John L. Waddington

Temporal lobe epilepsy (TLE) is linked to neuron death in the hippocampus. Now David Henshall and colleagues show that miR-134 is upregulated in humans with TLE and in an experimental epilepsy model in mice. Decreasing miR-134 before induction of epilepsy in mice reduces neuron death and the generation of spontaneous seizures. Temporal lobe epilepsy is a common, chronic neurological disorder characterized by recurrent spontaneous seizures. MicroRNAs (miRNAs) are small, noncoding RNAs that regulate post-transcriptional expression of protein-coding mRNAs, which may have key roles in the pathogenesis of neurological disorders. In experimental models of prolonged, injurious seizures (status epilepticus) and in human epilepsy, we found upregulation of miR-134, a brain-specific, activity-regulated miRNA that has been implicated in the control of dendritic spine morphology. Silencing of miR-134 expression in vivo using antagomirs reduced hippocampal CA3 pyramidal neuron dendrite spine density by 21% and rendered mice refractory to seizures and hippocampal injury caused by status epilepticus. Depletion of miR-134 after status epilepticus in mice reduced the later occurrence of spontaneous seizures by over 90% and mitigated the attendant pathological features of temporal lobe epilepsy. Thus, silencing miR-134 exerts prolonged seizure-suppressant and neuroprotective actions; determining whether these are anticonvulsant effects or are truly antiepileptogenic effects requires additional experimentation.

We performed a systematic analysis of blood DNA methylation profiles from 4483 participants from seven independent cohorts identifying differentially methylated positions (DMPs) associated with psychosis, schizophrenia, and treatment-resistant schizophrenia. Psychosis cases were characterized by significant differences in measures of blood cell proportions and elevated smoking exposure derived from the DNA methylation data, with the largest differences seen in treatment-resistant schizophrenia patients. We implemented a stringent pipeline to meta-analyze epigenome-wide association study (EWAS) results across datasets, identifying 95 DMPs associated with psychosis and 1048 DMPs associated with schizophrenia, with evidence of colocalization to regions nominated by genetic association studies of disease. Many schizophrenia-associated DNA methylation differences were only present in patients with treatment-resistant schizophrenia, potentially reflecting exposure to the atypical antipsychotic clozapine. Our results highlight how DNA methylation data can be leveraged to identify physiological (e.g., differential cell counts) and environmental (e.g., smoking) factors associated with psychosis and molecular biomarkers of treatment-resistant schizophrenia.

Background Although increased mortality is one of the most consistent and accepted epidemiological findings in schizophrenia, a high rate of suicide appears unable to account fully for this burden which remains poorly understood. Method A cohort of 88 in-patients was followed prospectively over a 10-year period and predictors of survival sought among demographic, clinical and treatment variables. Results Over the decade, 39 of the 88 patients (44%) died, with no instances of suicide. Reduced survival was predicted by increasing age, male gender, edentulousness and time since pre-terminal withdrawal of antipsychotics; additionally, two indices of polypharmacy predicted reduced survival: maximum number of antipsychotics given concurrently (relative risk 2.46, 95% C1 1.10-5.47; P =0.03) and absence of co-treatment with an anticholinergic (relative risk 3.33, 95% C1 0.99-11.11; P =0.05). Conclusions Receiving more than one antipsychotic concurrently was associated with reduced survival, in the face of little or no systematic evidence to justify the widespread use of antipsychotic polypharmacy. Conversely, over-cautious attitudes to the use of adjunctive anticholinergics may require re-evaluation.

Neuregulin-1 (NRG1) has been identified as a candidate susceptibility gene for schizophrenia. In the present study the functional role of the NRG1 gene, as it relates to cognitive and social processes known to be disrupted in schizophrenia, was assessed in mice with heterozygous deletion of transmembrane (TM)-domain NRG1 in comparison with wildtypes (WT). Social affiliative behavior was assessed using the sociability and preference for social novelty paradigm, in terms of time spent in: (i) a chamber containing an unfamiliar conspecific vs. an empty chamber (sociability), or (ii) a chamber containing an unfamiliar conspecific vs. a chamber containing a familiar conspecific (preference for social novelty). Social dominance and aggressive behavior were examined in the resident-intruder paradigm. Spatial learning and memory were assessed using the Barnes maze paradigm, while spatial working memory was measured using the continuous variant of the spontaneous alternation task. Barnes maze data revealed intact spatial learning in NRG1 mutants, with elevated baseline latency to enter the escape hole in male NRG1 mutants reflecting an increase in activity level. Similarly, although a greater number of overall arm entries were found, spontaneous alternation was unaffected in NRG1 mice. Social affiliation data revealed NRG1 mutants to evidence a specific loss of WT preference for spending time with an unfamiliar as opposed to a familiar conspecific. This suggests that NRG1 mutants show a selective impairment in response to social novelty. While spatial learning and working memory processes appear intact, heterozygous deletion of TM-domain NRG1 was associated with disruption to social novelty behavior. These data inform at a novel phenotypic level on the functional role of this gene in the context of its association with risk for schizophrenia.

The principal dopamine (DA) receptors mediating the antiparkinson effects of levodopa are D1 and D2, which are anatomically and functionally segregated. We hypothesize that DA receptor-mediated effects are critical for the development of treatment-related fluctuations in Parkinson's disease (PD). We suggest that two sequential processes occur to permit the emergence of the so-called short duration response and dyskinesias: (1) functional uncoupling of D1 and D2 receptor-mediated effects with shift to the left of the dose-response curve; and, (2) sensitization of the D1-mediated striatal output due to repetitive, primarily D1 receptor stimulation by DA. These mechanisms result in excessive, pathological inhibition of basal ganglia output neurons in the GPi producing dyskinesias and the short duration response.

Neuronal nicotinic acetylcholine receptors (nAChR) are present in high abundance in the nervous system (Decker et al., 1995). There are a large number of subunits expressed in the brain that combine to form multimeric functional receptors. We have generated an α₄nAChR subunit knock-out line and focus on defining the behavioral role of this receptor subunit. Homozygous mutant mice (Mt) are normal in size, fertility, and home-cage behavior. Spontaneous unconditioned motor behavior revealed an ethogram characterized by significant increases in several topographies of exploratory behavior in Mt relative to wild-type mice (Wt) over the course of habituation to a novel environment. Furthermore, the behavior of Mt in the elevated plus-maze assay was consistent with increased basal levels of anxiety. In response to nicotine, Wt exhibited early reductions in a number of behavioral topographies, under both unhabituated and habituated conditions; conversely, heightened levels of behavioral topographies in Mt were reduced by nicotine in the late phase of the unhabituated condition. Ligand autoradiography confirmed the lack of high-affinity binding to radiolabeled nicotine, cytisine, and epibatidine in the thalamus, cortex, and caudate putamen, although binding to a number of discrete nuclei remained. The study confirms the pivotal role played by the α₄ nAChR subunit in the modulation of a number of constituents of the normal mouse ethogram and in anxiety as assessed using the plus-maze. Furthermore, the response of Mt to nicotine administration suggests that persistent nicotine binding sites in the habenulo-interpeduncular system are sufficient to modulate motor activity in actively exploring mice.

A syndrome of spontaneous orofacial dyskinesia was identified in groups of rats treated for 6 months with a wide range of neuroleptic drugs. Phenothiazines, thioxanthenes, and substituted benzamides were particularly likely to induce the syndrome. It was observed in the presence of a functional blockade of dopamine receptors and endured for at least 2.5 months after drug withdrawal. There was no relation between the syndrome and changes in striatal dopamine receptors, as indexed by the binding of tritiated spiperone and tritiated cis(Z)-flupenthixol. The syndrome parallels several of the features of clinical tardive dyskinesia, whose pathophysiology thus may not involve changes in the characteristics of striatal dopamine receptors.

Context: Recent research suggests that variation in the gene encoding dystrobrevin binding protein (DTNBP1) confers susceptibility to schizophrenia.Thus far, no specific risk haplotype has been identified in more than 1 study.Objectives: To confirm DTNBP1 as a schizophrenia susceptibility gene, to identify and replicate specific risk and protective haplotypes, and to explore relationships between DTNBP1 and the phenotype.Design: Genetic association study based on mutation detection and case-control analysis.Setting: All subjects were unrelated and ascertained from general (secondary care) psychiatric inpatient and outpatient services.Participants: The Cardiff, Wales, sample included 708 white subjects from the United Kingdom and Ireland (221 females) who met DSM-IV criteria for schizophrenia and were individually matched for age, sex, and ethnicity to 711 blood donor controls (233 females).Mean±SD age at first psychiatric contact for cases was 23.6 ± 7.7 years; mean age at ascertainment was 41.8±13.5 years.The Dublin, Ireland, sample included 219 white subjects from the Republic of Ireland who met DSM-III-R criteria for schizo-phrenia or schizoaffective disorder and 231 controls.The mean age of the Irish cases was 46.0±8.5 years; mean age at first psychiatric contact was 25.2±12.4years.Main Outcome Measure: Evidence for association between the DTNBP1 locus and schizophrenia.

A range of 3- and 6-substituted 1-phenyl-1H-3-benzazepine analogues of SK & F 38393 with D-1 agonist activity were compared for their behavioural effects in the intact adult rat and for their relative affinities for D-1 and D-2 dopamine receptors in vitro. All compounds showed selective affinity for D-1 receptors and induced prominent grooming behaviour, but those with the lower D-1: D-2 selectivity ratios also induced additional episodes of non-stereotyped sniffing, locomotion and rearing. No vacuous chewing was noted. There were marked differences in in vivo potency, extending over a 100-fold range. These responses to the most potent agonist, SK & F 77434 (3N-allyl-SK & F 38393) were reduced enantioselectively by the D-1 antagonist R-SK & F 83566. They were also reduced enantioselectively by the D-2 antagonist R-piquindone, but this pretreatment additionally released a marked vacuous chewing response to SK & F 77434. Prominent grooming may be a characteristic behavioural response to a range of D-1 agonists. It is suggested that there may be at least two forms of functional interaction between D-1 and D-2 systems, manifested concurrently in distinct elements of behaviour: one co-operative, as in the regulation of grooming, and with correlates in the regulation of pallidal neural activity; the other oppositional, as in the regulation of vacuous chewing, and with correlates in the regulation of striatal adenylate cyclase activity.

Background. Evidence suggests that schizophrenia may be a disorder with origins in early intrauterine mal-development. We have constructed a comprehensive anthropometric scale for the evaluation of dysmorphic features as an index of the nature and timing of developmental disturbance.Method. A detailed set of craniofacial and bodily measures was compiled and applied to 174 patients with schizophrenia and 80 matched control subjects.Results. Patients had significantly higher scores on this scale and displayed multiple anomalies of the craniofacial region with an overall narrowing and elongation of the mid-face and lower face. Twelve craniofacial anomalies independently distinguished patients from controls and these variables correctly classified 95% of patients and 80% of control subjects.Conclusions. This new scale, while procedurally more exacting than the Waldrop scale, more clearly defines the topography of anomalies previously suspected in individuals with schizophrenia. These findings constitute direct evidence for disturbed craniofacial development in schizophrenia and indicate origins in the foetal period during which the characteristic human facial pattern evolves in close association with brain differentiation.

The critical period hypothesis proposes that deterioration occurs aggressively during the early years of psychosis, with relative stability subsequently. Thus, interventions that shorten the duration of untreated psychosis (DUP) and arrest early deterioration may have long-term benefits.To test the critical period hypothesis by determining whether outcome in non-affective psychosis stabilises beyond the critical period and whether DUP correlates with 8-year outcome; to determine whether duration of untreated illness (DUI) has any independent effect on outcome.We recruited 118 people consecutively referred with first-episode psychosis to a prospective, naturalistic cohort study.Negative and disorganised symptoms improved between 4 and 8 years. Duration of untreated psychosis predicted remission, positive symptoms and social functioning at 8 years. Continuing functional recovery between 4 and 8 years was predicted by DUI.These results provide qualified support for the critical period hypothesis. The critical period could be extended to include the prodrome as well as early psychosis.

