 2012).Several papers have reported a positive though moderateimpact of CBT on NS (mainly in association with antipsycho-tics), with a reduction of apathy and enhanced motivation,including studies in patients with predominant NS. Benefitsdepend upon the conditions of application, individual ses-sions are more effective than group therapy, not all studieshave been successful and overall effect size is modest for NS– and positive symptoms (Elis et al., 2013; Jauhar et al.,2014; Morrison et al., 2014). Also, just how specific andmarked the impact of CBT on NS is compared with CRTremains to be clarified (Klingberg et al., 2012). Nonethe-less, in light of evidence for enduring post-treatmentefficacy in major depression, where it has been moreextensively studied, it is interesting that effects maypersist after discontinuation in schizophrenia – though this


observation should not be conflated with any notion of apermanent cure (Cuijpers et al., 2013; Elis et al., 2013;Grant et al., 2012; Hollon et al., 2006; Sarin et al., 2011).Underpinning the significance of higher level operations inthe mediation of CBT, there is evidence for a role offunctional changes in the striatum and other cerebralregions like the insular cortex in transducing its effects onemotional processing, though the relationship of suchchanges to NS awaits clarification (Kumari et al., 2011).

A final and complementary intervention worth highlightinghere is Social Skills Training which aims to moderate NS by theuse of intensive and structured modules that educate patientsabout skills needed to improve their social function in thecommunity, including reciprocal use of verbal and nonverbalexchanges. A reinforcement of social cognition is evidently animportant element of this approach for countering NS, under-scoring arguments made above concerning their close inter-relationship and underpinning the notion that NS lie at leastpartially downstream of social cognition/processing (Section2.3) (Figure 4) (Elis et al., 2013; Valencia et al., 2013). Evidenceis accumulating to suggest the utility of group Social SkillsTraining for relief of NS (Elis et al., 2013; Rus-Calafell et al.,2013). Interestingly, coupled to family psychoeducation, SocialSkills Training was a lynchpin of the broad-based early-inter-vention “OPUS” programme in Denmark which reported positivefindings for the improvement of NS in individuals with first-episode psychosis (Hastrup et al., 2013; Nordentoft et al.,2014).

As for CRT and CBT, standardisation is an issue with SocialSkills Training, and it remains to be determined just howgeneral, robust, broadly-applicable and cost/time-effectiveeach of these interventions would be when used on a largerscale outside the framework of controlled and specialist-coordinated trials, but cautious optimism seems warranted(Jauhar et al., 2014). Further, by analogy to the uniting ofpharmacotherapy and non-drug based strategies, combiningcognitive-behavioural-psychosocial therapies could poten-tially boost efficacy, as reflected by Integrated Psychologi-cal Therapy, though no rigorous comparative data are yetavailable (Elis et al., 2013; Roder et al., 2011). Intriguingly,“cognitive-behavioural-psychosocial” therapies appears toimprove the real-world function of patients, and vocationalreintegration itself moderates NS, implying a sort of“positive feedback” (Bio and Gattaz, 2011).

As a final remark, while the focus above was on the PFC,certain alternative therapies like Social Skills Training likelyfacilitate social communication and motivation by promot-ing oxytocin release, itself deficient in NS. Yoga has beenclaimed as useful for treating NS and, notwithstanding anyreservations concerning the rigour of the underlying studies,yoga therapy aimed at improving socio-occupational func-tion was reported to increase plasma oxytocin levels(Jayaram et al., 2013). Thus, we may conclude this over-view of potential routes to superior therapy of NS with abrief consideration of the use of this hormone itself.

4.8. Oxytocin: countering NS via reinforcementof social cognition/processing

As pointed out above (Section 2.3), the interface between NSand impaired social cognition-processing is somewhat blurred

with several communalities in terms of their expression,underlying causes and neural substrates. It might be arguedthat certain domains of NS lie at least partially downstream of– and are driven by – impairments in social cognition as regardsboth of its components, emotional processing and Theory ofMind. Hence, reinforcing social cognitive should have abeneficial influence upon NS. While the pharmacology of socialcognition is not well developed, based on both experimentaland clinical work, at least one critical modulator has beenidentified, oxytocin. This neuropeptide possesses its own classof centrally localised oxytocin receptor, and interacts with avariety of neuromodulators in the expression of its actions,including 5-HT and DA in the nucleus accumbens and amyg-dala, respectively (Goodson and Thompson, 2010; Meyer-Lindenberg et al., 2011; Millan and Bales, 2013; Millanet al., 2012; Rosenfeld et al., 2011).

As discussed elsewhere, though its long-term actionsappears to be rather more complex and less unitary thanoriginally thought (De Berardis et al., 2013; Huang et al.,2014; Modabbernia et al., 2013), oxytocin is a powerfulfacilitator of social cognition under a diversity of conditions.By analogy to autism, intra-nasal administration of oxytocinfavours at least some components of social cognition inschizophrenia, notably Theory of Mind and emotion recogni-tion (Davis et al., 2013; De Berardis et al., 2013; Fischer-Shoffy et al., 2013; Millan et al., 2012). Further, certainstudies suggest a beneficial impact of adjunctive, long term(several weeks) – but not single dose (Davis et al., 2013) –

administration of intranasal oxytocin on NS in patientsstabilized on antipsychotics (Feifel et al., 2010; P.R. Leeet al., 2013; Modabbernia et al., 2013; Pedersen et al.,2011). These studies require consolidation and it is unclear:exactly which populations of patients are most likely torespond; in what context (possibly social enrichment); andas concerns which dimensions of NS – though avolition andanhedonia have been proposed (P.R. Lee et al., 2013). Italso remains to be established via which neuronal substratesoxytocin exerts its actions. Animal studies suggest a rolefor: (1) the nucleus accumbens in interaction with rewardmechanisms and 5-HT (Dolen et al., 2013) and (2) theamygdala-PFC in interaction with dopamine and emotionalprocessing (Rosenfeld et al., 2011), though these networksare likely interrelated. Oxytocin may also counter NS bypromoting social motivation (Gordon et al., 2011), or via amore strictly social cognitive mechanism such as anenhancement of Theory of Mind (Section 3.6) (Churchlandand Winkielman, 2012; Davis et al., 2013; Millan et al.,2012; Pedersen et al., 2011).

To echo a comment made above, irrespective of mechanisticniceties, a dual improvement in social cognition and NS wouldbe particularly appealing for restoring function both in schizo-phrenic subjects and in at-risk individuals prior to diagnosis.This promising avenue of research will hopefully soon beconsolidated and accelerated by the clinical availability ofnon-peptidergic PAMs at oxytocin receptors (Ring, 2010).

4.9. Prospects for improved clinical evaluationand treatment of NS

As evoked above, a common feature of pharmacotherapeu-tic, stimulation and cognitive–behavioural–psychosocial


techniques for countering NS is their recruitment of mech-anisms integrated in cortico-subcortical circuits, especiallythose involving the PFC. However, the precise neurochem-ical pathways engaged remain to be further clarified andthey presumably differ amongst various clinical strategies,each of which acts via a multiplicity of neural substrates.

It should also be stressed that, despite encouragingresults, no medication or alternative approach under inves-tigation promises to become a panacea in terms of universaland robust efficacy, cost effectiveness, ease of application,use as monotherapy and long-term control of NS togetherwith other classes of symptom. Despite all this, there aregrounds for guarded optimism.

First, from a methological perspective, there is an emer-ging consensus as to how focussed clinical trials should beoptimised for revealing a potentially beneficial influence ofa novel candidate drug against primary NS: inclusioncriteria, length of treatment and many other variables arebecoming increasingly well defined to favour the likelihoodof a successful outcome (Marder and Kirkpatrick, 2014).In addition, the European Medicine and Federal DrugAgencies appear increasingly open to dialogue concerninginnovative trial designs and novel concepts for treatingNS and other unmet needs in schizophrenia. Furthermore,several novel rating scales under exploration appear tobe more reliable and sensitive than conventional tools formonitoring the benefits of therapy (Section 2.1) (Malaspinaet al., 2014; Marder and Kirkpatrick, 2014). Within thisframework, it should soon become possible to differentiatethe impact of novel agents upon distinctive NS sub-domainslike diminished emotioanal expression vs avolition whichwill not necessarily be modulated in parallel, in line withtheir distinct pathophysiological substrates (Section 3).

Second, trial failures can be demoralising when hopeswere high and studies well-designed and well-conducted,as exemplified by bitopertin. However, rigorous analysis offull clinical data sets may reveal hidden beneficial actions,for example on sub-domains of NS or in specific subpopula-tions – and even permit re-purposing towards alternativepathologies. Additional clinical and experimental explora-tion of the “NMDA/glycine” hypothesis may reorient “R andD” in a more promising direction – in the case of bitopertin,one might argue, from glycine towards D-Serine basedtherapies (Section 4.5). Mirroring a plethora of recent trialsof potential pro-cognitive agents, bitopertin was tested inassociation with conventional antipsychotics but they maywell interfere with any benefical influence on impairedneurocognition, NS and deficits in social cognition (Section2.1) (Millan et al., 2012). Two non-exclusive solutions maybe evoked. (1) Integrate a novel and promising mechanismof action into a multi-target profile incorporating severalcomplementary pharmacological properties to underpinefficacy against NS and likewise control other classes ofsymptom. (2) Should a new agent (mono or multitarget) notbe suited to the control of positive symptoms, the drugconcerned can be tested either in patients presenting withpersistent NS or during the prodrome: in the latter instance,it would relieve the distress of prominent NS and potentiallyreduce transition to frank psychosis (Fusar-Poli et al.,2013a; Sabbag et al., 2011).

