title: Negative symptoms of schizophrenia: clinical characteristics, pathophysiological substrates, experimental models and prospects for improved treatment.
abstract: Schizophrenia is a complex and multifactorial disorder generally diagnosed in young adults at the time of the first psychotic episode of delusions and hallucinations. These positive symptoms can be controlled in most patients by currently-available antipsychotics. Conversely, they are poorly effective against concomitant neurocognitive dysfunction, deficits in social cognition and negative symptoms (NS), which strongly contribute to poor functional outcome. The precise notion of NS has evolved over the past century, with recent studies - underpinned by novel rating methods - suggesting two major sub-domains: "decreased emotional expression", incorporating blunted affect and poverty of speech, and "avolition", which embraces amotivation, asociality and "anhedonia" (inability to anticipate pleasure). Recent studies implicate a dysfunction of frontocortico-temporal networks in the aetiology of NS, together with a disruption of cortico-striatal circuits, though other structures are also involved, like the insular and parietal cortices, amygdala and thalamus. At the cellular level, a disruption of GABAergic-glutamatergic balance, dopaminergic signalling and, possibly, oxytocinergic and cannibinoidergic transmission may be involved. Several agents are currently under clinical investigation for the potentially improved control of NS, including oxytocin itself, N-Methyl-d-Aspartate receptor modulators and minocycline. Further, magnetic-electrical "stimulation" strategies to recruit cortical circuits and "cognitive-behavioural-psychosocial" therapies likewise hold promise. To acquire novel insights into the causes and treatment of NS, experimental study is crucial, and opportunities are emerging for improved genetic, pharmacological and developmental modelling, 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 a platform for this Special Issue of European Neuropsychopharmacology in which five clinical and five preclinical articles treat individual themes in greater detail. This Volume provides, then, a framework for progress in the understanding - and ultimately control - of the debilitating NS of schizophrenia.
authors.affiliation: Pole of Innovation in Neuropsychiatry, Institut de Recherche Servier, 125 Chemin de Ronde, 78290 Croissy-sur-Seine, Paris, France. Electronic address: mark.millan@fr.netgrs.com.
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Millan
authors.affiliation: School of Biomedical Sciences, Medical School, Queen׳s Medical Centre, Nottingham University, Nottingham NG72UH, UK.
authors.forename: Kevin
authors.initials: K
authors.lastname: Fone
authors.affiliation: Janssen Research and Development, Turnhoutseweg 30, 2340 Beerse, Belgium.
authors.forename: Thomas
authors.initials: T
authors.lastname: Steckler
authors.affiliation: VA Greater Los Angeles Healthcare System, University of California, Los Angeles, MIRECC 210A, Bldg. 210, 11301 Wilshire Blvd., Los Angeles, CA 90073, USA.
authors.forename: William P
authors.initials: WP
authors.lastname: Horan
mesh_terms: D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D001921:Brain / Q000187:drug effects / Q000254:growth & development / Q000473:pathology / Q000503:physiopathology; D004195:Disease Models, Animal; D006801:Humans; D008959:Models, Neurological; D008960:Models, Psychological; D009434:Neural Pathways / Q000187:drug effects / Q000254:growth & development / Q000473:pathology / Q000503:physiopathology; D011569:Psychiatric Status Rating Scales; D012559:Schizophrenia / Q000175:diagnosis / Q000188:drug therapy* / Q000235:genetics / Q000503:physiopathology*; D012565:Schizophrenic Psychology
chemical_list: D014150:Antipsychotic Agents
keywords: Motivation; Oxytocin; Prefrontal cortex; Social cognition; Social interaction; Striatum