Urbanicity has been repeatedly associated with increased incidence of schizophrenia. This article (a) presents results of a prospective study of urbanicity and schizophrenia in Ireland and (b) reviews the literature relating to urbanicity and schizophrenia. We prospectively compared incidence of schizophrenia and other psychoses in urban and rural catchment areas (over 4years and 7years, respectively) using face-to-face, DSM-III-R diagnostic interviews. Incidence of schizophrenia in males was higher in urban compared to rural areas, with an age-adjusted incidence rate ratio (IRR) of 1.92 (1.52-2.44) for males and 1.34 (1.00-1.80) for females. Incidence of affective psychosis was lower in urban compared to rural areas for males (IRR 0.48; 0.34-0.67) and females (IRR 0.60; 0.43-0.83). These findings are consistent with the literature, which provides persuasive evidence that risk for schizophrenia increases with urban birth and/or upbringing, especially among males. Register-based studies support this conclusion more consistently than studies using face-to-face diagnostic interviews, the difference being related to power. The mechanism of association is unclear but may relate to biological or social/environmental factors or both, acting considerably before psychotic symptoms manifest. There is a diversity of potential candidates, including air pollution, cannabis and social exclusion. Urbanicity may have a synergistic effect with genetic vulnerability. Future research is likely to focus on the relationship between urbanicity and neural maldevelopment, the possibility of rural protective factors (e.g. social capital, low social fragmentation), urbanicity in developing countries, cultural variables and geographical location, and associations between urbanicity and other disorders (e.g. affective psychosis).

Quality of life (QOL) has gained importance as a global measure of social and clinical outcome in schizophrenia.To identify the clinical correlates of QOL at the time of first presentation with schizophrenia.Over two years, consecutive first-episode psychosis patients presenting to a catchment area psychiatric service underwent validated clinical assessments of premorbid adjustment, illness duration, symptoms and QOL.At presentation, subjects already had a diminished QOL. Although independent of gender and age at onset of psychosis, QOL was influenced by premorbid adjustment, duration of untreated psychosis and symptoms.Reducing the duration of untreated psychosis may have a beneficial effect on the subsequent QOL of patients presenting with schizophrenia. First-episode patients with a protracted duration of untreated psychosis or impaired premorbid adjustment may warrant specific treatment interventions to prevent the development of secondary handicaps.

The putative D-3 dopamine receptor agonist 7-OH-DPAT (10 micrograms/kg, s.c.) reduced spontaneous activity in rats, without inducing yawning; higher doses (0.1-10.0 mg/kg, s.c.) stimulated non-stereotyped sniffing, locomotion and chewing, which were attenuated by the selective D-1 antagonist BW 737C (5.0 mg/kg, s.c.) without release of any atypical behaviours. Low doses of 7-OH-DPAT may act on inhibitory D-3 receptors, while higher doses may act at stimulatory D-3 or other "D-2-like" receptors that participate in cooperative but not oppositional interactions with D-1 receptors.

OBJECTIVE--To determine whether obstetric complications occur to excess in the early histories of individuals who go on to develop schizophrenia when compared with controls, and to seek clinical correlates of any such excess. DESIGN--Contemporaneous maternity hospital records were identified and extracted verbatim, and these extracts evaluated for obstetric complications by two independent assessors who were blind to subjects9 status. SUBJECTS--65 patients having an ICD-9 diagnosis of schizophrenia, the records of the previous same sex live birth being deemed to be those of a control subject. MAIN OUTCOME MEASURE--Presence of one or more obstetric complications recorded in maternity notes of patients and controls. RESULTS--When two recognised scales for specifying obstetric complications were used the patients with schizophrenia were significantly more likely than controls to have experienced at least one obstetric complication (odds ratio 2.44, 95% confidence interval 1.08 to 6.03). Patients also showed a greater number and severity of and total score for obstetric complications, fetal distress being the only complication to occur to significant individual excess (present in five (8%) patients, absent in controls). There was a marked sex effect, male patients being more vulnerable (odds ratio 4.24, 1.39 to 12.90) to such complications. Obstetric complications in patients were unrelated to family history or season of birth but were associated with a significantly younger age at onset of illness (mean difference--4.5 years,--1.2 to--7.8 years). CONCLUSIONS--Patients with schizophrenia, particularly males, have an excess of obstetric complications in their early developmental histories, and such complications are associated with a younger age at onset of their disease. Though the data are not conclusive, they also suggest that obstetric complications may be secondary to yet earlier events.

Rats with unilateral 5,7-DHT lesions, but not 5,6-DHT lesions, showed rotational responses to 5-HTergic drugs (5MeODMT and fenfluramine) that were qualitatively similar to those induced by DAergic drugs (apomorphine and amphetamine) after 6-OHDA lesions. However, 5,7-DHT-lesioned rats also themselves showed rotational responses to DAergic drugs. The merits and limitations of a unilateral 5,7-DHT-lesioned rotating rat model for studying 5-HTergic function are discussed. It is suggested that 5-HT and DA may function in a co-operative manner in the striatum. These findings may be important for the rational pharmacotherapy of Parkinson's disease in which 5-HT as well as DA has been shown to be substantially depleted.

Abstract There is now strong evidence that Neuregulin 1 (NRG1) is a susceptibility gene for schizophrenia. NRG1 mediates some of its effects through the tyrosine kinase receptor erbB4, and analysis of gene knock‐out animals suggests that the functional interaction of NRG1 and erbB4 mediates behaviors that may model some aspects of the schizophrenia phenotype in mice. Given these findings, we have sought evidence for association between schizophrenia and erbB4. Mutation screening of erbB4 in 14 DSMIV schizophrenics revealed 15 SNPs, none of which were nonsynonymous. Analysis of the allele frequencies of each SNP in pools of 368 DSMIV schizophrenics and 368 controls provided modest evidence for association with two of the SNPs, although individual genotyping in an extended sample of 680 cases did not confirm this. However, we did find evidence for a significant interaction between the NRG1 “Icelandic” schizophrenia risk haplotype and erbB4 ( P = 0.019). The NRG1 and erbB4 interacting marker was further genotyped in an independent sample of 290 cases and 634 controls from Dublin. Interaction between NRG1 and erbB4 remained significant in the combined sample of 970 cases and 1,341 controls, OR = 2.98 (CI: 1.16–7.64), P = 0.01, although it only showed a trend in the Dublin sample alone ( P = 0.11, two tailed). Our data require independent replication, but tentatively suggest that NRG1 may mediate its effects on schizophrenia susceptibility through functional interaction with erbB4, and that genetic interaction between variants at the two loci increases susceptibility to schizophrenia. © 2005 Wiley‐Liss, Inc.

The D-1 agonist R-SK&F 38393 induced non-stereotyped sniffing, rearing and locomotor responses that were blocked by the D-1 antagonist SCH 23390. The D-2 antagonist metoclopramide failed to block sniffing but blocked rearing and locomotion. Stereotyped sniffing and locomotion induced by apomorphine were each blocked by both antagonists. Either the criteria by which compounds are designated as D-1 or D-2 selective agents require revision, or else D-1 and D-2 mechanisms are able to reciprocally interact to influence the expression of behaviour initiated by stimulation of either receptor subtype.

A wealth of evidence indicates that schizophrenia is heritable. However, the genetic mechanisms involved are poorly understood. Furthermore, it may be that genes conferring susceptibility interact with one another and with non-genetic factors to modulate risk status and/or the expression of symptoms. Genome-wide scanning and the mapping of several regions linked with risk for schizophrenia have led to the identification of several putative susceptibility genes including neuregulin-1 (NRG1), dysbindin (DTNBP1), regulator of G-protein signalling 4 (RGS4), catechol-o-methyltransferase (COMT), proline dehydrogenase (PRODH) and disrupted-in-schizophrenia 1 (DISC1). Genetic animal models involving targeted mutation via gene knockout or transgenesis have the potential to inform on the role of a given susceptibility gene on the development and behaviour of the whole organism and on whether disruption of gene function is associated with schizophrenia-related structural and functional deficits. This review focuses on data regarding the behavioural phenotype of mice mutant for schizophrenia susceptibility genes identified by positional candidate analysis and the study of chromosomal abnormalities. We also consider methodological issues that are likely to influence phenotypic effects, as well as the limitations associated with existing molecular techniques.

While it has long been considered whether the pathobiology of schizophrenia extends beyond its defining symptoms to involve diverse domains of abnormality, in the manner of a systemic disease, studies of neuromotor dysfunction have been confounded by treatment with antipsychotic drugs. This challenge has been illuminated by a new generation of studies on first-episode schizophrenia before initiation of antipsychotic treatment and by opportunities in developing countries to study chronically ill patients who have remained antipsychotic naive due to limitations in provision of psychiatric care. Building from studies in antipsychotic-naive patients, this article reviews 2 domains of neuromotor dysfunction in schizophrenia: neurological signs and involuntary movements. The presence and characteristics of neurological signs in untreated vis-à-vis treated psychosis indicate a vulnerability marker for schizophrenia and implicate disruption to neuronal circuits linking the basal ganglia, cerebral cortex, and cerebellum. The presence and characteristics of involuntary movements in untreated vis-à-vis treated psychosis indicate an intrinsic feature of the disease process and implicate dysfunction in cortical-basal ganglia-cortical circuitry. These neuromotor disorders of schizophrenia join other markers of subtle but pervasive cerebral and extracerebral, systemic dysfunction, and complement current concepts of schizophrenia as a disorder of developmentally determined cortical-basal ganglia-thalamo-cortical/cerebellar network disconnectivity.

• Little is known of factors that, on an individual basis, confer vulnerability to the emergence of involuntary movements (tardive dyskinesia) during long-term neuroleptic treatment. In this study of 88 chronic schizophrenic inpatients, 22 variables (four demographic, 14 medication history, and four features of illness) were compared for any association(s) with the presence, by differing topographies and criteria of abnormality, and severity of involuntary movements. Irrespective of the criterion used, the presence of marked cognitive dysfunction—muteness bore a consistent and highly significant primary association with both the presence and the overall severity of orofacial dyskinesia; no such association was found in relation to the presence of limb-truncal dyskinesia. Flattening of affect was the only other variable consistently associated with the presence of orofacial movements. The reliability and prominence of the association between the presence of orofacial, but not of limb-truncal, movements and cognitive dysfunction—negative symptoms suggest that these varying topographies may not constitute a unitary syndrome. This strong association, not with indexes of neuroleptic exposure but rather with features of the illness for which that treatment was prescribed, suggests some neurologic process, more subtle than may previously have been appreciated, as a vulnerability factor of some importance. In schizophrenia it appears to be intimately related to the disease process.

Ketamine elicits rapid onset antidepressant effects in patients with clinical depression through mechanisms hypothesized to involve the genesis of neocortical dendritic spines and synapses. Yet, the observed changes in dendritic spine morphology usually emerge well after ketamine clearance, raising questions about the link between rapid behavioral effects of ketamine and plasticity.Here, we used two-photon glutamate uncaging/imaging to focally induce spinogenesis in the medial prefrontal cortex, directly interrogating baseline and ketamine-associated plasticity of deep layer pyramidal neurons in C57BL/6 mice. We combined pharmacological, genetic, optogenetic, and chemogenetic manipulations to interrogate dopaminergic mechanisms underlying ketamine-induced rapid enhancement in evoked plasticity and associated behavioral changes.We found that ketamine rapidly enhances glutamate-evoked spinogenesis in the medial prefrontal cortex, with timing that matches the onset of its behavioral efficacy and precedes changes in dendritic spine density. Ketamine increases evoked cortical spinogenesis through dopamine Drd1 receptor (Drd1) activation that requires dopamine release, compensating blunted plasticity in a learned helplessness paradigm. The enhancement in evoked spinogenesis after Drd1 activation or ketamine treatment depends on postsynaptic protein kinase A activity. Furthermore, ketamine’s behavioral effects are blocked by chemogenetic inhibition of dopamine release and mimicked by activating presynaptic dopaminergic terminals or postsynaptic Gαs-coupled cascades in the medial prefrontal cortex.Our findings highlight dopaminergic mediation of rapid enhancement in activity-dependent dendritic spinogenesis and behavioral effects induced by ketamine.

It is not only unclear why hallucinations in schizophrenia occur with different prevalence by modality, but also to what extent they do. Reliable prevalence estimates of hallucinations by modality in schizophrenia are currently lacking, particularly for non-auditory hallucinations. Studies have also tended to report lifetime, not point prevalence by modality. This study assessed the prevalence and co-occurrence of hallucinations, for both lifetime and point prevalence, across the auditory, visual, olfactory, and tactile modalities, in people diagnosed with chronic schizophrenia-spectrum disorders in Ireland (N=693) and Australia (N=218). Lifetime prevalence was 64–80% auditory, 23–31% visual, 9–19% tactile, and 6–10% olfactory. Past month prevalence was 23–27% auditory, 5–8% visual, 4–7% tactile, and 2% olfactory. The majority of participants had only hallucinated in one modality, with this nearly always being the auditory. Approximately one-third had hallucinated in two modalities, most commonly the auditory and visual. Most currently hallucinating patients also hallucinated in a single modality, again, nearly always the auditory. Whereas 30–37% of patients with lifetime auditory hallucinations had experienced visual hallucinations, 83–97% of patients with experience of visual hallucinations had experienced auditory hallucinations. These findings help delineate the modality distribution of hallucinations in schizophrenia, and provide an explanatory target for theoretical models.