Third, as indicated above, pharmacotherapy is not theonly avenue towards improved therapy for NS: alternative

strategies warrant systematic evaluation from corticalstimulation, to a suite of “cognitive-behavioural-psycho-social” interventions exploited alone and/or in “packages”(Elis et al., 2013). As argued elsewhere for other classes ofsymptom – and disorder (Chou et al., 2012; Millan, 2006,2012; Valencia et al., 2013) – it may prove more productiveto consider the association of a new pharmacologicalmechanism of action with a non-pharmacotherapeuticstrategy for optimal expression of advantages, rather thanpersisting in adjunctive use with conventional antipsycho-tics. Whether this goal is attainable in the course of initialclinical development remains to be seen but, as indicatedabove, imaginative trial design together with supportfrom regulatory agencies could eventually make suchstudies, like drug evaluation in the prodrome, a realisticproposition.

Finally, improved knowledge of the pathogenesis of NS interms of the cerebral circuits involved and their molecularunderpinnings will hopefully reveal novel targets forimproved pharmacotherapy (Table 2). In addition to increas-ingly refined studies in patients, success will depend uponthe progressive improvement of animal models, as outlinedin the following section.

5. Experimental studies of negativesymptoms: readouts and animal models

5.1. Animal models for studying NS: generalconsiderations

As intimated in the previous section, an important issueaddressed in this Special Volume is the use of experimentalparadigms for modelling NS, for elucidating their pathophy-siological substrates, and for the identification and valida-tion of novel agents for their alleviation (Figure 6). It wouldbe naïve to imagine that one could fully reproduce NS andthe uniquely human condition of schizophrenia in an animal.Accordingly, we are concerned with models for rather thanof NS and schizophrenia, and in each case designed to shedlight on specific underlying mechanisms and symptoms – it isunlikely than any hypothetical “one-stop” paradigm will befound. In this light, apart from core considerations of modelreliability and reproducibility, it is useful to keep in mindthe familiar criteria of: (1) face value (models for NS shouldat least partially mirror observations in human patients);(2) construct value (they should reproduce or mimic at leastcertain pathophysiological (neural and neurochemical)mechanisms underpinning NS) and (3) predictive value(the influence of pharmacotherapy on measures for NSshould correlate with and anticipate clinical activity inpatients). The latter goal is the most challenging of all foressentially any animal model, but particularly so for NSsince no robustly-active therapeutic agent is known (Section4). As sketched out below and analysed in this SpecialVolume, fulfilling the other two criteria is likewise anythingbut straightforward (Der-Avakian and Markou, 2012;Gururajan et al., 2010; Pratt et al., 2012; Trezza et al.,2011a, 2011b).

The two interrelated and cores themes are. First, read-outs relevant to NS, of which the most accessible in rodentsare social behaviour – as discussed by Wilson and Koenig

Models(can be combined)

General read-outs(preferably multiple)

NS Sub-domains(may overlap)

Pharmacologicala:- NMDA antag.

- Cannabinoid (CB1) ago. - LSD

- Haloperidol?

Geneticb:- Neuregulin-1 OE/KO

- MHC-2 KO- D2R OE/D3R OE- NMDA (NR1) KD- Oxytocin R KO- CNVs (22q11.2)

Developmental:- Prenatal stress

- Peri-natal Poly I:CNeonatal VH lesions

- Neonatal PCP - Adolescent isolation

Behavioural:- Locomotion (approach/exploration etc)

- Operant lever pressing- Place conditioning - Maze learning

- ICSS - Sucrose consumption/preference (hedonic state)- Communication - USV, tactile, olfactory

- Nest-building

Mechanistic (cells to circuits):- Biochemistry

- Neurochemistry (dialysis)- Electrophysiology

- Structural/functional imaging

Asociality:- Soc. preference- Soc. interaction- Soc. place pref- Adolescent play

Blunted affect:- USV

- Touch/grooming- Body movements- Gestures/Gazea

Amotivation/Anhedoniab:

- PR responding (effort)- Planned behaviour

- Adolescent play- Sex. behaviours

aPrimates

bSingle gene -examples,Copy Number Variants (CNV)

aAcute, sub-chronic, long-term and withdrawal

bAnticipatory

Figure 6 The diversity of experimental models and readouts available for experimental study of various sub-domains of NS.While procedures for studying asociality and amotivation are fairly well-established, blunted affect is far less accessible – fewspecific readouts have been proposed, and alogia may be inaccessible. In most published accounts, only one or two readouts havebeen employed and a single model for schizophrenia, with little effort to interlink behavioural observations to potential neuralsubstrates. Hence, considerable work remains to be undertaken to improve the experimental study of the causes and modulation ofNS, and there are many promising opportunities for progress. Abbreviations not in text: OE, overexpression; KO, knockout, KD,Knockdown (hypomorphic mice); R; Receptor; V Hipp, Ventral hippocampus; I:C, Inosine:Cytosine; Soc, Social; and PR,Progressive ratio.


(2014) – and motivation/reward-driven behaviour – asconsidered by Barnes et al. (2014). Second, animal modelsfor the induction of NS-like behaviours provoked bypharmacological (Neill et al., 2014), developmental(O’Tuathaigh et al., 2014) and genetic (Moser, 2014) manip-ulations. The following paragraphs: underscore the majormessages of these papers, present several procedures out-side their scope, highlight some new and insightful observa-tions, discuss prospects for improved experimental study ofNS and – a little provocatively – ask whether the endlesshand-wringing over the ostensibly unique difficulties facedin setting up models and readouts of NS in animals isgenuinely legitimate compared to other cardinal symptomsof schizophrenia.

5.2. Models for NS compared to cognitive andpositive symptoms in rodents: a unique challenge?

As mentioned above, it is bemoaned – or at least intrinsi-cally assumed – that modelling NS of schizophrenia isinherently more complicated than other dimensions of thedisorder. However, it is worth reflecting as to whether thisgenuinely the case, in particular in comparing NS to positivesymptoms.

Procedures for interrogating neurocognitive domains likeattention, working memory and executive function arefairly well-established in rodents – with several translatableto humans and their disruption can be studied in a variety of

experimental models for schizophrenia, despite the con-tinuing challenge of social cognition (Buchanan et al.,2011b; Millan and Bales, 2013).

As regards positive symptoms, the tacit assumption isthat animal models are pretty undemanding. However, thisseems based on the unspoken notion that easy to treat inpatients must mean easy to model in animals. Yet, asregards “face value”, delusional thinking and paranoia seemquite a long way removed from motor readouts like climbingbehaviour (apomorphine), avoidance responses (condi-tioned) and hyperactivity (psychostimulant-induced) in rats,while recording head twitches in mice likewise seems a farcry from auditory hallucinations in patients (Castagné et al.,2009). These empirical measures reflect activation of D2and 5-HT2A receptors, respectively, paralleling the antago-nist properties of currently-used second generation anti-psychotics at D2 and 5-HT2A receptors (Section 4.1)(Meltzer, 2012). On the other hand, other mechanismsinvolved in the induction of positive symptoms like disrup-tion of GABAergic and glutamatergic transmission in FCX arenot integrated into these models. This is a critical pointsince refractory patients may have a more “glutamatergic”than dopaminergic pathology and it is the resistance totreatment of positive symptoms in up to 30% of patients thatis the genuine problem today: this notion of constructvalidity is poorly integrated into current models (Gilmouret al., 2012; Hashimoto et al., 2013; Javitt, 2012; Leuchtet al., 2013; Poels et al., 2014). Though NMDA antagonistsare widely used for characterisation of drug actions against


positive symptoms – as well as NS (Neill et al., 2014) – theylikewise have serious limitations (Javitt, 2012; Millan et al.,1999; Pratt et al., 2012) and animal models for DA-independent and refractory positive symptoms do notappear to be even on the horizon.

Thus, we may be naive in considering models of positivesymptoms as unproblematic: other than predictively fordetecting D2 receptor blockade, they are well off the radaras regards the current therapeutic need to find agents ofgreater efficacy in resistant patients. In addition, run of themill models have tended to foster a mono-dimensional DA-centric approach to treatment of positive symptoms anddrug screening for the best part of 50 years. Putativemodels for positive symptoms irresponsive to D2 (and5-HT2A) antagonists may be the way to go if we wish toameliorate treatment of positive symptoms. Yet it is pre-cisely the criteria of good responsiveness to clinical-usedagents that paradoxically may be impeding progress in thedevelopment of procedures for studying “resistance”. Lackof effect of a clinically-used agent tends to downgrade themodel and render claims of positive actions of drugs withnovel mechanisms of actions suspect – at least in the eyes ofthose making key decisions for drug development. Some-thing of a Catch 22, since if the drug does actually work in aconventional model it risks being unoriginal and lacking ininherent advantages over existing agents.