Neurodevelopmental disorders such as intellectual disability, autism spectrum disorder and schizophrenia lack precise boundaries in their clinical definitions, epidemiology, genetics and protein–protein interactomes. This calls into question the appropriateness of current categorical disease concepts. Recently, there has been a rising tide to reformulate neurodevelopmental nosological entities from biology upward. To facilitate this developing trend, we propose that identification of unique proteomic signatures that can be strongly associated with patient’s risk alleles and proteome-interactome-guided exploration of patient genomes could define biological mechanisms necessary to reformulate disorder definitions.

Background It is unclear whether there is a direct link between economic crises and changes in suicide rates. Aims The Lopez-Ibor Foundation launched an initiative to study the possible impact of the economic crisis on European suicide rates. Method Data was gathered and analysed from 29 European countries and included the number of deaths by suicide in men and women, the unemployment rate, the gross domestic product (GDP) per capita, the annual economic growth rate and inflation. Results There was a strong correlation between suicide rates and all economic indices except GPD per capita in men but only a correlation with unemployment in women. However, the increase in suicide rates occurred several months before the economic crisis emerged. Conclusions Overall, this study confirms a general relationship between the economic environment and suicide rates; however, it does not support there being a clear causal relationship between the current economic crisis and an increase in the suicide rate.

Determining the extent to which relationships between duration of untreated psychosis (DUP) and outcome endure longitudinally across the lifetime course of psychotic illness requires prospective, systematic studies of epidemiologically representative incidence cohorts across decades. Transience, persistence, or heterogeneity in associations between DUP and distinct outcome domains are yet to be investigated over such time frames.Prospective, sequential follow-up studies of an epidemiologically representative first-episode psychosis incidence cohort in Ireland were conducted at 6 months and 4, 8, 12, and 20 years (N=171). Linear mixed-model analyses were applied to determine whether prospective associations of DUP with symptoms, functioning, and quality of life were consistent or varied across psychotic illness trajectory over a 20-year period. Evaluations included time, DUP quartile, and DUP quartile-by-time interaction effects.Prospective, sequential follow-ups showed positive and negative symptoms, function, and quality of life to exhibit distinct trajectories of improvement in relation to shorter DUP. Despite heterogeneity in course and relationship to premorbid features, associations between shorter DUP and greater improvement were still evident 20 years after the first psychotic episode. Across the long-term course of psychotic illness, trajectories of association between shorter DUP and better outcome differed between domains of psychopathology, functionality, and quality of life. Nevertheless, such associations with shorter DUP were sustained for at least 20 years.These profiles indicate that while associations between DUP and long-term outcome can vary according to the domain of outcome, they are sustained across decades in a manner that could not be fully accounted for in terms of premorbid features or lead-time bias.

In the first half of the 20th century, well before the antipsychotic era, paratonia, Gegenhalten and psychomotor hypertonia were described as new forms of hypertonia intrinsic to particular psychoses and catatonic disorders. A series of astute clinical observations and experiments supported their independence from rigidity seen in Parkinson's disease. After World War II, motor disorders went out of fashion in psychiatry, with drug-induced parkinsonism becoming the prevailing explanation for all involuntary resistance to passive motion. With the 'forgetting' of paratonia and Gegenhalten, parkinsonism became the prevailing reading grid, such that the rediscovery of hypertonia in antipsychotic-naive patients at the turn of the 21st century is currently referred to as "spontaneous parkinsonism", implicitly suggesting intrinsic and drug-induced forms to be the same. Classical descriptive psychopathology gives a more nuanced view in suggesting two non-parkinsonian hypertonias: (i) locomotor hypertonia corresponds to Ernest Dupré's paratonia and Karl Kleist's reactive Gegenhalten; it is a dys-relaxation phenomenon that often needs to be activated. (ii) Psychomotor hypertonia is experienced as an admixture of assistance and resistance that partially overlaps with Kleist's spontaneous Gegenhalten, but was convincingly isolated by Henri Claude and Henri Baruk thanks to electromyogram recordings; psychomotor hypertonia is underpinned by "anticipatory contractions" of cortical origin, occurrence of which in phase or antiphase with the movement accounted for facilitation or opposition to passive motions. This century-old knowledge is not only of historical interest. Some results have recently been replicated in dementia and as now known to involve specific premotor systems.

Psychiatry is currently negotiating several challenges that are typified by (but are not unique to) schizophrenia: do periodic refinements in operational diagnostic algorithms (a) resolve intricacies and subtleties within and between psychotic and non-psychotic disorders that are authentic and impactful, or (b) constitute arbitrary and porous boundaries that should be complemented, or even replaced, by dimensional-continuum concepts of abnormality and dysfunction. Critically, these issues relate not only to apparent boundaries between diagnoses but also to those between 'health' and 'illness'. This article considers catatonia within evolving dimensional-continuum approaches to the description of impairment and dysfunction among psychotic and non-psychotic disorders. It begins by considering the definition and assessment of catatonia vis-à-vis other disorders, followed by its long-standing conjunction with schizophrenia, relationship with antipsychotic drug treatment, transdiagnostic perspectives and relationships, and pathobiological processes. These appear to involve dysfunction across elements in overlapping neural networks that result in a confluence of psychopathology and intrinsic hypo- and hyperkinetic motor dysfunction. It has been argued that while current diagnostic approaches can have utility in defining groups of cases that are closely related, contemporary evidence indicates categorical diagnoses to be arbitrary divisions of what is essentially a continuous landscape. Psychotic and non-psychotic diagnoses, including catatonia, may reflect arbitrary areas around points of intersection between orthogonal dimensions of psychopathology and intrinsic movement disorder in a poly-dimensional space that characterises this continuous landscape of mental health and dysfunction.

Twenty eight schizophrenic patients and 20 normal volunteers underwent proton magnetic resonance spectroscopy (MRS) on the left temporal and frontal lobe regions. Male patients showed a significant reduction in frontal but not temporal n-acetylaspartate (an intraneuronally distributed metabolite) in comparison with either male controls or female patients; frontal choline was raised in male patients relative to these groups. Putative neurodevelopmental indices, including obstetric complications, family history of schizophrenia, and minor physical anomalies, proved unrelated to MRS resonances. However, multiple aspects of memory function in patients were related to temporal but not frontal creatine, a pattern that was not apparent among controls. These MRS findings complement some previous structural MRI studies and much clinical and epidemiological evidence of important gender differences in schizophrenia. The findings also suggest that memory dysfunction in patients with schizophrenia may be associated with a particular pattern of temporal lobe metabolism on MRS.

The epidemiology of first-episode psychosis is poorly understood because of the paucity of systematic studies, yet it constitutes the fundamental basis for understanding the disorder and the foundations on which clinical, biological, therapeutic, and long-term outcome studies are built. A particular need is to clarify the diagnostic breadth of first-episode psychosis and, on this basis, to undertake systematic comparisons across representative populations of the psychoses, to include comparisons with first-episode mania. Considered here is the new generation of prospective studies that may be able to inform in some way on these issues. Attainment of the above goals requires prolonged accrual of "all" cases of nonaffective, affective, and any other psychotic illness, including first-episode mania, to derive the required representative populations. To illustrate some of the challenges, the structure of the Cavan-Monaghan prospective first episode study is described and its interim findings are outlined, as rural Ireland provides psychiatric care based on strict catchment areas and is characterized by substantive ethnic and socioeconomic homogeneity and stability. It is argued that there are 3 primary diagnostic nodes (schizophrenia spectrum psychosis, bipolar disorder, and major depressive disorder with psychotic features) around which there exist numerous additional, overlapping, and well-populated diagnostic categories that are distinct only in terms of their operational definition. Only through systematic, epidemiologically based studies that access this intrinsic diversity are we likely to understand fully the origins and pathobiology of first-episode psychosis.

A recent study identified a putative association between variants in the regulator of G-protein signalling 4 (RGS4) and schizophrenia, Chowdari et al. [2002: Hum Mol Genet 11: 1373-1380]. RGS4 is both a positional and functional candidate gene for schizophrenia. Chowdari and colleagues identified association at this locus in a number of distinct and ethnically diverse samples, although the pattern of association was not the same in all the samples. Our study attempted to replicate this association in an independent Irish sample of schizophrenia cases and controls. We succeeded in detecting evidence of association at the RGS4 locus. The signal comes from a four-marker haplotype that is in significant excess in our case sample. The same haplotype is in excess in the Caucasian schizophrenia sample used by Chowdari et al. [2002: Hum Mol Genet 11: 1373-1380]. This study provides further support for the contribution of RGS4 to schizophrenia susceptibility.

Nine structurally related 1-phenyl-1H-3-benzazepine derivatives and two thienopyridines were tested for agonist and antagonist properties at the adenylate cyclase-coupled D1 dopamine receptor in homogenates of the striatum of the rat. The benzazepines SK&F 77434 and SK&F 82958, both of which contain a catechol ring, were agonists; the intrinsic activity of SK&F 77434 was similar to that of SK&F 38393, whereas SK&F 82958 was a full agonist. The remaining benzazepines inhibited the stimulation of adenylate cyclase by dopamine. Antagonist potency depended on the nature of the substituent at position 7 of the benzazepine molecule, 7-halogen compounds being the most potent. The Ki values, obtained from analysis of the antagonism of dopamine-stimulated adenylate cyclase, were significantly correlated with the Ki values for displacement of D1 ligands in binding experiments. Furthermore, antagonist activity of the resolved racemic benzazepine SK&F 83566 resided almost exclusively in the R-enantiomer. The thienopyridine derivatives SK&F 89641 and SK&F 89145 were partial agonists with greater efficacies than SK&F 38393.

Two recent association studies have implicated the neuregulin-1 gene (NRG1) at chromosome 8p21-22 as a susceptibility gene for schizophrenia. Stefansson et al identified three 'at-risk' haplotypes (HapA, B and C) which spanned the NRG1 locus and shared a common core haplotype. Subsequently, they demonstrated evidence that the core haplotype was associated with schizophrenia in an independent Scottish sample. To confirm and refine this haplotype we investigated the NRG1 locus in an independent Irish case-control sample. We did not find the core haplotype to be associated in our sample. However, we identified a refined 2-marker haplotype (HapB(IRE)) that shared common alleles with one of the Icelandic 'at-risk' haplotypes and is in significant excess in the Irish cases (19.4%) vs controls (12.3%) (P=0.013). This refined 'at-risk' haplotype is also in significant excess in the Scottish case sample (17.0% vs 13.5%; P=0.036). Interestingly, this refined 'at-risk' haplotype is positioned close to an EST cluster of unknown function (Hs.97362) within intron 1 of NRG1.

Although it is well recognised that schizophrenic patients are more often born in winter, the significance of this finding remains obscure. Data relating to season of birth and family history were analysed for 561 patients with an ICD-9 diagnosis of schizophrenia. Patients with no family history of any psychiatric disorder group were significantly more likely to be born in winter than patients with a first-degree relative affected by schizophrenia. In comparison with normal population controls, only those without a family history exhibited a significant excess of winter births, suggesting an environmental factor of greater aetiological significance in these patients.

The effects of age on the binding of dopaminergic ligands to rat striatal membranes were studied. When compared with four month old animals, at 22 months there was a significant decrease in the density of specific binding sites for the D-2 ligand [3H]spiperone while their affinity was unaltered. However, the specific binding of [3H]piflutixol to D-1 sites was unaltered between these age groups. The non-specific binding of [3H]piflutixol was significantly increased in aged preparations. Age-related loss of striatal D-2 dopamine receptors does not extend to the D-1 type. Alterations in non-specific [3H]piflutixol binding may reflect other pathophysiological changes associated with senescence.

Transgenic R6/1 mice incorporate a human genomic fragment containing promoter elements exon 1 and a portion of intron 2 of the Huntingtin gene responsible for Huntington's disease. They develop late-onset neurological deficits in a manner similar to the motor abnormalities of the disorder. As essential fatty acids are phospholipid components of cell membranes which may influence cell death and movement disorder phenotype, R6/1 and normal mice were randomised to receive a mixture of essential fatty acids or placebo on alternate days throughout life. Over mid-adulthood, topographical assessment of behaviour revealed R6/1 transgenics to evidence progressive shortening of stride length, with progressive reductions in locomotion, elements of rearing, sniffing, sifting and chewing, and an increase in grooming. These deficits were either not evident or materially diminished in R6/1 transgenics receiving essential fatty acids. R6/1 transgenics also showed reductions in body weight and in brain dopamine D(1)-like and D(2)-like quantitative receptor autoradiography which were unaltered by essential fatty acids.These findings indicate that early and sustained treatment with essential fatty acids are able to protect against motor deficits in R6/1 transgenic mice expressing exon 1 and a portion of intron 2 of the Huntingtin gene, and suggest that essential fatty acids may have therapeutic potential in Huntington's disease.

SYNOPSIS The significance of the excess of obstetric complications which appears to characterize the histories of schizophrenic patients is critically dependent on the validity of the source of obstetric information, especially when this is obtained by maternal recall. Twenty-one biological mothers of 17 schizophrenic and four other patients were interviewed for their recollections of individual events characterizing the pregnancy and delivery relating to each patient. These were then compared with those events documented in maternity hospital records. Only in two of the 21 instances (9·5%) were inconsistencies of detail apparent which would have affected the designation of the relevant patient as having, or as not having, experienced major obstetric complication(s). It is concluded that maternal recall can be a surprisingly accurate source of obstetric information in relation to research on schizophrenia.

Background There has been controversy as to whether early intervention in psychosis can improve the outcome of the disorder. Aims To establish if there is an association between duration of untreated psychosis and the 4-year outcome of persons with a first episode of psychosis. Method Prospective naturalistic follow-up study of the outcome of consecutive first presentations with DSM–IV psychosis attending a community-based psychiatric service. Results A longer duration of untreated psychosis was associated with a significantly poorer functional and symptomatic outcome 4 years later. For schizophrenia and schizophreniform disorder, each increment in duration of untreated psychosis was associated with a 7.8 point decrease in global functioning and an increase in positive symptoms scores by 1.9 points. Conclusions This study extends the findings of short-term follow-up studies by confirming an association between duration of untreated psychosis and ‘midterm’ outcome.

Many studies have confirmed that the risk of suicide is high in the period after first presentation. There is relatively little information about the risk of suicide using illness onset as the starting point. We assessed suicidality in a cohort of 166 individuals from an urban catchment area during the period of untreated psychosis and at 4 year follow up. Nearly 10% of individuals attempted suicide prior to presentation. Four years later 18% had made a suicide attempt and 3% completed suicide. Suicide attempts prior to presentation were associated with a longer duration of untreated psychosis.

Abnormal involuntary movements indistinguishable from those now described as tardive dyskinesia were reported in schizophrenic patients by Kraepelin long before the introduction of neuroleptic drugs. Two large surveys of mental hospital patients including patients who had never received neuroleptics also revealed involuntary movements; indeed, the incidence was not substantially different from that in drug-treated patients. This fact casts doubt on the widely held assumption that these movements are persistent and irreversible effects of neuroleptic drugs. In an animal model of dyskinesia, abnormal movements were seen after administration of a phenothiazine and a thioxanthene but not after haloperidol. The syndrome appeared to be unrelated to dopamine receptor blockade or to changes in dopamine receptors. In postmortem striatal tissue from patients with schizophrenia, ligand binding to D-1 and D-2 dopamine receptors was not increased in patients who had been found to have abnormal involuntary movements in comparison with those who did not have such movements; as previously reported, binding to D-2 receptors was increased in patients with schizophrenia in comparison with controls. It is concluded that dyskinetic changes occur as a consequence of the process of schizophrenia and perhaps other diseases. Whether or not persistent and irreversible changes can be caused either in animals or humans by neuroleptic administration has yet to be clearly established. Whether they occur as a manifestation of the disease process or a consequence of drug administration, such dyskinesias are unassociated with changes in D-1 or D-2 receptors.

Cannabis use confers a two-fold increase in the risk for psychosis, with adolescent use conferring even greater risk. A high–low activity catechol-O-methyltransferase (COMT) polymorphism may modulate the effects of adolescent Δ-9-tetrahydrocannabinol (THC) exposure on the risk for adult psychosis. Mice with knockout of the COMT gene were treated chronically with THC (4.0 and 8.0 mg/kg over 20 days) during either adolescence (postnatal days (PDs) 32–52) or adulthood (PDs 70–90). The effects of THC exposure were then assessed in adulthood across behavioral phenotypes relevant for psychosis: exploratory activity, spatial working memory (spontaneous and delayed alternation), object recognition memory, social interaction (sociability and social novelty preference), and anxiety (elevated plus maze). Adolescent THC administration induced a larger increase in exploratory activity, greater impairment in spatial working memory, and a stronger anti-anxiety effect in COMT knockouts than in wild types, primarily among males. No such effects of selective adolescent THC administration were evident for other behaviors. Both object recognition memory and social novelty preference were disrupted by either adolescent or adult THC administration, independent of genotype. The COMT genotype exerts specific modulation of responsivity to chronic THC administration during adolescence in terms of exploratory activity, spatial working memory, and anxiety. These findings illuminate the interaction between genes and adverse environmental exposures over a particular stage of development in the expression of the psychosis phenotype.

In agreement with other workers we report increased [3H]R05-4864 binding in kainate-lesioned rat striatum. [3H]R05-4864 binding, a possible glial marker, was also increased in temporal cortex obtained post-mortem from patients with Alzheimer's disease. [3H]Flunitrazepam binding was decreased in these brain samples, possibly indicative of neuronal cell loss. It is suggested that the poor binding characteristics of [3H]R05-4864 in human brain samples may limit its usefulness in assessing gliosis.

With the introduction of the selective D-1 dopamine receptor agonist and antagonist benzazepines, especially as enantiomeric pairs, there is now a range of D-1 compounds to complement the previously available selective D-2 agents. These have been used to investigate whether sub-types of dopamine receptors might be differentially involved in locomotor behavior. Stereotyped locomotion induced by the non-selective D-2 agonist apomorphine and by the selective D-2 agonist RU 24213 were blocked by the selective D-2 antagonists metoclopramide and Ro 22-2586 ((−)-piquindone). Responses to either D-2 agonist were also blocked by the selective D-1 antagonists SCH 23390 and R-(but not S-) SK&F 83566. Non-stereotyped locomotion was induced by R-(but notS-SK&F 38393, a stereoselective D-1 agonist, and was blocked by SCH 23390. Responses to the D-1 agonist were also antagonised by metoclopramide. Such results suggest concerted D-1:D-2 interplay in the regulation of at least some dopaminergic behaviors, such as locomotion.

Four benzazepine derivatives, racemic SK&F 38393, its resolved R- and S-enantiomers, anad SCH 23390 have been investigated for their interactions with striatal D1 and D2 dopamine receptors, as indexed by the binding of [3H]piflutixol and [3H]spiperone respectively. For the agonist SK&F 38393, its R-enantiomer was active in displacing [3H]piflutixol while its S-antipode was 100 fold less potent. In contrast, both enantiomers showed similar and negligible activity to displace [3H]spiperone. SCH 23390, an antagonist analogue with an R-configuration, potently displaced [3H]piflutixol but not [3H]spiperone. R-SK&F 38393 and SCH 23390 may help clarify the structural requirements for, and functional consequences of, selective actions at the D1 dopamine receptor.

Clinical genetic studies have implicated neuregulin-1 [NRG1] as a leading susceptibility gene for schizophrenia. NRG1 is known to play a significant role in the developing brain, which is consistent with the prevailing neurodevelopmental model of schizophrenia. Thus, the emotional and social phenotype of adult mice with heterozygous ‘knockout’ of transmembrane [TM]-domain NRG1 was examined further in both sexes. Emotional/anxiety-related behaviour was assessed using the elevated plus-maze and the light–dark test. Social behaviour was examined in terms of dyadic interactions between NRG1 mutants and an unfamiliar C57BL6 conspecific in a novel environment. There was no effect of NRG1 genotype on performance in either test of emotionality/anxiety. However, previous reports of hyperactivity in NRG1 mutants were confirmed in both paradigms. In the test of social interaction, aggressive following was increased in NRG1 mutants of both sexes, together with an increase in walkovers in female mutants. These findings elaborate the specificity of the NRG1 phenotype for the social rather than the emotional/anxiety-related domain. They indicate that NRG1 is involved in the regulation of reciprocal social interaction behaviour and thus suggest a putative role for NRG1 in a schizophrenia-related endophenotype.

The duration of untreated psychosis is well recognised as an independent predictor of symptomatic and functional outcome in the short term and has facilitated the development of worldwide early intervention programmes. However, the extent and mechanisms by which it might influence prognosis beyond a decade remain poorly understood. The authors examined the relationship between duration of untreated psychosis and outcome 12 years after a first episode of psychosis and assessed whether its relationship with function is affected by symptoms in a prospective, 12-year follow-up of an epidemiologically-based inception cohort. Longer duration of untreated psychosis predicted poorer remission status, more severe positive and negative symptoms, and greater impairment in general functioning, social functioning and quality of life at 12 years on standardised measures, independent of other factors at baseline. It was not associated with gainful employment, for which education was the only predictor, or independent living, for which age was the only predictor. The relationship between duration of untreated psychosis and functional outcome was mediated by concurrent psychopathology, particularly negative symptoms. These results provide qualified support for the potential long-term benefit of reduction in the duration of untreated psychosis in terms of improvement in symptoms and functional outcome. Its failure to predict real-life outcomes such as independent living and gainful employment could reflect the importance of pre-existing socio-cultural factors such as individual opportunity. The relationship between duration of untreated psychosis and negative symptoms was largely responsible for its effect on function, suggesting a possible long-term protective mechanism against disability.

Rats were treated with haloperidol (1.5mg/kg/day) in their drinking water for 9 months, with or without a subsequent withdrawal period of 7–10 days. Compared with controls, spontaneous locomotion and apomorphine-induced stereotypy were reduced in rats maintained on haloperidol whereas both behaviours were increased after the withdrawal period. Maximum specific 3H-spiperone binding to striatal membrane preparations was increased (about 65%) in drug-treated rats with or without a withdrawal period. The dissociation constant for 3H-spiperone binding was significantly increased only in those rats maintained on haloperidol with no withdrawal period. The increase in maximum binding of 3H-spiperone was larger than that reported after less prolonged administration of neuroleptics. The size of the change should be taken into account in assessing the increased ligand binding reported in post-mortem brains of schizophrenics.

Catechol-O-methyltransferase is an important enzyme in the metabolism of dopamine and an important regulator of aspects of dopamine-dependent working memory in prefrontal cortex that are disturbed in schizophrenia. This study investigated the phenotype of mice with heterozygous deletion vs. homozygous knockout of the catechol-O-methyltransferase gene across paradigms that access processes relevant for psychotic illness. Homozygotes evidenced improved performance in spontaneous alternation, an index of immediate spatial working memory; this effect appeared more substantive in males and was reflected in performance in aspects of the Barnes maze, an index of spatial learning/memory. Heterozygotes evidenced impaired performance in object recognition, an index of recognition memory; this effect was evident for both sexes at a retention interval of 5 min but appeared more enduring in males. There were no material effects for either genotype in relation to sociability or social novelty preference. While homozygous catechol-O-methyltransferase deletion results in improvement in spatial learning/working memory with little effect on social behavior, heterozygous deletion results in impairment of recognition memory. We have reported recently, using similar methods, that mice with deletion of the schizophrenia risk gene neuregulin-1 evidence disruption to social behavior, with little effect on spatial learning/working memory. The data suggest that catechol-O-methyltransferase and neuregulin-1 may influence, respectively, primarily cognitive and social endophenotypes of the overall schizophrenia syndrome.

There is a paucity of animal models by which the contributions of environmental and genetic factors to the pathobiology of psychosis can be investigated. This study examined the individual and combined effects of chronic social stress during adolescence and deletion of the schizophrenia risk gene neuregulin-1 (NRG1) on adult mouse phenotype. Mice were exposed to repeated social defeat stress during adolescence and assessed for exploratory behaviour, working memory, sucrose preference, social behaviour and prepulse inhibition in adulthood. Thereafter, in vitro cytokine responses to mitogen stimulation and corticosterone inhibition were assayed in spleen cells, with measurement of cytokine and brain-derived neurotrophic factor (BDNF) mRNA in frontal cortex, hippocampus and striatum. NRG1 mutants exhibited hyperactivity, decreased anxiety, impaired sensorimotor gating and reduced preference for social novelty. The effects of stress on exploratory/anxiety-related parameters, spatial working memory, sucrose preference and basal cytokine levels were modified by NRG1 deletion. Stress also exerted varied effect on spleen cytokine response to concanavalin A and brain cytokine and BDNF mRNA expression in NRG1 mutants. The experience of psychosocial stress during adolescence may trigger further pathobiological features that contribute to the development of schizophrenia, particularly in those with underlying NRG1 gene abnormalities. This model elaborates the importance of gene × environment interactions in the etiology of schizophrenia.