5.3. Readouts of NS-like behaviours in rodents

As for putative models for NS, the situation is radicallydifferent: “validation” by agents robustly active in theclinic is unfeasible – there simply are not any. Proof ofirresponsiveness to haloperidol and other currently-usedantipsychotics is simple to show, yet hardly convincing asan alternative strategy. While a modest response toclozapine, amisulpride, glycine reuptake inhibitors oroxytocin might be considered as encouraging (Section4), there are no persuasive means of therapeutically-relevant, pharmacological validation. The predictive sta-tus of animal work on NS is then, unfortunately, nebulous,and will remain so until we finally find medication that isconsistently effective against NS in patients. On the otherhand, there seems no reason not to promote the constructvalidity of models and readouts by back-translating fromhuman work (Section 3) and evaluating the status of, forexample, frontocortical-temporal and cortico-striatalnetworks; GABA-glutamate coupling; DA release, andoxytocinergic transmission. This would necessitate anoverdue mechanistic expansion of readouts from thebehavioural measures classically used today (Figure 6).For example, how do alterations in social motivation andbehaviour relate to oxytocin release and to electrophy-siological measures of changes in fronto-temporal net-work activity, and how do alterations in effort invested togain a reward relate to changes in the striatal release ofcannabinoids and altered fronto-striatal circuit function(see further below, Section 5.8).

On the other hand, concerning face value, the status ofanimal studies of NS may not be as disastrous as one mightthink, despite the fact that our knowledge of their aetiologyis limited (Section 3). Most obviously, asociality is accessible

via direct measurement of active social interaction(Gururajan et al., 2010; Trezza et al., 2011a, 2011b) whichcan be modified by a variety of manipulations from the pro-psychotic agent, PCP (Neill et al., 2014), to developmental(Moser, 2014) and genetic (O’Tuathaigh et al., 2014) models.As discussed in these papers, and in the keystone article ofWilson and Koenig (2014), it is crucial to control for theinfluence of diverse factors that are not an intrinsiccomponent of the asociality of NS, like attention, motorperformance, sensory status, aggression and fear. The sameholds for studies of mice in which the widely used 3-chamber test of social preference-sociability-social affilia-tion has been undertaken (Silverman et al., 2010; Millan andBales, 2013). In all procedures, as accentuated above, it isimportant to control for the intertwined factor of socialcognition (Millan and Bales, 2013). In any event, from theperspective of face value, social behaviour in rodentsclearly does provide a framework for examining the pertur-bation and restoration of a core facet of NS, asociality.

As regards the hedonic state of consummatory pleasure(liking), this is only modestly compromised in schizophreniawhereas the anticipation of reward (wanting) and theinitiation of behaviours to acquire it are strongly impacted(Foussias et al., 2014). Measures of each of these dimen-sions of reward – and of the underpinning cognitive opera-tions – have been well-studied in rodents, including socialreward (Trezza et al., 2011a, 2011b), as discussed by Barneset al. (2014).

To summarise, the study of NS is certainly not simple,blunted affect still represents something of a conundrumand alogia (strictu sensu) may be intransigent to investiga-tion in rodents. Nevertheless, there are sufficient experi-mental handles for progress to be made, especially asregards the sub-domains of asociality and amotivation(Section 5.8). The principle handicap remains the lack ofan agent clinically effective against NS for test validation.

5.4. Induction of NS-like behaviours in diversemodels for schizophrenia

Historically speaking, there has been a shift from pharma-cological (psychostimulants, hallucinogens, NMDA antago-nists etc.) to neurodevelopmental to genetic models forschizophrenia, with a recent tendency to reassert theprimacy of developmental models and, ideally, to super-impose them on a genetic background (Section 5.8.3).Some environmental manipulations, like prenatal stress orperinatal inflammation, are not specific for modellingschizophrenia vs other psychiatric disorders – depressionand autism, respectively (Fatemi and Folsom, 2009; Meyerand Feldon, 2010; Millan, 2013). Further, certain risk geneslike Disrupted in Schizophrenia-1 and Neuregulin-1 areassociated with other disorders – bipolar disorder andautism, respectively (Meyer and Feldon, 2010; Millanet al., 2012; Pratt et al., 2012; Sullivan et al., 2012). Thisshould be borne in mind in interpreting the significance ofNS-like symptoms. It should also be stressed that devel-opmental, genetic and pharmacological models usuallyaim to mimic a risk factor posited to increase suscept-ibility for – or even provoke – schizophrenia, rather thanjust NS per se. In this sense, it might be argued that there


are no genuine animal models for NS as such. Rather, NS-like behaviours and responses are examined in parallelwith other symptoms and, over the past decade or so, theemphasis has been on a positive-like phenotype andneurocognitive disruption with only secondary attentiondevoted to NS – and social cognition (Millan et al., 2012;Pratt et al., 2012). This has somewhat biased the litera-ture and even studies of social interaction (examinedfairly routinely) have often not been sufficiently rigorousin dissecting out components directly related to NS, alimitation articulated by Wilson and Koenig (2014), Moser(2014), and O’Tuathaigh et al. (2014) in this volume.

Accordingly, despite a revival of interest in NS, theliterature is still fairly meagre as concerns their character-isation in animal models for schizophrenia. Further,very few studies have shown that NS-like observations canbe normalised by pharmacological treatment, and evenfewer have examined the actions of agents other thanantipsychotics.

5.5. Social interaction and other measures ofsocial behaviour

5.5.1. Pharmacological proceduresUnder conditions minimising anxiety, active and non-aggressive social interaction is fairly straightforward torecord in rats, and it is consistently disrupted by acuteand sub-chronic administration treatment of NMDA recep-tor open channel blockers like PCP and ketamine, with theeffects of long-term exposure sometimes outlastingadministration schedules (Gururajan et al., 2010; Koroset al., 2007; Neill et al., 2010, 2014; Sams-Dodd, 1995;Wilson and Koenig, 2014). This disruption of social inter-action has frequently been termed “social withdrawal”,though it is not obvious that any active process of “with-drawal” per se is actually taking place, and it is difficultto assert with confidence that diminished social motiva-tion or reward is involved. Nonetheless, effects of NMDAreceptor antagonists appear to be specific and, in view oftheir ability to induce NS in humans, it is not unreason-able to consider this procedure as relevant to theasociality of schizophrenia (Gururajan et al., 2010;Javitt, 2012; Neill et al., 2014). Interestingly, and mirror-ing their clinical profiles in patients, haloperidol does notprevent perturbation of social interaction by PCP whileclozapine and second generation antipsychotics exertinconsistent effects (Gururajan et al., 2010; Neill et al.,2014; Wilson and Koenig, 2014). Curiously, amisulpridedoes not appear to have been examined and, irrespectiveof ambivalent clinical findings, the glycine reuptakeinhibitor, bitopertin, would be of interest to examine.Conversely, there is evidence that 5-HT1A agonists coun-ter impairment of social interaction by NMDA receptorantagonists (Boulay et al., 2004) and Cholecystokininreceptor 2 antagonists are likewise effective – sincebenzodiazepines were inactive, their mutual anxiolyticproperties are presumably not relevant (Seillier et al.,2013). Of special interest, oxytocin reverses the suppres-sion of social interaction by PCP via an action in theamygdala, one putative site of action for enhancement ofsocial behaviour: the actions of oxytocin are mimicked by

vasopressin which, in a context-dependent manner, alsoexpresses pro-social properties (Goodson and Thompson,2010; Katayama et al., 2009; Lee et al., 2005; Matsuokaet al., 2005).

It may be remarked that antagonists at mGluR5 recep-tors, which are functionally coupled to NMDA receptors(Millan, 2005), likewise reduce social interaction in ratsthough this potential model has not apparently beenexploited for the characterisation of mechanisms relatedto NS (Koros et al., 2007).

As regards other mechanisms known to control socialbehaviour (and reward) and relevant to NS, cannabinoidsare of particular interest in view of their effects in humans,and since PCP decreases social interaction at least partiallyby modulating endocannabinoid transmission in the PFC –

and probably amygdala (Seillier et al., 2010, 2013). Notleast as regards social behaviour, the pharmacology ofcannabinoids is complex (and confusing) but, as reviewedby Gururajan et al. (2010), tetrahydrocannabinol (the mainactive constituent of cannabis) and acute exposure tosynthetic agonists generally suppress social interaction.Their effects are blunted by the (non-psychotropic) antago-nist, cannibidiol, and by drugs interfering with endogenouscannibinioid metabolism (Trezza and Vanderschuren, 2008).Though the potential influence of cannibinoidergic mechan-isms on anxiety should not be neglected, comparisons of themodulation by cannibinoid agonists vs NMDA antagonists ofsocial interaction could offer novel insights into the originsand control of NS (Almeida et al., 2013; Gururajan et al.,2010; Seillier et al., 2010, 2013).

Another agent of interest is the hallucinogen, Lysergicacid diethylamide (LSD), which behaves as a potent agonistat 5-HT2A (and D2) receptors. LSD produces a discriminativestimulus in rats which is potentiated by PCP (Winter et al.,2000). Chronic exposure of rats to low doses of LSD leads toimpaired social interaction, and a broader phenotypereminiscent of the effects of acute and sub-chronic treat-ment with NMDA receptor antagonists. This includes: ele-vated release of glutamate in the PFC; hyperlocomotion(blunted by olanzapine and haloperidol); irritability,enhanced aggression, and a reduction in sucrose consump-tion suggesting an anhedonic state (Marona-Lewicka et al.,2011). This model warrants further evaluation.