We present a method for the automatic localization of facial landmarks that integrates nonrigid deformation with the ability to handle missing points. The algorithm generates sets of candidate locations from feature detectors and performs combinatorial search constrained by a flexible shape model. A key assumption of our approach is that for some landmarks there might not be an accurate candidate in the input set. This is tackled by detecting partial subsets of landmarks and inferring those that are missing, so that the probability of the flexible model is maximized. The ability of the model to work with incomplete information makes it possible to limit the number of candidates that need to be retained, drastically reducing the number of combinations to be tested with respect to the alternative of trying to always detect the complete set of landmarks. We demonstrate the accuracy of the proposed method in the face recognition grand challenge database, where we obtain average errors of approximately 3.5 mm when targeting 14 prominent facial landmarks. For the majority of these our method produces the most accurate results reported to date in this database. Handling of occlusions and surfaces with missing parts is demonstrated with tests on the Bosphorus database, where we achieve an overall error of 4.81 and 4.25 mm for data with and without occlusions, respectively. To investigate potential limits in the accuracy that could be reached, we also report experiments on a database of 144 facial scans acquired in the context of clinical research, with manual annotations performed by experts, where we obtain an overall error of 2.3 mm, with averages per landmark below 3.4 mm for all 14 targeted points and within 2 mm for half of them. The coordinates of automatically located landmarks are made available on-line.

Cannabis use confers a two-fold increase in risk for psychosis, with adolescent use conferring an even greater risk. A high-low activity polymorphism in catechol-O-methyltransferase (COMT), a gene encoding the COMT enzyme involved in dopamine clearance in the brain, may interact with adolescent cannabis exposure to increase risk for schizophrenia. The impact of such an interaction on central neurotransmitter pathways implicated in schizophrenia is unknown. Male mice with knockout of the COMT gene were treated chronically with delta-9-tetrahydrocannabinol (THC) during adolescence (postnatal day 32-52). We measured the size and density of GABAergic cells and the protein expression of cannabinoid receptor 1 (CB1R) in the prefrontal cortex (PFC) and hippocampus (HPC) in knockout mice relative to heterozygous mutants and wild-type controls. Size and density of dopaminergic neurons was also assessed in the ventral tegmental area (VTA) across the genotypes. COMT genotype × THC treatment interactions were observed for: (1) dopaminergic cell size in the VTA, (2) CB1R protein expression in the HPC, and (3) parvalbumin (PV) cell size in the PFC. No effects of adolescent THC treatment were observed for PV and dopaminergic cell density across the COMT genotypes. COMT genotype modulates the effects of chronic THC administration during adolescence on indices of neurotransmitter function in the brain. These findings illuminate how COMT deletion and adolescent cannabis use can interact to modulate the function of neurotransmitters systems implicated in schizophrenia.

The Schizophrenia Psychiatric Genome-wide Association (GWAS) Consortium recently reported on five novel schizophrenia susceptibility loci. The most significant finding mapped to a micro-RNA, MIR-137, which may be involved in regulating the function of other schizophrenia and bipolar disorder susceptibility genes. We genotyped 821 patients with confirmed DSM-IV diagnoses of schizophrenia, bipolar affective disorder I and schizoaffective disorder for the risk SNP (rs1625579) and investigated the clinical profiles of risk allele carriers using a within-case design. We also assessed neurocognitive performance in a subset of cases (n = 399) and controls (n = 171). Carriers of the risk allele had lower scores for an OPCRIT-derived positive symptom factor (p = 0.04) and lower scores on a lifetime measure of psychosis incongruity (p = 0.017). Risk allele carriers also had more cognitive deficits involving episodic memory and attentional control. This is the first evidence that the MIR-137 risk variant may be associated with a specific subgroup of psychosis patients. Although the effect of this single SNP was not clinically relevant, investigation of the impact of carrying multiple risk SNPs in the MIR-137 regulatory network on diagnosis and illness profile may be warranted.

Patients who experience the onset of psychotic illness with a comorbid diagnosis of cannabis dependence experience poor clinical outcomes. Few studies have identified interventions that reduce cannabis use and improve clinical outcome in this population. We undertook a multi-center, randomized controlled trial of a group psychological intervention for psychosis with comorbid cannabis dependence to determine whether there was any impact on cannabis use symptoms, global functioning, insight, attitudes to treatment and subjective quality of life. Across three centers, we compared a group psychological intervention, based on cognitive behavioral therapy and motivational interviewing, with treatment as usual among patients experiencing their first psychotic episode or early in the course of psychotic illness. Substance misuse and indices of clinical outcome were assessed at baseline, 3 months and 1 year. At 3 month and 1 year follow-ups, there was no evidence for an intervention effect on cannabis use, symptoms, global functioning insight or attitude to treatment. However, the intervention improved subjective quality of life at 3 months and this effect was sustained at 1 year. Over the early phase of psychotic illness, group psychological interventions for those with comorbid cannabis dependence improved subjective quality of life. However, this was not associated with reduction in use of cannabis or improvement in clinical outcomes.

Risk of schizophrenia is likely to involve gene × environment (G × E) interactions. Neuregulin 1 (NRG1) is a schizophrenia risk gene, hence any interaction with environmental adversity, such as maternal infection, may provide further insights into the basis of the disease. This study examined the individual and combined effects of prenatal immune activation with polyriboinosinic-polyribocytidilic acid (Poly I:C) and disruption of the schizophrenia risk gene NRG1 on the expression of behavioral phenotypes related to schizophrenia. NRG1 heterozygous (NRG1 HET) mutant breeding pairs were time-mated. Pregnant dams received a single injection (5 mg/kg i.p.) of Poly I:C or vehicle on gestation day 9 (GD9). Offspring were then cross-fostered to vehicle-treated or Poly I:C-treated dams. Expression of schizophrenia-related behavioral endophenotypes was assessed at adolescence and in adulthood. Combining NRG1 disruption and prenatal environmental insult (Poly I:C) caused developmental stage-specific deficits in social behavior, spatial working memory and prepulse inhibition (PPI). However, combining Poly I:C and cross-fostering produced a number of behavioral deficits in the open field, social behavior and PPI. This became more complex by combining NRG1 deletion with both Poly I:C exposure and cross-fostering, which had a robust effect on PPI. These findings suggest that concepts of G × E interaction in risk of schizophrenia should be elaborated to multiple interactions that involve individual genes interacting with diverse biological and psychosocial environmental factors over early life, to differentially influence particular domains of psychopathology, sometimes over specific stages of development.

The autophagy-lysosome pathway (ALP) plays a critical role in the pathology of Parkinson’s disease (PD). Clk1 (coq7) is a mitochondrial hydroxylase that is essential for coenzyme Q (ubiquinone) biosynthesis. We have reported previously that Clk1 regulates microglia activation via modulating microglia metabolic reprogramming, which contributes to dopaminergic neuronal survival. This study explores the direct effect of Clk1 on dopaminergic neuronal survival. We demonstrate that Clk1 deficiency inhibited dopaminergic neuronal autophagy in cultured MN9D dopaminergic neurons and in the substantia nigra pars compacta of Clk^+/− mutant mice and consequently sensitized dopaminergic neuron damage and behavioral defects. These mechanistic studies indicate that Clk1 regulates the AMP-activated protein kinase (AMPK)/rapamycin complex 1 pathway, which in turn impairs the ALP and TFEB nuclear translocation. As a result, Clk1 deficiency promotes dopaminergic neuronal damage in vivo and in vitro, which ultimately contributes to sensitizing 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)–induced dopaminergic neuronal death and behavioral impairments in Clk1-deficient mice. Moreover, we found that activation of autophagy by the AMPK activator metformin increases dopaminergic neuronal survival in vitro and in the MPTP-induced PD model in Clk1 mutant mice. These results reveal that Clk1 plays a direct role in dopaminergic neuronal survival via regulating ALPs that may contribute to the pathologic development of PD. Modulation of Clk1 activity may represent a potential therapeutic target for PD.

<h3>Importance</h3> A recently published study of national data by McGrath et al in 2014 showed increased risk of schizophrenia (SCZ) in offspring associated with both early and delayed parental age, consistent with a U-shaped relationship. However, it remains unclear if the risk to the child is due to psychosocial factors associated with parental age or if those at higher risk for SCZ tend to have children at an earlier or later age. <h3>Objective</h3> To determine if there is a genetic association between SCZ and age at first birth (AFB) using genetically informative but independently ascertained data sets. <h3>Design, Setting, and Participants</h3> This investigation used multiple independent genome-wide association study data sets. The SCZ sample comprised 18 957 SCZ cases and 22 673 controls in a genome-wide association study from the second phase of the Psychiatric Genomics Consortium, and the AFB sample comprised 12 247 genotyped women measured for AFB from the following 4 community cohorts: Estonia (Estonian Genome Center Biobank, University of Tartu), the Netherlands (LifeLines Cohort Study), Sweden (Swedish Twin Registry), and the United Kingdom (TwinsUK). Schizophrenia genetic risk for each woman in the AFB community sample was estimated using genetic effects inferred from the SCZ genome-wide association study. <h3>Main Outcomes and Measures</h3> We tested if SCZ genetic risk was a significant predictor of response variables based on published polynomial functions that described the relationship between maternal age and SCZ risk in offspring in Denmark. We substituted AFB for maternal age in these functions, one of which was corrected for the age of the father, and found that the fit was superior for the model without adjustment for the father's age. <h3>Results</h3> We observed a U-shaped relationship between SCZ risk and AFB in the community cohorts, consistent with the previously reported relationship between SCZ risk in offspring and maternal age when not adjusted for the age of the father. We confirmed that SCZ risk profile scores significantly predicted the response variables (coefficient of determination<i>R2</i> = 1.1E-03,<i>P</i> = 4.1E-04), reflecting the published relationship between maternal age and SCZ risk in offspring by McGrath et al in 2014. <h3>Conclusions and Relevance</h3> This study provides evidence for a significant overlap between genetic factors associated with risk of SCZ and genetic factors associated with AFB. It has been reported that SCZ risk associated with increased maternal age is explained by the age of the father and that de novo mutations that occur more frequently in the germline of older men are the underlying causal mechanism. This explanation may need to be revised if, as suggested herein and if replicated in future studies, there is also increased genetic risk of SCZ in older mothers.

Over the last three decades, movement disorder as well as sensorimotor and psychomotor functioning in schizophrenia (SZ) and other psychoses has gained greater scientific and clinical relevance as an intrinsic component of the disease process of psychotic illness; this extends to early psychosis prediction, early detection of motor side effects of antipsychotic medication, clinical outcome monitoring, treatment of psychomotor syndromes (e.g. catatonia), and identification of new targets for non-invasive brain stimulation. In 2017, a systematic cooperation between working groups interested in movement disorder and sensorimotor/psychomotor functioning in psychoses was initiated across European universities. As a first step, the members of this group would like to introduce and define the theoretical aspects of the sensorimotor domain in SZ and other psychoses. This consensus paper is based on a synthesis of scientific evidence, good clinical practice and expert opinions that were discussed during recent conferences hosted by national and international psychiatric associations. While reviewing and discussing the recent theoretical and experimental work on neural mechanisms and clinical implications of sensorimotor behavior, we here seek to define the key principles and elements of research on movement disorder and sensorimotor/psychomotor functioning in psychotic illness. Finally, the members of this European group anticipate that this consensus paper will stimulate further multimodal and prospective studies on hypo- and hyperkinetic movement disorders and sensorimotor/psychomotor functioning in SZ and other psychotic disorders.