The 3 chamber test in mice has been widely used toexplore sociability, social preference, social motivation andsocial novelty discrimination, albeit mainly in the field ofautism (Silverman et al., 2010; Millan and Bales, 2013). In arecent study, resistance to antipsychotics and sensitivity toD-Cycloserine were used as criteria of “predictive” validityto characterise a model of disruption of social preference bypharmacological stimuli (Hanks et al., 2013). While thesecriteria may be debatable (D-Cycloserine has only been usedadjunctively in humans and it is not consistently effectiveagainst NS) (Section 4.6) (Davis et al., 2014; Javitt, 2012)the findings are interesting. Thus, PCP was inactive,whereas a GABAA inverse agonist diminished sociabilityand its actions were blunted by D-Cycloserine, but neitherby clozapine nor the anxiolytic, alprazolam (Hanks et al.,2013). In view of interest in GABAAα2 subunit agonists (notunfortunately tested) for treating NS and other symptoms ofschizophrenia (Section 4.4), additional research with thismodel is justified.


5.5.2. Developmental modelsSocial interaction is the readout that has been most widelyexploited in early-life and adolescent neurodevelopmentalmodels for schizophrenia, employing a diverse suite ofperturbations from (1) prenatal stress and disruption ofneurogenesis to (2) perinatal ventral hippocampus lesions(VHL) and exposure to viral mimics/pro-inflammatoryagents to (3) post-weaning isolation (Fatemi and Folsom,2009; Fone and Porkess, 2008; Meyer and Feldon, 2010;Piontkewitz et al., 2012; Pratt et al., 2012; Tseng et al.,2009). A highly consistent observation has been reductionsin social interaction in adults, as discussed by Wilson andKoenig (2014) and Moser (2014), in this Special Volume.

One interesting example is VHL in rats, which is usuallyeffected by local injection of isobotenic acid at post-natalday 7. Decreases in social interaction are already seenduring adolescence (prior to the appearance of changesrelated to positive symptoms) and they persist throughoutadult life (Tseng et al., 2009). Early emergence may berelated to prodromal NS in humans prior to the first frankpsychotic episode (Fusar-Poli et al., 2013a, 2014). Thedecrease in social interaction, which is antipsychotic-insen-sitive, is accompanied by increased aggression and impairedsocial memory, observations accentuating the point thatchanges in a readout for “NS” should never be examinedindependently of other behaviours when contemplatingtheir relevance (Pratt et al., 2012; Tseng et al., 2009).More generally, it is important to confirm, as has beenachieved in several studies, that alterations in social inter-action can be dissociated from anxiety (Moser, 2014).

It is intriguing that VHL-induced decreases in socialinteraction were attenuated by the neurotrophic agent,cerebrolysin, which enhances synaptic plasticity in the PFCand limbic structures (Vázquez-Roque et al., 2012, 2014).Conversely, though few data with antipsychotics are avail-able for developmental models, they do not seem to beeffective in reversing social interaction deficits, includingthose seen in the VHL paradigm (Koike et al., 2009; Leeet al., 2007; Neill et al., 2014; Rueter et al., 2004; Tsenget al., 2009). By analogy to pharmacological models of NS,this lack of reversal by antipsychotics mirrors the situationin patients, but deficits in social interaction seen in a viralmodel of perinatal inflammation were, contrariwise,reversed by D-Serine (Nagai et al., 2012).

As for other behavioural readouts, reductions in socialpreference in a 3 chamber test were seen in adult mice thathad undergone perinatal inflammation (Smith et al., 2007). Inthis procedure, decreases in pup play were perhaps related,like the adolescent reductions in social interaction followingVHL, to the high-risk prodromal state and justify furtherexploration (Kirsten et al., 2010). Indeed, as cogently arguedby Trezza et al. (2011a, 2011b), adolescent play in rats (andsocial proximity in mice) could be profitably exploited tocharacterise social motivation and reward in developmentaland other models of schizophrenia (Section 5.8).

5.5.3. Genetic models: transgenic miceDespite high heritability, the genetics of schizophrenia areheterogeneous, complex and multi-factorial with a poly-genic burden of minor risk factors distributed across hun-dreds of genes in most patients, whereas a minority of

subjects reveal (usually de novo) high-impact geneticaberrations involving larger, structural (copy number) var-iants. Not only protein-coding genes are implicated: forexample, there is a strong association between the micro-RNA, miR137 – a regulator of cortical neurodevelopment –

and schizophrenia, though any specific role in the genesis ofNS awaits elucidation (Millan, 2013, Sullivan et al., 2012).Note that many genetic risk factors for schizophrenia over-lap with those for other developmental disorders and/orbipolar depression (Andreassen et al., 2014; Malhotra andSebat, 2012; Purcell et al., 2014; Sullivan et al., 2012).

These elements complicate the generation of broadly-relevant genetic models for schizophrenia and, to reiteratethe point made above, no genetic model has been describedthat specifically and exclusively is aimed at reproducing NS.Nonetheless, considerable progress has been made, asexpertly discussed by O’Tuathaigh et al., 2014 in this SpecialVolume. Much experimental work has been influenced bygenetic susceptibility factors in patients, with severalrecent studies focussing on: (1) genes revealed byGenome-Wide (unbiased) Association Studies and (2) rareCopy Number Variants (Hiroi et al., 2013; K.W. Lee et al.,2012). Interestingly, the genes concerned tend to controldevelopmentally-regulated synaptic networks and signallingplasticity, often with the participation of NMDA receptors.Hence, genetic models for schizophrenia often convergeonto mechanisms targeted by pharmacological and devel-opmental models.

Perhaps the best known Copy Number Variant linked toschizophrenia is 22q11.2 where deletions and duplicationsare also related to autism – including Di George syndrome,which has an about 30 fold greater risk of schizophrenia(Baker and Skuse, 2005; Hiroi et al., 2013; Malhotra andSebat, 2012, Millan, 2013). Many genes are involved in thisaccrued risk of psychosis and the (not always “psychosis-like”) behavioural changes in mice with manipulation of thisregion, but of special interest is a 200 kB region containingthe Serp5 gene (Hiroi et al., 2013). Its overexpressionfacilitates affiliative social behaviour whereas deletionleads to its diminution and – further suggesting a link toNS – delayed acquisition of rewarded approach behaviour(Harper et al., 2012; Suzuki et al., 2009). This gene meritsadditional analysis.

One of the most robust findings to emerge from GenomeWide analyses was the association of several polymorphismsin the developmentally-important Major HistocompatabilityComplex (MHC) with schizophrenia (Andreassen et al., 2014;K.W. Lee et al., 2012; Sullivan et al., 2012). Schnurri-2(MHC-binding protein 2), constitutively binds to and inhibitsNuclear Factor-kappa B which itself acts at the MHCpromoter to enhance gene expression. Schnurri-2 knockoutmice show widespread brain inflammation and GABAergicinterneurone down-regulation linking this model to devel-opmental paradigms. Further, they reveal both anhedonia(decreased sucrose consumption) as well as reduced nest-building behaviour, a behavioural change related to NS andobserved in, for example, animals with disrupted NMDAreceptors and developmental models for schizophrenia(Baharnoori et al., 2012; Halene et al., 2009; Takaoet al., 2013). Attenuation of deficits in Schnurri-2 deficientmice by anti-inflammatory drugs reinforces the notionthat inflammation-related disruption of glutamatergic


transmission is linked to schizophrenia (Müller et al., 2013).This is of interest in the light of clinical investigations of thepotential utility of cyclo-oxygenase inhibitors and minocy-cline. The latter agent acts via anti-inflammatory mechan-isms (though not exclusively) to exert a surprisinglyconsistent pattern of efficacy against NS in patients (Daviset al., 2014; Dean et al., 2012; Khodaie-Ardakani et al.,2014; Levkovitz et al., 2010; Liu et al., 2014; Monte et al.,2013; Müller et al., 2013).

Another gene worth citing is Neuregulin-1 since, amongstother actions, it is inhibitory to Src Kinase-facilitation ofNMDA receptor-mediated signalling and may be overex-pressed in schizophrenia (Pitcher et al., 2011). Interestingly,in line with the importance of correct gene dosage (Millan,2013), both over and under-expression of the Neuregulin-1gene in mice disrupts social behaviour, and the effects of itsgenetic manipulation depend on the nature of the mutation,underscoring the complexity of even single gene models forstudying NS (O’Tuathaigh et al., 2007, 2014).

As for glutamatergic transmission itself, there are fewerdata than might be imagined. Nonetheless, genetic disrup-tion of D-Amino-Acid Oxidase (which catabolises D-Serine)partially restores deficits in social behaviour provoked bymutations in the NMDA receptor subunit, “Grin1”, a pointworth underlining in light of positive data with D-Amino-AcidOxidase inhibitors against NS in patients (Labrie et al.,2010; Lane et al., 2013). Along these lines, the geneencoding the ionotropic GluD1 glutamate receptor is linkedboth to schizophrenia and to anomalous operation of fronto-thalamic networks (Nenadic et al., 2012). Its deletion isassociated with a reduction in social interaction abrogatedby D-Cycloserine (Yadav et al., 2012). Finally, the GABABreceptor agonist, baclofen, opposed the reduced sociabilitytriggered by genetic deletion of the NR1 subunit of NMDAreceptors, likely by restoring NMDA-GABAergic andexcitatory-inhibitory balance in the cortex – the clinicalinfluence of GABAB agonists on NS remains, surprisingly,unknown despite their current development for manage-ment of autism (Gandal et al., 2012; Millan, 2013).