Current classification systems use the terms "catatonia" and "psychomotor phenomena" as mere a-theoretical descriptors, forgetting about their theoretical embedment. This was the source of misunderstandings among clinicians and researchers of the European collaboration on movement and sensorimotor/psychomotor functioning in schizophrenia and other psychoses or ECSP. Here, we review the different perspectives, their historical roots and highlight discrepancies. In 1844, Wilhelm Griesinger coined the term "psychic-motor" to name the physiological process accounting for volition. While deriving from this idea, the term "psychomotor" actually refers to systems that receive miscellaneous intrapsychic inputs, convert them into coherent behavioral outputs send to the motor systems. More recently, the sensorimotor approach has drawn on neuroscience to redefine the motor signs and symptoms observed in psychoses. In 1874, Karl Kahlbaum conceived catatonia as a brain disease emphasizing its somatic - particularly motor - features. In conceptualizing dementia praecox Emil Kraepelin rephrased catatonic phenomena in purely mental terms, putting aside motor signs which could not be explained in this way. Conversely, the Wernicke-Kleist-Leonhard school pursued Kahlbaum's neuropsychiatric approach and described many new psychomotor signs, e.g. parakinesias, Gegenhalten. They distinguished 8 psychomotor phenotypes of which only 7 are catatonias. These barely overlap with consensus classifications, raising the risk of misunderstanding. Although coming from different traditions, the authors agreed that their differences could be a source of mutual enrichment, but that an important effort of conceptual clarification remained to be made. This narrative review is a first step in this direction.

Different types of resistance to passive movement, i.e. hypertonia, were described in schizophrenia spectrum disorders (SSD) long before the introduction of antipsychotics. While these have been rediscovered in antipsychotic-naïve patients and their non-affected relatives, the existence of intrinsic hypertonia vs drug-induced parkinsonism (DIP) in treated SSD remains controversial. This integrative review seeks to develop a commonly accepted framework to specify the putative clinical phenomena, highlight conflicting issues and discuss ways to challenge each hypothesis and model through adversarial collaboration. The authors agreed on a common framework inspired from systems neuroscience. Specification of DIP, locomotor paratonia (LMP) and psychomotor paratonia (PMP) identified points of disagreement. Some viewed parkinsonian rigidity to be sufficient for diagnosing DIP, while others viewed DIP as a syndrome that should include bradykinesia. Sensitivity of DIP to anticholinergic drugs and the nature of LPM and PMP were the most debated issues. It was agreed that treated SSD should be investigated first. Clinical features of the phenomena at issue could be confirmed by torque, EMG and joint angle measures that could help in challenging the selectivity of DIP to anticholinergics. LMP was modeled as the release of the reticular formation from the control of the supplementary motor area (SMA), which could be challenged by the tonic vibration reflex or acoustic startle. PMP was modeled as the release of primary motor cortex from the control of the SMA and may be informed by subclinical echopraxia. If these challenges are not met, this would put new constraints on the models and have clinical and therapeutic implications.

While duration of the psychosis prodrome (DPP) attracts attention in relation to the developmental trajectory of psychotic illness and service models, fundamental issues endure in the context of dimensional-spectrum models of psychosis. Among 205 epidemiologically representative subjects in the Cavan-Monaghan First Episode Psychosis Study, DPP was systematically quantified and compared, for the first time, across all 12 DSM-IV psychotic diagnoses. DPP was also compared with duration of untreated psychosis (DUP) and each was then analysed in relation to premorbid features across three age ranges: <12, 12–15 and 16–18 years. For each diagnosis, medians for both DPP and DUP were shorter than means, indicating common right-skewed distributions. Rank orders for both DPP and DUP were longest for schizophrenia, intermediate for other schizophrenia-spectrum psychoses, psychotic depression and psychotic disorder not otherwise specified, and shortest for brief psychotic disorder, bipolar disorder and substance-induced psychotic disorder, though with overlapping right-skewed distributions. DPP was longer than DUP for all diagnoses except substance-induced psychotic disorder. Across functional psychotic diagnoses, longer DPP was predicted by higher premorbid intelligence and better premorbid adjustment during age 16–18 years. These findings indicate that, trans-diagnostically, DPP and DUP share right-skewed continuities, in accordance with a dimensional-spectrum model of psychotic illness, and may reflect a unitary process that has been dichotomized at a subjective threshold along its trajectory. Better premorbid functioning during age 16–18 years appears to confer resilience by delaying progression to overt psychotic symptoms and may constitute a particular target period for psychosocial interventions.

Background. Although it is well recognized that individuals with schizophrenia display evidence of subtle neurological impairment, its aetiopathological and clinical significance continues to be unclear. Methods. Patients presenting with a first episode of schizophrenia or schizophreniform psychosis (DSM-IV criteria) were examined using two previously validated neurological examinations. The majority ( N = 35) were examined prior to their ‘first ever’ dose of neuroleptic while the remaining patients ( N = 21) had been medicated for less than one month. The manner in which neurological functioning is influenced by symptomatology and handedness was ascertained. Results. The majority of patients who were examined neuroleptic-naive displayed evidence of neurodysfunction. A combination of relative hand preference and symptomatology explained a significant proportion of the variance in neurological functioning. Mixed handedness among adults at the time of first presentation with schizophrenia was associated with more severe neurological impairment and a history of poorer scholastic attainment and pre-morbid social adjustment. Conclusions. Neurological soft signs are an intrinsic part of schizophrenia rather than a direct consequence of treatment. Early developmental processes are associated with the level of subsequent neurological impairment in first episode schizophrenia. However, symptomatology appears to have an influence on the apparent severity of neurological impairment.

Background. It has been suggested that the expression of psychosis may reflect an active morbid process that is associated with increasingly poor outcome unless ameliorated by antipsychotic drugs.Methods. The subjects of this study were 48 in-patients with schizophrenia, many of whom had been admitted before the introduction of antipsychotic drugs to rural Irish psychiatric hospitals in the late 1950s. Each patient was assessed for positive and negative symptoms, and for general and executive (frontal) cognitive function.Results. After controlling for age and for duration and continuity of subsequent antipsychotic treatment, current severity both of negative symptoms and of general cognitive impairment was predicted strongly by increasing duration of initially untreated psychosis; duration of illness following initiation of antipsychotic medication failed to predict the severity thereof. Neither of these indices of illness duration predicted the severity of positive symptoms or of executive dyscontrol.Conclusions. Increasing duration of initially untreated psychosis was associated specifically with heightened accrual of prominent negative symptoms and general cognitive impairment. Executive dyscontrol, though also prominent in these patients, may be ‘locked-in’ at an earlier phase of the illness.

A “read-back” analysis of schizophrenia, from chronic illness, through the first psychotic episode, to psychosocial and neurointegrative abnormalities of childhood and infancy, leads to the intrauterine period as a primary focus for etiological events. Evidence for a characteristic topography of cerebro-craniofacial dysmorphology in schizophrenia is reviewed, and interpreted to estimate: (i) the timing of dysmorphic event(s); (ii) the nature of early cellular and molecular mechanisms which might determine that topography of dysmorphogenesis; and (iii) the population homogeneity of these processes. It is argued that early cerebro-craniofacial dysmorphogenesis in schizophrenia should be conceptualized as a first stage not in a static but rather in a dynamic, lifetime trajectory of disease.

Background: Over early fetal life, when disturbances in schizophrenia have been posited and craniofacial dysmorphogenesis reported, cerebral morphogenesis proceeds in embryological intimacy with craniofacial morphogenesis. Digitization technologies now allow 3D recording of craniofacial surface landmarks and modeling of craniofacial shape differences using geometric morphometrics. Methods: Using normal sexual dimorphism as an exemplar, facial surfaces of 131 Medical School employees [82 females, 49 males] were recorded in 3D using a portable, handheld laser scanner; 3D coordinate data were then analyzed using geometric morphometrics. Results: Males and females differed markedly on an omnibus test of craniofacial shape. Logistic regression analysis of 16 principal components of shape variability, explaining 84.9% of the overall sample variance, generated 8 principal components as significant and independent discriminators. On visualization, the female face is wider and flatter; the eyes are more lateral, anterior and are further apart, and nasal bridge is posterior; the nose is smaller; the lips are fuller and the chin more forward. These findings are complementary to sexual dimorphism in cerebral structures. Conclusions: This technique reliably discriminates geometric features of craniofacial morphology that are associated with aspects of cerebral morphology, and may inform on putative neurodevelopmental disorders characterised by dysmorphogenesis.

Current clinical correlates of duration of initially untreated psychotic symptoms were investigated in a cross-sectional analysis followed by a 10-year prospective study among 88 in-patients with a long-standing schizophrenic illness, many of whom had experienced prolonged periods of untreated psychosis due to illness onset and hospital admission in the pre-neuroleptic era. After controlling for the effects of age, and duration and continuity of subsequent neuroleptic treatment, the primary clinical correlate of duration of initially untreated psychosis was muteness. Over the subsequent 10-year-period, no new cases of muteness emerged and some existing cases of muteness partially resolved, though the speech that emerged remained very sparse and revealed generally gross cognitive debility. The pathophysiology underlying active, unchecked psychosis may also constitute an active morbid process that is associated with the further progression of severe negative symptoms and cognitive dysfunction in the long-term.

1. D-1 receptors are now recognised to play a critical psychopharmacological role in the regulation of unconditioned motor and numerous other aspects of behaviour. 2. There appears to exist a broad family of 'D-1-like' receptors in terms both of differential coupling to distinct messenger/transduction mechanisms and of gene cloning, whose behavioural roles remain to be clarified. 3. The adenylyl cyclase-inhibiting benzazepine SK&F 83959 induces behavioural responses in rats that are similar to those induced by the full efficacy cyclase-stimulating isochroman A 68930 but not to those induced by its high efficacy partial agonist benzazepine congener R-6-Br-APB; these data indicate roles for individual 'D-1-like' receptors in mediating distinct elements of dopaminergic behaviour. 4. The putative D-1 autoreceptor agonist B-HT 920 and the putative D-3 agonist 7-OH-DPAT demonstrate different behavioural profiles when given both alone and in combination with the selective 'D-1-like' antagonist BW 737C; D-3 receptors may participate in cooperative/synergistic but not in oppositional 'D-1-like': 'D-2-like' interactions. 5. Such interactions apparent at the level of behaviour are complemented by evidence for similar interactions at numerous alternative levels of function, though these may differ between rodent and primate species. 6. A broader range of more selective agonists and antagonists, able to distinguish between individual members of the 'D-1-like' and of the 'D-2-like' receptor families are needed to clarify these issues.

A recent family-based association study identified a putative association between variants in the dystrobrevin binding protein 1 (dysbindin) gene (DTNBP1) and schizophrenia. This study used a sample of 270 Irish pedigrees multiply affected with schizophrenia. We attempted to replicate these findings in an independent Irish sample of 219 schizophrenia cases and 231 controls. No evidence was found to suggest an association between the DTNBP1 gene and schizophrenia in our sample. Possible reasons for these findings are discussed.

The tardive dyskinesia refers to a syndrome of abnormal, involuntary, choreoathetoid movements that emerges as a late-onset, adverse effect of long-term treatment with neuroleptic drugs. This syndrome is seen only in a proportion of patients so treated, and when present can affect the orofacial, limb, and trunk regions of the body and the respiratory musculature; classical buccal-lingualmasticatory dyskinesia is perhaps the most widely considered manifestation. Concept of tardive dyskinesia including phenomena such as tardive dystonia, tardive Tourette syndrome, and tardive akdthisia. Clearly, to investigate the syndrome of tardive dyskinesia, one must exclude patients with extrapyramidal disorders, such as Huntington's disease, which are known to involve involuntary, choreoathetoid movements as an inherent feature of the illness independent of any possible exposure to neuroleptics. Evidence supports that long-term treatment with neuroleptics does not cause tardive dyskinesia. Rather, their fundamental action in this regard may be (1) to interact with a neurological process that is (usually) an intrinsic neurodevelopmental or atrophic component of the disorder for which that treatment is prescribed, and (2) to hasten the emergence of an inappropriate and overelaborated form of an innate buccal-lingual-masticatory motor pattern that has an unappreciatedly high likelihood of ultimately occurring spontaneously with increasing cerebral dysfunction.