Though surprisingly little information pertinent to socialbehaviour has emerged from genetic manipulation of dopa-minergic transmission, mice with a null mutation for the DAtransporter showed a deficit in the social transmission offood preference. This alteration is clearly relevant toimpaired social cognition but is also of interest with regardto NS since, like other deficits, it was blunted by pregne-nelone, a positive modulator of transmission at NMDA andGABAA receptors under study for alleviation of NS inpatients (Sections 4.4 and 4.5) (Wong et al., 2012). Asregards DA receptors themselves, studies have to datefocussed more on their relationship to avolition than tosocial behaviour (Section 5.6.4). Nonetheless, inasmuch asD3 receptor over-expression decreases motivation, and D3receptor inactivation is associated with enhanced socialnovelty discrimination, social interaction and nest-buildingbehaviour in mice, further study of the significance of D3and other classes of DA receptor to asociality appearswarranted (Gross et al., 2013; Watson et al., 2012).

Finally, oxytocin has not unnaturally evoked considerableinterest, and genetic interference with oxytocin receptors con-sitently disrupts social behaviour, cognition and communicationin mice with both homozygotes and – perhaps more specifically

– heterozygotes displaying deficits in both sociability and socialnovelty preference (Goodson and Thompson, 2010: Millan andBales, 2012; Pobbe et al., 2012; Sala et al., 2013). Importantly,these models exemplify the difficulty of extrapolating to anyspecific diagnostic entity in humans since observations havemainly been linked to autism rather than schizophrenia, despiteevidence that the latter disorder is characterised by defectiveoxytocinergic transmission (Section 4.8) (Meyer-Lindenberget al., 2011).

5.5.4. Genetic models: specific mice strainsIn addition to transgenic strategies, it is interesting toconsider the complementary “genetic” strategy of comparingspecific mouse strains.

For example, “reeler” mice are deficient for the risk genereelin which is epigenetically silenced in GABAergic inter-neurons both in the PFC of subjects with schizophrenia, andin corresponding animal models (Millan, 2013; Pratt et al.,2012). Reelin mice display reduced levels of oxytocin (Liuet al., 2005; Millan, 2013) and, while NS like symptoms havenot yet been described, social withdrawal has been seen inanother instructive strain, “sandy” mice, deficient in theschizophrenia risk gene, dysbindin (Talbot, 2009).

As a further example, the “Black and Tan Brachyury”(BTBR) inbred line has attracted particular attention. Thismouse displays a spectrum of deficits in social behaviour,sociability and social communication, including scent mark-ing and Ultrasonic Vocalisations (USV), which collectivelyunderscore its pertinence to autism, as well as schizophre-nia (Meyza et al., 2013; Scattoni et al., 2013; Yang et al.,2013). Indeed, BTBR mice reveal decreases in grey mattervolume in the PFC and anomalies of white matter, recallingobservations in schizophrenic patients (Section 3.2) (Doderoet al., 2013; Ellegood et al., 2013). The recent finding thatlevels of kynenurenic acid are elevated in BTBR mice isespecially interesting (McTighe et al., 2013) since, asmentioned above, this endogenous antagonist of NMDAreceptors has been implicated in the pathophysiology ofschizophrenia (Millan, 2005; Müller et al., 2013). Moreover,the Glycine B/NMDA receptor partial agonist, D-cycloserine,improved sociality in this strain (Burket et al., 2013).Finally, in light of the implication of frontocortical mTOR(mammalian target of rapamycin) over-activation in theimpairment of social cognition in schizophrenia (Meffreet al., 2012), it is interesting that the inhibitor, rapamycin,promoted sociability in BTBR mice (Burket et al., 2014)

It is not always evident to find the right strain forcomparative studies, but more intensive characterisationof BTBR and other inbred mice populations should providefurther insights into the origins and modulation of NS (Millanand Brocco, 2008; O’Tuathaigh et al., 2014).

5.6. Amotivation, avolition and disruption ofanticipatory reward

5.6.1. Procedures for evaluating mechanismscontrolling reward, motivation and hedonic statesGenerally speaking, deficits in motivation have been lessextensively studied than disruption of social behaviourin rodent models for schizophrenia. Nonetheless, data arebeginning to accumulate with clear indications of how


progress can be made, and comparisons can instructively beentertained to a larger opus of data showing that dopami-nergic pathways fulfil a crucial role in motivation andreward processes: see articles by Neill et al., 2014, Moser,2014 and O’Tuathaigh et al., 2014 in this Special Volumeand, in particular, that of Barnes et al., 2014 who authori-tively discuss the surprisingly broad range of proceduresavailable to characterise reward-related deficits in rodentstudies of NS.

Many studies have concentrated on sucrose consumptionand, in certain cases, intracranial self-stimulation as directmeasures of hedonic states. However, as discussed above(Section 2.1), schizophrenic patients primarily displayimpairments of motivation (anticipation, wanting) ratherthan reward (experience, liking) (Table 1) (Foussias et al.,2014; Huxley and Fonseca, 2014), which are differentiallyintegrated by corticlimbic circuits (Berridge et al., 2009;Berridge and Kringelbach, 2013; Strauss et al., 2014).Hence, experimental procedures that differentiate thesefunctions are especially significant (Barnes et al., 2014;Pratt et al., 2012). In the context of motivation for reward,procedures reflecting the effort (physical and/or cognitive)that a subject is prepared to invest to obtain a reward arecrucial: these include Progressive/Random Reinforcementprocedures where, for each successive reward, the work(level presses needed) increases/varies (Bardgett et al.,2009; Barnes et al., 2014; Ghods-Sharifi and Floresco, 2010;Hosking et al., 2014; Salamone et al., 2012; Ward et al.,2011). Finally, apart from cost, the element of delayedgratification, whereby a preference for a more substantialyet later reward over a smaller yet more rapidly availablereward (“delayed discounting”) is likewise accessible toexperimental study (Barnes et al., 2014; Pittaras et al.,2014). This is relevant to schizophrenics in which a pro-spective (uncertain) reward may be undervalued, hencediminishing motivation to invest in its acquisition (Goldet al., 2013; Salamone et al., 2012; Strauss et al., 2014).

5.6.2. Pharmacological modelsAs analysed by Neill et al., 2014, it has been suggested thatthe suppression of sucrose preference in rats by acuteadministration of (usually high) doses of ketamine and otherNMDA receptor open channel blockers may be pertinent tothe NS of schizophrenia. For example, Baird et al. (2008)demonstrated a reduction in the intake of palatable solutionof sucrose without any specific interference with taste,while Vardigan et al. (2010) reported that dizocilpinereduced sucrose preference in a manner separable fromany interference with motor function: its actions wereblunted by D-Serine and clozapine, but not by haloperidol.Inasmuch as NMDA antagonists manifest (rapid-onset) anti-depressant properties, it seems unlikely that a depresso-genic action is involved: indeed, deficits in sucrosepreference associated with models of depression are alle-viated by comparatively low doses of ketamine, a drug indevelopment for resistant depression (Ma et al., 2013).

Other studies suggest that chronic exposure to NMDAantagonists leads to a post-withdrawal phase of anhedoniain tests of sucrose consumption and intracranial self-stimu-lation, possibly due to depletion of corticolimbic pools of DA(Barnes et al., 2014; Jentsch et al., 1997; Millan et al.,

1999; Millan, 2006). These observations merit further con-sideration but they appear to principally effect a change inconsummatory as opposed to anticipatory anhedonia sotheir genuine relevance to NS remains uncertain. Indeed,Neill et al., 2014 mention that chronic PCP does notinterfere with anticipatory reward as measured in a Pro-gressive Ratio model of motivation. On the other hand,using a chronic intermittent protocol of PCP administrationand a T-maze with a choice between a high effort/highreward vs low effort/low reward arm, rats opted for thelatter suggesting low motivation for investing effort toattain the greater reward (Morris et al., 2005; Prattet al., 2012). Furthermore, as discussed by Barnes et al.,2014, amphetamine-withdrawn rats show a reduction inbehaviour directed towards the performance of sexualbehaviour, rather than any deficits in the act itself. Theanhedonic-like state that accompanies cocaine-withdrawalhas been related to activation of mesolimbic populations ofkappa opioid receptors: their blockade is associated withantidepressant properties, but whether this mechanismexerts a direct impact on NS remains to be elucidated(Chartoff et al., 2012).

Finally, many elegant mechanistic studies have beenundertaken to examine neuronal circuitry implicated inreward processes and potentially disrupted in NS: forexample, GABAergic inactivation of the PFC leads to altereddopaminergic encoding of expected rewards (Jo et al.,2013). However, such specialised procedures cannot realis-tically be used for characterisation of potential pharma-cotherapy on a broad scale.

Thus, currently there is no simple and well-establishedpharmacological model for studying NS related to amotiva-tion, but some promising avenues of research justify furtherexploration. In future work, elements of anticipation andeffort invested to attain reward warrant more intensivestudy (Section 5.8).