Behavioural responses to the new benzazepine derivative, SK&amp;F 83959, a compound that both fails to stimulate adenylyl cyclase and inhibits the stimulation of adenylyl cyclase induced by dopamine, were characterized in detail. In rat striatal membrane preparations, radioligand binding studies with [ 3 H]‐SCH 23390 and [ 3 H]‐spiperone indicated SK&amp;F 83959 had a high affinity and &gt; 250 fold selectivity for D 1 over D 2 receptors. Using a rapid time‐sampling behavioural check list technique, SK&amp;F 83959 (0.01‐1.25 mg kg −1 ) induced grooming in the manner of all known D 1 receptor agonists, together with some vacuous chewing, which declined at higher doses with the emergence of directed chewing and rearing as an adjunct to prominent sniffing; no stereotyped behaviour was evident. Grooming to SK&amp;F 83959 (0.05 mg kg −1 ) was blocked by the selective D 1 receptor antagonists, SCH 23390 (0.01‐1.0 mg kg −1 ) and BW 737C (0.04–5.0 mg kg −1 ) and was attenuated by the selective D 2 receptor antagonist, YM 09151‐2 (0.005‐0.5 mg kg −1 ); vacuous chewing to SK&amp;F 83959 was not influenced by either SCH 23390 or BW 737C and was enhanced by YM 09151‐2. The paradoxical induction of typical D 1 receptor agonist‐induced grooming by SK&amp;F 83959, an agent satisfying criteria for a D 1 receptor antagonist as classically defined, together with its blockade by typical D 1 antagonists, strongly suggests mediation via a ‘D 1 ‐like’ site that appears to respond similarly to agents independent of whether they exert agonist or antagonist actions at the classical adenylyl cyclase‐coupled D 1 receptor. This direct functional evidence for a ‘D 1 ‐like’ site that is not linked to adenylyl cyclase readily complements neurochemical data suggesting the existence of a cyclase‐independent ‘D 1 ‐like’ receptor that may be coupled to phosphoinositide hydrolysis.

Minor physical anomalies, together with obstetric complications, family history, and handedness status, were assessed to explore putative neurodevelopmental disturbance(s) in patients with schizophrenia whose cerebral structure had been examined previously by magnetic resonance imaging. Minor physical anomalies were related to negative symptoms in males and to premorbid intellectual function in females, but not to ventricular volume; however, three patients with evident neurodevelopmental anomalies of the ventricular system showed prominent minor physical anomalies. In exploratory analyses, obstetric complications were associated with left ventricular asymmetry, and a positive family history with inverse profiles of asymmetry in males vs. females; non—right-handedness was associated with increased ventricular volume in males but with poorer premorbid intellectual function in females. This nexus of relationships and their gender specificities suggest early dysmorphogenesis in schizophrenia that is related to sexual dimorphism. Minor physical anomalies, together with obstetric complications, family history, and handedness status, were assessed to explore putative neurodevelopmental disturbance(s) in patients with schizophrenia whose cerebral structure had been examined previously by magnetic resonance imaging. Minor physical anomalies were related to negative symptoms in males and to premorbid intellectual function in females, but not to ventricular volume; however, three patients with evident neurodevelopmental anomalies of the ventricular system showed prominent minor physical anomalies. In exploratory analyses, obstetric complications were associated with left ventricular asymmetry, and a positive family history with inverse profiles of asymmetry in males vs. females; non—right-handedness was associated with increased ventricular volume in males but with poorer premorbid intellectual function in females. This nexus of relationships and their gender specificities suggest early dysmorphogenesis in schizophrenia that is related to sexual dimorphism.

Abstract Over early fetal life the anterior brain, neuroepithelium, neural crest and facial ectoderm constitute a unitary, three‐dimensional (3D) developmental process. This intimate embryological relationship between the face and brain means that facial dysmorphogenesis can serve as an accessible and informative index of brain dysmorphogenesis in neurological and psychiatric disorders of early developmental origin. There are three principal challenges in seeking to increase understanding of disorders of early brain dysmorphogenesis through craniofacial dysmorphogenesis: (i) the first, technical, challenge has been to digitize the facial surface in its inherent three‐dimensionality; (ii) the second, analytical, challenge has been to develop methodologies for extracting biologically meaningful shape covariance from digitized samples, making statistical comparisons between groups and visualizing in 3D the resultant statistical models on a ‘whole face’ basis; (iii) the third, biological, challenge is to demonstrate a relationship between facial morphogenesis and brain morphogenesis not only in anatomical–embryological terms but also at the level of brain function. Here we consider each of these challenges in turn and then illustrate the issues by way of our own findings. These use human sexual dimorphism as an exemplar for 3D laser surface scanning of facial shape, analysis using geometric morphometrics and exploration of cognitive correlates of variation in shape of the ‘whole face’, in the context of studies relating to the early developmental origins of schizophrenia.

Unilateral injection of kainic acid into the nucleus accumbens of the rat produced moderate depletions of the GABA synthesising enzyme glutamic acid decarboxylase in the accumbens and ventral tegmental area, but failed to alter these parameters in the striatum or substantia nigra. Similar injections into the striatum produced opposite effects to those seen following accumbens injections. These results are consistent with a GABA-ergic accumbal-ventral tegmental pathway analogous to the well defined striatonigral pathway. However, alternative interpretations, possibly in terms of a non-GABAergic accumbal-ventral tegmental pathway modulating GABA interneurons intrinsic to the tegmentum, must be considered.

Intellectual impairment, negative symptoms, and medication history were assessed in chronic schizophrenic patients with and without abnormal involuntary movements (tardive dyskinesia). Patients with involuntary movements had received neither longer nor more intensive treatment with neuroleptics or anticholinergics. However, the presence or absence of involuntary movements was prominently associated with the presence or absence of intellectual impairment/negative symptoms; these features are characteristic of the defect state/type II syndrome of schizophrenia, in which structural abnormalities of the brain may be over-represented. The role of subtle organic changes in conferring vulnerability to the emergence of such involuntary movements should be re-evaluated.

The neuregulin-1 gene is widely expressed in the central nervous system and is associated with increased risk for schizophrenia. Using an ethologically based approach, the phenotype of neuregulin-1 heterozygous knockout mice was examined by revealing the individual elements of behaviour in the murine repertoire over the prolonged course of interaction with the environment. During initial exploration, neuregulin-1 mutants displayed a phenotype characterized by increases in locomotion and rearing free, with sex-specific alterations in sifting and grooming. Over subsequent habituation, certain initial effects endured while new phenotypic effects emerged, some of which were again sex-specific. These studies elaborate a pleiotropic role of neuregulin-1 in development, plasticity and function, including sexual dimorphism, by defining the elemental, temporal and sex-specific characteristics of the neuregulin-1 mutant ethogram.

Abstract Neuregulin‐1 (NRG1) has been shown to play a role in glutamatergic neurotransmission and is a risk gene for schizophrenia, in which there is evidence for hypoglutamatergic function. Sensitivity to the behavioural effects of the psychotomimetic N ‐methyl‐ d ‐aspartate receptor antagonists MK‐801 and phencyclidine (PCP) was examined in mutant mice with heterozygous deletion of NRG1. Social behaviour (sociability, social novelty preference and dyadic interaction), together with exploratory activity, was assessed following acute or subchronic administration of MK‐801 (0.1 and 0.2 mg/kg) or PCP (5 mg/kg). In untreated NRG1 mutants, levels of glutamate, N ‐acetylaspartate and GABA were determined using high‐performance liquid chromatography and regional brain volumes were assessed using magnetic resonance imaging at 7T. NRG1 mutants, particularly males, displayed decreased responsivity to the locomotor‐activating effects of acute PCP. Subchronic MK‐801 and PCP disrupted sociability and social novelty preference in mutants and wildtypes and reversed the increase in both exploratory activity and social dominance‐related behaviours observed in vehicle‐treated mutants. No phenotypic differences were demonstrated in N ‐acetylaspartate, glutamate or GABA levels. The total ventricular and olfactory bulb volume was decreased in mutants. These data indicate a subtle role for NRG1 in modulating several schizophrenia‐relevant processes including the effects of psychotomimetic N ‐methyl‐ d ‐aspartate receptor antagonists.

We generated a mouse line harboring an autosomal-dominant nocturnal frontal lobe epilepsy (ADNFLE) mutation: the alpha4 nicotinic receptor S248F knock-in strain. In this mouse, modest nicotine doses (1-2 mg/kg) elicit a novel behavior termed the dystonic arousal complex (DAC). The DAC includes stereotypical head movements, body jerking, and forelimb dystonia; these behaviors resemble some core features of ADNFLE. A marked Straub tail is an additional component of the DAC. Similar to attacks in ADNFLE, the DAC can be partially suppressed by the sodium channel blocker carbamazepine or by pre-exposure to a very low dose of nicotine (0.1 mg/kg). The DAC is centrally mediated, genetically highly penetrant, and, surprisingly, not associated with overt ictal electrical activity as assessed by (1) epidural or frontal lobe depth-electrode electroencephalography or (2) hippocampal c-fos-regulated gene expression. Heterozygous knock-in mice are partially protected from nicotine-induced seizures. The noncompetitive antagonist mecamylamine does not suppress the DAC, although it suppresses high-dose nicotine-induced wild-type-like seizures. Experiments on agonist-induced 86Rb+ and neurotransmitter efflux from synaptosomes and on alpha4S248Fbeta2 receptors expressed in oocytes confirm that the S248F mutation confers resistance to mecamylamine blockade. Genetic background, gender, and mutant gene expression levels modulate expression of the DAC phenotype in mice. The S248F mouse thus appears to provide a model for the paroxysmal dystonic element of ADNFLE semiology. Our model complements what is seen in other ADNFLE animal models. Together, these mice cover the spectrum of behavioral and electrographic events seen in the human condition.

Negative symptoms encompass diminution in emotional expression and motivation, some of which relate to human attributes that may not be accessible readily in animals. Additionally, their refractoriness to treatment precludes therapeutic validation of putative models. This review considers critically the application of mutant mouse models to the study of the pathobiology of negative symptoms. It focuses on 4 main approaches: genes related to the pathobiology of schizophrenia, genes associated with risk for schizophrenia, neurodevelopmental-synaptic genes, and variant approaches from other areas of neurobiology. Despite rapid advances over the past several years, it is clear that we continue to face substantive challenges in applying mutant models to better understand the pathobiology of negative symptoms: the majority of evidence relates to impairments in social behavior, with only limited data relating to anhedonia and negligible data concerning avolition and other features; even for the most widely examined feature, social behavior, studies have used diverse assessments thereof; modelling must proceed in cognizance of increasing evidence that genes and pathobiologies implicated in schizophrenia overlap with other psychotic disorders, particularly bipolar disorder. Despite the caveats and challenges, several mutant lines evidence a phenotype for at least one index of social behavior. Though this may suggest superficially some shared relationship to negative symptoms, it is not yet possible to specify either the scope or the pathobiology of that relationship for any given gene. The breadth and depth of ongoing studies in mutants hold the prospect of addressing these shortcomings.

Activation of dopamine D1 receptors (D1Rs) has been shown to induce epileptiform activity. We studied the molecular changes occurring in the hippocampus in response to the administration of the D1-type receptor agonist, SKF 81297. SKF 81297 at 2.5 and 5.0 mg/kg induced behavioural seizures. Electrophysiological recordings in the dentate gyrus revealed the presence of epileptiform discharges peaking at 30-45 min post-injection and declining by 60 min. Seizures were prevented by the D1-type receptor antagonist, SCH 23390, or the cannabinoid CB1 receptor agonist, CP 55,940. The effect of SKF 81297 was accompanied by increased phosphorylation of the extracellular signal-regulated protein kinases 1 and 2 (ERK), in the granule cells of the dentate gyrus. This effect was also observed in response to administration of other D1-type receptor agonists, such as SKF83822 and SKF83959. In addition, SKF 81297 increased the phosphorylation of the ribosomal protein S6 and histone H3, two downstream targets of ERK. These effects were prevented by genetic inactivation of D1Rs, or by pharmacological inhibition of ERK. SKF 81297 was also able to enhance the levels of Zif268 and Arc/Arg3.1, two immediate early genes involved in transcriptional regulation and synaptic plasticity. These changes may be involved in forms of activity-dependent plasticity linked to the manifestation of seizures and to the ability of dopamine to affect learning and memory.

While recent research on psychotic illness has focussed on the nosological, clinical, and biological relationships between schizophrenia and bipolar disorder, little attention has been directed to the most common other psychotic diagnosis, major depressive disorder with psychotic features (MDDP). As this diagnostic category captures the confluence between dimensions of psychotic and affective psychopathology, it is of unappreciated heuristic potential to inform on the nature of psychotic illness. Therefore, the epidemiology and clinical characteristics of MDDP were compared with those of schizophrenia and bipolar disorder within the Cavan-Monaghan First Episode Psychosis Study (n = 370). Epidemiologically, the first psychotic episode of MDDP (n = 77) was uniformly distributed across the adult life span, while schizophrenia (n = 73) and bipolar disorder (n = 73) were primarily disorders of young adulthood; the incidence of MDDP, like bipolar disorder, did not differ between the sexes, while the incidence of schizophrenia was more common in males than in females. Clinically, MDDP was characterized by negative symptoms, executive dysfunction, neurological soft signs (NSS), premorbid intellectual function, premorbid adjustment, and quality of life similar to those for schizophrenia, while bipolar disorder was characterized by less prominent negative symptoms, executive dysfunction and NSS, and better quality of life. These findings suggest that what we currently categorize as MDDP may be more closely aligned with other psychotic diagnoses than has been considered previously. They indicate that differences in how psychosis is manifested vis-à-vis depression and mania may be quantitative rather than qualitative and occur within a dimensional space, rather than validating categorical distinctions.