5.6.3. Developmental modelsGreat care must be taken to ensure that a behavioural changegenuinely relates to a schizophrenia-like phenotype and speci-fically to NS. An interesting example was provided above asregards the altered social interaction seen in neonatal VHL rats,and this model serves to illustrate the comparable complexityof studies of reward mechanisms (Brady et al., 2008; Tsenget al., 2009). Le Pen et al., 2002 showed that VHL subjectsdisplay a diminished preference both for a saccharine solutionand for a conditioned place preference to amphetamine,indicative of an impaired hedonic state (Trezza et al., 2011a,2011b). However, it is unclear how this anhedonia relates to thereward deficits of NS in schizophrenia since this model did notincorporate measures of anticipatory motivation. Conversely,this dimension was addressed by Brady et al. (2008) using aProgressive Ratio schedule to determine the effort and motiva-tion that VHL rats were prepared to invest for attaining theirgoal (an injection of methamphetamine), a model with greaterface value for NS. Ironically then, VHL rats actually workedharder before responding was discontinued. This observationwas interpreted as reflecting an increase in the reward-ing properties of methamphetamine – commensurate withthe comorbidity of addictive behaviour in schizophrenics(Heidbreder and Newman, 2010). Nevertheless, it might


alternatively be considered as challenging the relevanceof decreased sucrose consumption/amphetamine place-preference in rodents to the NS of schizophrenia. Further workis necessary to clarify this issue. Oddly enough, there are littleother data concerning NS-related changes in motivation withdevelopmental models of schizophrenia, a field ripe for expan-sion using procedures mentioned above and more comprehen-sively discussed in Barnes et al. (2014).

5.6.4. Genetic modelsThe preceding section evoked the important elements ofanticipation and motivation to work for reward, of which adeficiency epitomises NS (see also Section 3.3). This pro-vides a useful transition to several elegant and interrelatedstudies of amotivation undertaken in rats with genetically-manipulated D2 and, more recently, D3 receptors (Drewet al., 2007; Li et al., 2011; Simpson et al., 2011, 2014;Trifilieff et al., 2013; Ward et al., 2009, 2011).

Transgenic mice that selectively overexpress D2 receptorson medium spiny neurones in the striatum may be comparedto the “overactivation” of subcortical dopaminergic trans-mission seen in schizophrenia. These animals stop respond-ing sooner in Progressive and Random Ratio schedules oflever-pressing for food. This cannot be explained by satiety,fatigue or lack of hedonic pleasure, rather to a lack ofwillingness to work and to insensitivity to the value offuture reward, perhaps due to poor internal representationor faulty computation of cost vs benefit relationships (Drewet al., 2007; Ward et al., 2012). This dissociation betweenincentive motivation and hedonic appreciation of rewardresembles the profile of NS in schizophrenia underscoringthe interest of the model (Table 1) (Kring and Barch, 2014;Strauss et al., 2014). The effects of striatal D2 receptoroverexpression likely involve a frontocortico-striatal loopand disruption of excitatory-inhibitory signalling in the PFC(Li et al., 2011), supporting relevance to the induction andexpression of NS (Section 3).

As regards potential modulation, 5-HT2C receptors wereup-regulated in the striatum of D2 receptor overexpressingmice, and 5-HT2C receptor antagonists rescued thedecreased motivation (Simpson et al., 2011). Accordingly,it was posited that 5-HT2C receptor antagonists may beuseful for restoring motivation in schizophrenia. However,despite concomitant benefits for moderating social anxietyand depression, there is a risk of exacerbating positivesymptoms since 5-HT2C receptors inhibit mesolimbicrelease of DA (Dekeyne et al., 2000, 2008; Meltzer, 2012;Millan, 2006). Indeed, this was the basis for proposing 5-HT2C agonists for the treatment of schizophrenia and, veryrecently, the first clinical data were released with tentativeimprovement of both positive symptoms and, surprisingly,NS (Shen et al., 2014). Thus, the status of 5-HT2C receptorsas a target for the control of NS and other dimensions ofschizophrenia awaits further clarification (Section 4.3).

More recently, another model was introduced in which alentivirus elicited (more pronounced) D2 receptor over-expression specifically in the nucleus accumbens and, incontrast to the above model, motivation to work to obtain areward was enhanced, with no change in consummatorybehaviour. This observation mirrors the increased motiva-tion produced by enhanced mesolimbic release of DA in

humans and animals, and provides a counterpart to itsdiminution by DA antagonists (Salamone et al., 2012;Barnes et al., 2014; Trifilieff et al., 2013). The data arealso globally consistent with the use of psychostimulants toalleviate NS (Lindenmayer et al., 2013). However, the dataalso emphasise that: (1) at first site similar models can showimportant differences; (2) the role of DA in reward mechan-isms is complex and regionally-specific and (3) directexploitation of dopaminergic substrates for the control ofNS might need to be local. This presents a formidable if notinsuperable therapeutic challenge – further underlined bythe central importance of D2 receptor blockade in thecontrol of positive symptoms.

A final and rather more auspicious, dimension ofcomplexity is provided by the contrasting roles of D3receptors – which are not differentiated from D2 recep-tors by any antipsychotic currently available for pre-scription (Millan and Brocco, 2008). D3 receptoroverexpression restricted to the striatum led todecreased motivation in a Progressive Ratio schedule ofreinforcement (Simpson et al., 2014). This observation isimportant since it suggests that blockade of striatal D3receptors may counter the amotivation of schizophrenia.Several other observations suggest that D3 receptorblockade should counter NS, such as facilitation ofnesting behaviour and social contact (Gross et al.,2013). Moreover these actions are complemented by aPFC-mediated and broad-based enhancement of socialcognition and multiple neurocognitive domains (Table 2)(Gross et al., 2013; Millan et al., 2007; Millan andBrocco, 2008; Nakajima et al., 2013; Watson et al.,2012). D3 receptor blockade also counters co-morbiddrug-seeking behaviour, though hypothesised benefits forthe control of positive symptoms await clinical evalua-tion (Gross et al., 2013; Heidbreder and Newman, 2010;Millan and Brocco, 2008; Mugnaini et al., 2013). Bizarrelyenough, despite the availability of well-tolerated andthoroughly-characterised D3 receptor antagonists, theirinfluence on NS has never been specifically determinedat appropriate doses (op. cit.).

Despite this intriguing and extensive body of data concern-ing dopaminergic mechanisms, disappointingly few data areavailable concerning NS-related impairment of motivationfrom other genetic models for schizophrenia (O’Tuathaighet al., 2014).

5.7. Blunted expression: procedures and readoutsof potential utility

In a sense, rodents “speak to us with their feet”, so their(loco)motor behaviour is an expression of their emotionaland internal state (Figure 6). Hence, behaviours likedecreased sociability and social interaction, reduced leverpressing for reward and decreased anticipatory approachbehaviour may at least partially reflect blunted expression(Barnes et al., 2014; Wilson and Koenig, 2014). However,this possibility does not appear to have been formallyaddressed, nor this sub-dimension of NS factored out instudies evoked above. Furthermore, there appearsto be no currently-accepted and broadly-used readout


specifically related to blunted expression for use in animalmodels. The following points are nevertheless of interest.

There are indications that ketamine induces emotionalblunting in humans (Abel et al., 2003; Millan, 2005) and itsdisruption of amygdala-integrated fear conditioning in rats,as measured by both behavioural and neurochemical mea-sures, was proposed as a measure of emotional bluntingirresponsive to conventional antipsychotics (Pietersenet al., 2007). However, it is hard to be certain that thismodel relates to NS rather than modulation of anxiety perse and further validation is awaited before its utility can bemore rigorously assessed.

Likewise, though increased immobility in a forced swim-ming test following chronic exposure of NMDA antagonistshas been considered analogous to the induction of “emo-tional blunting” in schizophrenia, the specificity and perti-nence of this readout remains debatable (Neill et al., 2014).Though the induction of immobility by neuroleptics/D2receptor blockade might be claimed as related to “second-ary NS”, it is hard to differentiate a putative impact ofdrugs on motor behaviour, depressed mood and otherfactors from any putative induction of “emotional blunt-ing”. Nonetheless, the enhanced immobility associated withchronic exposure to PCP was reversed by D-Cycloserine (andsub-chronic clozapine, but not haloperidol) suggesting thatfurther study is warranted (Murai et al., 2007; Turgeonet al., 2007).

The procedures outlined above, despite their interest,still require more rigorous characterisation, so several otherapproaches of potentially greater face validity for examin-ing blunted expression are evoked below (Section 5.8.2).

5.8. Prospects for further refinement ofexperimental studies of NS

5.8.1. Major lines of study to date and possibleextensions: motivation and social interactionFrom the above discussion, it is apparent that a surprisinglybroad range of readouts and measures are potentiallyavailable for examining social behaviour, reward and moti-vation in rodent models for schizophrenia (Figure 6) (Laiet al., 2014; Lahvis et al., 2011; Markou et al., 2013;Silverman et al., 2010; Trezza et al., 2011a, 2011b;Tzschentke, 2007). On the other hand, the number ofpharmacological mechanisms suggested to actually modifyNS-like behaviours in animal models (Table 2), and thebreadth of measures exploited to date is fairly restricted.