Seizures are common during the neonatal period, often due to hypoxic-ischemic encephalopathy and may contribute to acute brain injury and the subsequent development of cognitive deficits and childhood epilepsy. Here we explored short- and long-term consequences of neonatal hypoxia-induced seizures in 7 day old C57BL/6J mice. Seizure activity, molecular markers of hypoxia and histological injury were investigated acutely after hypoxia and response to chemoconvulsants and animal behaviour was explored at adulthood. Hypoxia was induced by exposing pups to 5% oxygen for 15 min (global hypoxia). Electrographically defined seizures with behavioral correlates occurred in 95% of these animals and seizures persisted for many minutes after restitution of normoxia. There was minimal morbidity or mortality. Pre- or post-hypoxia injection of phenobarbital (50mg/kg) had limited efficacy at suppressing seizures. The hippocampus from neonatal hypoxia-seizure mice displayed increased expression of vascular endothelial growth factor and the immediate early gene c-fos, minimal histological evidence of cell injury and activation of caspase-3 in scattered neurons. Behavioral analysis of mice five weeks after hypoxia-induced seizures detected novel anxiety-related and other behaviors, while performance in a spatial memory test was similar to controls. Seizure threshold tests with kainic acid at six weeks revealed that mice previously subject to neonatal hypoxia-induced seizures developed earlier, more frequent and longer-duration seizures. This study defines a set of electro-clinical, molecular, pharmacological and behavioral consequences of hypoxia-induced seizures that indicate short- and long-term deleterious outcomes and may be a useful model to investigate the pathophysiology and treatment of neonatal seizures in humans.

It is well known that suicidal rates vary considerably among European countries and the reasons for this are unknown, although several theories have been proposed. The effect of economic variables has been extensively studied but not that of climate. Data from 29 European countries covering the years 2000–2012 and concerning male and female standardized suicidal rates (according to WHO), economic variables (according World Bank) and climate variables were gathered. The statistical analysis included cluster and principal component analysis and categorical regression. The derived models explained 62.4 % of the variability of male suicidal rates. Economic variables alone explained 26.9 % and climate variables 37.6 %. For females, the respective figures were 41.7, 11.5 and 28.1 %. Male suicides correlated with high unemployment rate in the frame of high growth rate and high inflation and low GDP per capita, while female suicides correlated negatively with inflation. Both male and female suicides correlated with low temperature. The current study reports that the climatic effect (cold climate) is stronger than the economic one, but both are present. It seems that in Europe suicidality follows the climate/temperature cline which interestingly is not from south to north but from south to north-east. This raises concerns that climate change could lead to an increase in suicide rates. The current study is essentially the first successful attempt to explain the differences across countries in Europe; however, it is an observational analysis based on aggregate data and thus there is a lack of control for confounders.

Clock (Clk)1/COQ7 is a mitochondrial hydroxylase that is necessary for the biosynthesis of ubiquinone (coenzyme Q or UQ). Here, we investigate the role of Clk1 in neuroinflammation and consequentially dopaminergic (DA) neuron survival. Reduced expression of Clk1 in microglia enhanced the LPS-induced proinflammatory response and promoted aerobic glycolysis. Inhibition of glycolysis abolished Clk1 deficiency-induced hypersensitivity to the inflammatory stimulation. Mechanistic studies demonstrated that mTOR/HIF-1α and ROS/HIF-1α signaling pathways were involved in Clk1 deficiency-induced aerobic glycolysis. The increase in neuronal cell death was observed following treatment with conditioned media from Clk1 deficient microglia. Increased DA neuron loss and microgliosis were observed in Clk1+/− mice after treatment with MPTP, a rodent model of Parkinson’s disease (PD). This increase in DA neuron loss was due to an exacerbated microglial inflammatory response, rather than direct susceptibility of Clk1+/− DA cells to MPP+, the active species of MPTP. Exaggerated expressions of proinflammatory genes and loss of DA neurons were also observed in Clk1+/− mice after stereotaxic injection of LPS. Our results suggest that Clk1 regulates microglial metabolic reprogramming that is, in turn, involved in the neuroinflammatory processes and PD.

Neuronal nicotinic acetylcholine receptors (nAChR) are present in high abundance in the nervous system (Decker et al., 1995). There are a large number of subunits expressed in the brain that combine to form multimeric functional receptors. We have generated an alpha(4) nAChR subunit knock-out line and focus on defining the behavioral role of this receptor subunit. Homozygous mutant mice (Mt) are normal in size, fertility, and home-cage behavior. Spontaneous unconditioned motor behavior revealed an ethogram characterized by significant increases in several topographies of exploratory behavior in Mt relative to wild-type mice (Wt) over the course of habituation to a novel environment. Furthermore, the behavior of Mt in the elevated plus-maze assay was consistent with increased basal levels of anxiety. In response to nicotine, Wt exhibited early reductions in a number of behavioral topographies, under both unhabituated and habituated conditions; conversely, heightened levels of behavioral topographies in Mt were reduced by nicotine in the late phase of the unhabituated condition. Ligand autoradiography confirmed the lack of high-affinity binding to radiolabeled nicotine, cytisine, and epibatidine in the thalamus, cortex, and caudate putamen, although binding to a number of discrete nuclei remained. The study confirms the pivotal role played by the alpha(4) nAChR subunit in the modulation of a number of constituents of the normal mouse ethogram and in anxiety as assessed using the plus-maze. Furthermore, the response of Mt to nicotine administration suggests that persistent nicotine binding sites in the habenulo-interpeduncular system are sufficient to modulate motor activity in actively exploring mice.

Basic cognitive function was assessed at initial and at 5- and 10-year follow-up assessments among 41 primarily middle-aged in-patients manifesting the severest form of schizophrenia; additionally, the presence and severity of tardive dyskinesia was evaluated on each occasion. Overall, there was a modest but significant deterioration in cognitive function over the decade, particularly among older men. Longitudinally, patients with persistent tardive (orofacial) dyskinesia continued to show poorer cognitive function than those consistently without such movement disorder, though within neither group did cognitive function change over the decade. Those patients demonstrating prospectively the emergence of orofacial dyskinesia showed a marked deterioration in their cognitive function over the same time-frame within which their movement disorder emerged, but this decline did not progress further thereafter. There appears to exist some modes, progressive deterioration in cognitive function even late in the chronic phase of severe schizophrenic illness which appears to derive primarily from patients showing de novo emergence of tardive orofacial dyskinesia.

The phenotype of spontaneous behaviour in mice with targeted gene deletion of the D1A dopamine receptor was investigated topographically. Via direct visual observation, individual elements of behaviour were resolved and quantified using an ethologically-based, rapid time-sampling behavioural check-list procedure. Relative to wildtypes (D1A +/+), D1A-null (−/−) mice evidenced over initial exploration significant reductions in rearing free, sifting and chewing, but significant increases in locomotion, grooming and intense grooming. Sniffing and rearing to a wall habituated less readily in D1A-null mice such that these behaviours occurred subsequently to significant excess: increases in locomotion were persistent. The ethogram of spontaneous behaviour in D1A-null mice was characterised by neither ‘hypoactivity’ or ‘hyperactivity’ but, rather, by prominent topographical shifts between individual elements of behaviour that could not be encapsulated by either term. Given the substantial body of evidence that grooming and particularly intense grooming constitute the most widely accepted behavioural index of D1-like receptor function, the elevation of such behaviour in D1A-null mice was paradoxical; it may reflect (over)compensatory processes subsequent to developmental absence of D1A receptors and/or the involvement of a D1-like receptor other than/additional to the D1A subtype.

Objective: This study investigated the rate of spontaneous abnormal involuntary movements in a group of patients presenting with a first episode of schizophrenia or schizophreniform psychosis. Method: Seventy-nine patients with a first episode of schizophrenia or schizophreniform psychosis who presented to a catchment area psychiatric service over a 3-year period, and who were neuroleptic-naive or had been medicated for less than 1 month, were examined for the presence of involuntary movements with use of the Abnormal Involuntary Movement Scale.Results: Six patients (7.6%) had spontaneous dyskinesia as defined by the criteria of Schooler and Kane, and nine other patients had mild orofacial involuntary movements. The patients with spontaneous dyskinesia had completed significantly fewer years of education than the patients without dyskinesia. Spontaneous involuntary movements were unrelated to age at presentation for treatment. Conclusions: Spontaneous abnormal involuntary movements were evident among a proportion of patients with first-episode schizophrenia or schizophreniform psychosis at baseline presentation and were associated with reduced educational attainment. This finding supports previous suggestions that abnormal involuntary movements in schizophrenia may be related to the pathophysiology of the illness and therefore cannot be attributed entirely to the adverse effects of neuroleptic medication. Am J Psychiatry 1998; 155: 1202-1206

Understanding the temporal origin(s) of schizophrenia, through specifying the earliest identifiable pathology, might indicate when to look for etiological factor(s), what their nature might be, and how course of illness might evolve from these origins. From this premise, earlier formulations are elaborated to offer a rigorously data-driven model that roots schizophrenia in cerebro-craniofacial dysmorphogenesis, particularly along the mid-line but involving other structures, over weeks 9/10 through 14/15 of gestation. However, a brain that has been compromised very early in fetal life is still subject to the normal endogenous programme of developmental, maturational and involutional processes on which a variety of exogenous biological insults and psychosocial stressors can impact adversely over later pregnancy, through infancy and childhood, to maturation and into old age, to sculpt brain structure and function; it should be emphasised that the effects of such endogenous programmes and exogenous insults on such an already developmentally-compromised brain may be different from their effects on a brain whose early fetal origins were unremarkable. From these early origins, a lifetime trajectory model for schizophrenia from developmental basis to 'neuroprogressive' process is constructed. Thereafter, consideration is given to what the model can explain, including cerebral asymmetry and homogeneity, what it cannot explain, what empirical findings would challenge or disprove the model, what cellular and molecular mechanisms might underpin the model, and what are its implications.

Obstetric complications were more common in the histories of those schizophrenic outpatients without a family history of psychiatric disorder, and were associated with an earlier onset of their illness. Those patients with tardive dyskinesia were more likely to have a family history of psychiatric disorder, less likely to have experienced obstetric complications, and showed greater cognitive deficit. Obstetric complications should be considered in juxtaposition with genetic factors in evaluating the putative familial-sporadic distinction in schizophrenia. Additionally, familial/genetic factors appear to contribute to vulnerability to tardive dyskinesia.

Although it is recognized that patients with schizophrenia demonstrate more neurological soft signs (NSS) than control subjects, the significance and clinical correlates of these signs remain poorly defined. The present study examined 48 patients with DSM-III-R schizophrenia for evidence of NSS. The majority (98%) of patients demonstrated at least one NSS, although the range of scores was wide. There was no relationship between current dosage of neuroleptic medication and NSS score. Among males, there was a significant relationship between NSS and duration of illness. Males whose mothers experienced obstetric complications had higher NSS scores, while females with a family history of schizophrenia exhibited higher scores. These relationships in schizophrenia between NSS and factors of etiological importance such as obstetric complications and family history require further evaluation. The present findings are in accord with a body of evidence which suggests that gender may influence the impact of genetic and environmental factors on the neurology of the disorder.

Neurological soft signs (NSS) are well described among patients with schizophrenia, the neurology of other psychoses is relatively unexplored and few comparative studies have prospectively examined these signs in first-episode patients. We assessed neurological functioning in 242 patients presenting with a first episode of psychosis (in accordance with DSM-IV diagnosis) using the Condensed Neurological Examination (CNE). We sought to determine whether NSS were specific to patients with schizophrenia, bipolar affective disorder and other forms of psychosis. We also examined the factors associated with and predictive of neurodysfunction at first presentation and at 4 year follow-up. NSS were not specific to any diagnostic group. Neurological functioning was closely associated with psychopathology and mixed-handedness at first presentation. At follow-up there was a statistically significant improvement in neurological functioning. Persistent neurodysfunction at this stage was related to enduring negative symptoms and associated with poorer outcome. Schizophrenia and bipolar disorder are indistinguishable in terms of neurodysfunction at presentation. At presentation and 4 years NSS closely parallel psychopathology and mixed-handedness indicating that NSS may be a function of these factors or possibly an independent factor operates equally upon both symptoms and neurological function.