For example, little has been done as regards amotivationin developmental and genetic models. Measures of sucroseconsumption as a readout of hedonic states (consummatoryreward) have been (questionably) prioritised and, even inpharmacological models, the rich repertoire of proceduresfor differentiating changes in anticipatory vs consummatoryanhedonia has been under-utilised. Though the specialistnature of some behavioural paradigms may admittedly bedissuasive for neophytes, there is clearly much that could beundertaken (Barnes et al., 2014; Pittaras et al., 2014).

As regards social behaviour, social interaction has greatlypredominated as a readout (not invariably with rigorouscontrols for interference by factors like social anxiety andsocial cognition), and tests of sociability and social novelty

preference etc. in mice have been comparatively littleadopted (Silverman et al., 2010; Trezza et al., 2011a,2011b). Social motivation is a particularly interesting areafor improved future study. Trezza et al. (2011a, 2011b)pointed out that maternal pup care, sexual behaviour andplay are all highly motivating in post-partum females, adultsand adolescents/juveniles, respectively. The latter twobehaviours could be instructively employed in experimentalstudies of NS in rats, employing either operant, maze-basedand or place-conditioning paradigms – for adolescent mice,social proximity would be the readout. For example, in aconditioned social place preference procedure, rats pre-ferred a compartment previously associated with a socialpartner compared to one where it was absent (Tzschentke,2007). This preference is disrupted by sub-chronic PCP,and further exploration of this procedure would be ofconsiderable interest (Schwabe et al., 2006; Thiel et al.,2008). Learning in T-maze models is also of interest in lightof the need to remember and recall past rewarding experi-ences in order to anticipate, positively value and strive forpotential future rewards (Berridge et al., 2009; Berridgeand Kringelbach, 2013; Kring and Barch, 2014; Trezza et al.,2011a, 2011b).

There are ample opportunities for substantially enrichingstudies of social motivation and reward in animal models forschizophrenia focussing on NS.

5.8.2. Alternative approaches to evaluating diminishedemotional expressionAs pointed out in Section 5.7. there is considerable room forimprovement as regards the NS sub-dimension of decreasedexpression.

One human trait poorly back-translatable into animals isfully syntactical, recursive and abstract language (Fitchet al., 2010; Poeppel, 2012), of which a loss of fluentproduction (alogia) characterises NS (Table 1) (Foussiaset al., 2014). While the full complexity of verbal language– and non-verbal visual signals – cannot be studied inrodents, there are other modes of social communicationthat could prove instructive, such as the olfactory andtactile: mutual grooming in rodents – and primates – ispromoted by oxytocin and relevant both to restrictedexpression and to asociality (Dunbar, 2010). The mostdynamic, pro-active and rich mode of exchange is arguablyUSVs. USVs are emitted in a context and emotional state-dependent manner, notably during tests of social preferenceand social interaction amongst adults and/or pups, and in amanner influenced by genetic background. Thus, the mon-itoring of USVs (quantity, spectral distribution, pattern) andtheir modulation during tests of social contact could providemajor insights relevant to decreased expression – as well associal motivation and engagement – though extrapolation offindings to human speech (alogia) should be made with greatcaution, if at all (Lahvis et al., 2011; Nikiforuk et al., 2013;Wohr and Schwarting, 2013; Yang et al., 2013). Under-pinning the interest of such work, altered emission ofUSV accompanies reduced social interaction, disruption ofnest-building behaviour and compromised subcortical dopa-minergic transmission in models of pre-natal infection/inflammation (Baharnoori et al., 2012; Kirsten et al.,2010, 2012). Tactile and USV means of communication – as


well as yawning – have been advocated for studies of socialcognition and could well prove useful in work on NS inrodents (Millan and Bales, 2013).

Facial expressions and licking patterns have been mon-itored during consumption of rewarding and aversive solu-tions, so it would be worth assessing a putative role in theactive transmission of affective state to conspecifics(Berridge et al., 2009; Lydall et al., 2010; Peciña andSmith, 2010).

5.8.3. Combinations of developmental and geneticmodels in rodentsIn much the same way that studies of individual risk genes inhumans are migrating to analysis of epistatic interactionsbetween genes (Purcell et al., 2014; Sullivan et al., 2012),there is a move to combine risk factors as a more realisticapproach for generating core feature of schizophrenia inrodents (O’Tuathaigh et al., 2014; Hida et al., 2013). Whiledouble genetic manipulations are feasible, of greater inter-est are studies were the interface between genetic andenvironmental risk factors has been mimicked by super-imposing a developmental insult upon a vulnerable geneticbackground. In one particularly interesting example,Desbonnet et al., 2012 showed that social defeat inadolescent mice synergistically impaired social interactionwhen performed in subjects bearing a deletion of the geneencoding Neuregulin-1. Further, other studies haveexploited mice with mutated genes for the risk gene,Disrupted in Schizophrenia-1, and combined this geneticbackground with perinatal inflammation. This dual-hit para-digm is especially interesting since inflammatory mechan-isms converge on many intracellular signals that interactwith this protein (Abazyan et al., 2010; Kamiya et al.,2012). It was accompanied by reductions in social prefer-ence and social interaction, observations unaffected byantipsychotics (Nagai et al., 2011). Models combining riskfactors seem a particularly fruitful direction for additionalstudy since they are more faithful to multi-hit concepts ofthe origins of schizophrenia (Figure 1).

5.8.4. Induction of pathophysiological mechanisms indiscrete brain regionsA likewise novel yet rather different approach, mirroringVHL in rats (Tseng et al., 2009) and inactivation of GABAer-gic transmission in the PFC (Jo et al., 2013), consists in theinduction of pathophysiological mechanisms in discretebrain regions to more precisely define the neural substratesunderlying NS. For example, localised expression of adominant-negative Disrupted in Schizophrenia-1 mutantgene in mouse PFC provoked oxidative stress and beha-vioural changes reminiscent of NS, including aberrant socialbehaviour and reduced performance in a operant procedureof effort-related reward procurement (Johnson et al.,2013). Further, not just genetic manipulations are con-cerned. For example, rather than induction of systemicinflammation, intra-hippocampal injection in neonatal ratsof the pro-inflammatory agent, lipopolysaccharide, led tomicroglial activation and deficits in adult social behaviour(Zhu et al., 2014).

5.8.5. Alternative species: from primates to zebrafishmodelsCertain parameters relevant to social motivation and com-munication, and interlinked both with NS and social cogni-tion, cannot realistically be modelled in rodents, mostobviously those pertaining to the visual domain. This raisesthe possibility of studies in non-human primates. Forexample, analysis of gaze-following has been forwarded asa strategy for improving our understanding of social cogni-tion, and opportunities likewise may arise in primates forgaining insights (behaviour, imaging, EEG etc.) into theasociality of NS and its modulation (Millan and Bales,2013). In addition, primates have been employed foranalysing the role of PFC sub-territories and the amygdalain social motivation and reward-guided behaviour, processesdisrupted in schizophrenia (Murray and Rudebeck, 2013)(Section 3.3). Social interaction (cognition) is well-studiedin primates (Byrne and Bates, 2010), and the interplaybetween dopaminergic transmission and social hierarchieshas been explored in relation to cocaine reward, providinganother experimental template of potential relevance to NS(Nader et al., 2012). A further possibility may be studies ofthe social effects of ketamine, which has been exploited asa pharmacological mimic for schizophrenia in studies ofcognitive performance and ERPs in primates (Gil-da-Costaet al., 2013; Nakako et al., 2013). As recently reviewedelsewhere (Millan and Bales, 2013), and mirroring models inrodents, developmental procedures in primates involvinginduction of inflammation, disruption of neurogenesis andearly-life cerebral lesions could be expanded for theinvestigation of NS. Such studies must only be undertakenin specialised labs, with rigorous ethical precautions, andpreferably with freely-moving subjects in a naturalistic andhighly social environment, and they should best be kept to aminimum. Nonetheless, they could prove crucial for valida-tion of novel therapeutic concepts, and in a translationalcontext before advancing a promising agent into humans forpotential relief of NS.

In a mirror image of the primate, there is increasing interestin zebrafish for the rapid screening of potentially-novelpsychotropic drugs, and for enhancing our understandingof the cellular origins of neurodevelopment disorders likeschizophrenia (Maaswinkel et al., 2013; Norton, 2013). Genetichomology is substantial with mammals and gene-manipulationsare rapid and straightforward; glutamatergic and dopaminer-gic mechanisms are well characterised; reward and socialbehaviour can be monitored; and administration of ketamine isknown to disrupt social interaction and the dynamics of socialgroups, with its actions blunted by sulpride – but nothaloperidol (Collier and Echevarria, 2013; Seibt et al., 2011;Zakhary et al., 2011). Once novel mechanisms for potentiallymodulating NS have been identified in higher species, zebrafishmay prove a useful initial model for screening the correspond-ing drugs.

5.8.6. More intensive linking of behaviouralobservations to mechanistic basesApart from the above-mentioned importance of enrichingbehavioural readouts, it would also be advantageous tomore closely link behavioural indices of NS to their potentialneural and neurochemical substrates using structural and

Table 3 Overview of core themes and observations addressed in this Special Volume, and of major questions under study.

Theme (SpecialVolume, focussedarticle)

Core issues addressed in this article and the Special Volume Key questions(mostly outstanding)

Clinicalcharacteristicsof NS in relationto other classesof symptom(1–5)

Core features ofschizophrenia, majorsocio-economic burden,still a major therapeuticneed.

Diagnostic criteria forNS: two major sub-domains, and advent ofDSM-5. Primary vssecondary NS – hard todistinguish despitecontrasting causes.

Measurement of NS,importance of new ratingscales. Evaluation of NSin therapeutic trials.Studies of persistent NS,and of NS duringprodromal phase insubjects at risk oftransition.

What is the relativecontribution of primaryand secondary forms ofNS in patients?What is the preciserelationship betweenNS, impaired socialcognition and othersymptoms?

Clinical profile of NS: realworld function severelyaffected.

Is the deficit syndrome agenuine entity?Why (and how) do NSoccur in otherpsychiatric andneurological disorders?

Pathophysiologicalmechanismsunderlying sub-domains of NS(4,7)

Neural substrates andcerebral circuitsimplicated in NS. Pivotalroles for frontocortico-temporal cortices andcortico-striatal loops.Ventral and dorsalstriatum dysfunctioncentral to amotivationand anticipatoryanhedonia. Otherregions: amygdala etc.

Neurochemical andcellular substrates ofdysfunctional networks.Key significance forglutamate, DA, oxytocinand cannabinoids inreward and socialfunction.

Use of structural andfunctional imaging,electrophysiology,Magnetic ResonanceSpectroscopy and othertechniques to identifynetworks, structures andneuromodulatorsimplicated in NS. Time ofonset: mainly prior todiagnosis.

Whichpathophysiologicalmechanisms are specificto NS vs other classes ofsymptoms?How can we betterdefine the molecularand neurochemicalbases of NS and linkthem to alterations ofneural circuits?Are changes seen inschizophrenia not onlycausal to, but alsocounter-regulatory ofNS?Are mechanisms causingNS the same as thosemaintaining them?

Clinical treatmentand potentiallyimprovedcontrol of NS (5)

Impact of currently-available (5-HT2A4D2)antipsychotics on NS.Potential utility of otherclasses of medication(antidepressants andanxiolytics).

Novel mechanisms ofaction in development;Oxytocin, GABAA andglutamatergic agents,increased frontocorticalDA release, minocycline.

Non-pharmacotherapeuticstrategies: electrical-magnetic “stimulation”of cortex, and cognitive-behavioural-psychosocialtherapies.

Can we identify novelmedication targets?What are the relativemerits/drawbacks ofpharmacotherapy vsother approaches, andcan we adopt andvalidate combinedtreatments?Are agents thatexclusively improve NSuseful?Would pre-diagnostictreatment of NS (andsocial cognition) reducetransition to psychosis?

Experimentalmodels andreadout forstudying NS,prospects forprogress (6–10)

Readouts of distinctcomponents of NS:asociality (most studied);amotivation, (complexbut accessible) andblunted affect

Validation of proceduresand models: face value(resemblance to clinicalNS); aetiological value(underlying mechanisms)and predictive value

Actions of clinically-usedantipsychotics,glutamatergicmodulators and otherclasses of agents. Mostdata for acute

Can we identitytranslational readoutsof NS sub-domains foruse in clinical drugtesting?


Table 3 (continued )

Theme (SpecialVolume, focussedarticle)

Core issues addressed in this article and the Special Volume Key questions(mostly outstanding)

(few data).Pharmacological,developmental andgenetic models forinduction of NS.

(drug actions predictsclinical efficacy).

administration to adultrodents, with only onemodel and/or readout:few data for prodromaladministration.

How can we bettercouple behaviouralmeasures of NS toneurochemical,biochemical andelectrophysiologicalsubstrates?How should we bestcombine risk factors toimprove experimentalmodels of NS?What is the utility ofnon-rodent species?

The numbers refer to the papers of this Special Volume dedicated to the issues specified. (1) Foussias et al. (in press), (2) Malaspinaet al. (in press), (3) Marder and Kirkpatrick (in press), (4) Kring and Barch (in press), (5) Davis et al. (in press), (6) Wilson and Koenig(in press), (7) Barnes et al. (in press), (8) Moser (in press), (9) O’Tuathaigh et al. (in press) and (10) Neill et al. (in press). The presentpaper, in addition to a synthetic overview of all the themes specified above, discusses the neural and neurochemical substrates of NS,a topic not covered in detail in the other papers, and the same holds for cognitive-behavioural-psychosocial therapies forcontrolling NS.


functional imaging, electrophysiological parameters, anddialysis measures of the release of glutamate, DA andoxytocin etc.: such work is being intensified (Murai et al.,2007; Neill et al., 2010; Piontkewitz et al., 2012; Prattet al., 2012). While the focus here (and elsewhere) has verymuch been on glutamategic and dopaminergic mechanisms,together with oxytocin where the interface with socialcognition is concerned, there should be greater attentionto other relevant cellular mechanisms modulating rewardand social behaviour, and potentially related to corefeatures of NS.

For example, cannabinoids may transduce the impact ofPCP on social behaviour in rodent models and they interactwith corticolimbic dopaminergic transmission and controlreward mechanisms. Further, cannabidiol (which enhancesendogenous levels of anandamide) reduced NS and othersymptoms in a small trial in schizophrenic patients, while anincrease in the nucleus accumbens density of CB1 receptorshas been correlated with the intensity of NS in patients(Section 3.6) (Ceccarini et al., 2013; Leweke et al., 2012;Seillier et al., 2010, 2013).

It is likely that we have still only identified a smallminority of endogenous mechanisms potentially exploitableby pharmacotherapy for the improvement of NS in schizo-phrenia (Table 2).

5.8.7. Evaluating novel mechanisms for potentiallypreventing NSDrug treatments have almost invariably been undertaken inadults upon acute administration, and after the appearanceof changes reflecting psychosis. It should be evaluatedwhether longer-term administration of agents to adolescentsubjects prior to the appearance of positive-like symptoms

in adults may: (1) alter those components of NS alreadypresent and (2) hinder their emergence and progression inadults. This would be analogous to the study in models forschizophrenia of potential strategies for preventing theonset of structural changes and cognitive impairment(Clifton et al., 2013; Piontkewitz et al., 2012). Indeed,more generally, there is a need to intensify studies of animalmodels during (and just after) the adolescent phase whenNS-like changes may be apparent or emerging, even prior tothe manifestation of changes related to positive symptoms.

Finally, while it might be assumed that only pharma-cotherapeutic approaches can be evaluated for their poten-tial efficacy against NS – or for impeding the development ofNS – recent work suggests that experimental models mayalso be amenable to the study of “cognitive-behavioural-psychosocial” strategies for preventing the emergence of NS(H. Lee et al., 2012).

6. Concluding comments

As summarised in Table 3, and more comprehensivelyarticulated in the individual articles of this Special Volume,the current lack of effective treatment for the debilitatingNS accompanying schizophrenia has triggered considerableefforts to: refine their clinical characterisation and mea-surement; deepen our understanding of the neural andneurochemical substrates of NS; improve the performanceof clinical trials for innovative and potentially superiortherapy; explore clinical strategies for controlling NS com-plementary to pharmacotherapy; and to broaden andadvance animal models and readouts for the experimentalstudy of NS. This all remains very much a “work inprogress”, many fundamental questions await elucidation,


and the kinetics and complexities of rigorous clinicalcharacterisation of novel medication for NS are likely toremain largely incompressible (Table 3). Nonetheless, pre-competitive, industrial–academic–governmental initiativeslike “MATRICS” (US) and the Innovative Medicines Initiative(EU) are proving increasingly beneficial for target charac-terisation and the development of clinical biomarkers,while an on-going dialogue with the Federal Drug andEuropean Medicines Agencies is likewise useful in the designof clinical trials for the improved control of NS. Overall,there are grounds for cautious optimism.

Our knowledge of the causes, characteristics and potentialcontrol of NS – and other facets – of schizophrenia is system-atically progressing. While much remains to be learned, thisaffords some hope that we should eventually be in a positionto propose novel strategies for the more effective treatmentof NS and other symptoms of this devastating disorder.

Role of funding source

None declared.

Contributors

Mark J. Millan prepared a complete first version of the paper, uponwhich the co-authors provided comments and feedback. All authorshave read and approved the final version.

Conflict of interest

Mark J. Millan and Thomas Steckler are full-time employees of theInstitut de Recherche Servier and Janssen Pharmaceuticals, respec-tively. Otherwise, they have no interests to declare. Kevin Fone andWilliam Horan have no interests to declare.

Acknowledgements

We would like to thank all the authors for their excellent contribu-tions to this Special Issue on NS, and also the Chief Editor, MichaelDavidson, for feedback and encouragement. Marianne Soubeyron isthanked for loyal secretarial support and San-Michel Rivet forexpertise with PowerPoint Graphics. Brain Morris is thanked forhelpful comments on the manuscript. We also thank Emma Pendle,Herb Niemirow and their Colleagues at Elsevier for their skill andsupport in putting the Special Volume together.

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Negative symptoms of schizophrenia Clinical ... · schizophrenia Negative symptoms prominent: Figure 1 Negative symptoms throughout the lifespan of schizophrenia. Schizophrenia, which