[show abstract][hide abstract] ABSTRACT: Little is known about associations between the social environment and risk for psychosis within rural settings. This study sought to investigate whether such associations exist within a rural context using a prospective dataset of unusual epidemiological completeness.
Using the Cavan-Monaghan First Episode Psychosis Study database of people aged 16years and older, both ecological analyses and multilevel modelling were applied to investigate associations between incidence of psychosis by place at onset and socio-environmental risk factors of material deprivation, social fragmentation and urban-rural classification across electoral divisions.
The primary finding was an association between more deprived social contexts and higher rates of psychotic disorder, after adjustment for age and sex [all psychoses: incidence rate ratio (IRR)=1.12, 95% CI (1.03-1.23)].
These findings support an association between adverse socio-environmental factors and increase in risk for psychosis by place at onset within a predominantly rural environment. This study suggests that social environmental characteristics may have an impact on risk across the urban-rural gradient.
Schizophrenia Research 12/2013; · 4.59 Impact Factor
[show abstract][hide abstract] ABSTRACT: Cannabis use is an established risk factor for the development of schizophrenia and related psychotic disorders. Factors that may mediate susceptibility to the psychosis-inducing effects of cannabis include the age at onset of first cannabis use, genetic predisposition, as well as interaction with other environmental risk variables. Clinical and preclinical genetic studies provide increasing evidence that, in particular, genes encoding proteins implicated in dopamine signalling are implicated in the cannabis-psychosis association. In the present review, we focus on both human and animal studies which have focused on identifying the neuronal basis of these interactions. We conclude that further studies are required to provide greater mechanistic insight into the long-term and neurodevelopmental effects of cannabis use, with implications for improved understanding of the cannabis-psychosis relationship.
Progress in Neuro-Psychopharmacology and Biological Psychiatry 11/2013; · 3.55 Impact Factor
[show abstract][hide abstract] ABSTRACT: Progressive cell loss is observed in the striatum, cerebral cortex, thalamus, hypothalamus, subthalamic nucleus and hippocampus in Huntington disease. In the striatum, dopamine-responsive medium spiny neurons are preferentially lost. Clinical features include involuntary movements, gait and orofacial impairments in addition to cognitive deficits and psychosis, anxiety and mood disorders. We utilized the Cre-LoxP system to generate mutant mice with selective postnatal ablation of D1 dopamine receptor-expressing striatal neurons to determine which elements of the complex Huntington disease phenotype relate to loss of this neuronal subpopulation. Mutant mice had reduced bodyweight, locomotor slowing, reduced rearing, ataxia, a short stride length wide-based erratic gait, impairment in orofacial movements and displayed haloperidol-suppressible tic-like movements. The mutation was associated with an anxiolytic profile. Mutant mice had significant striatal-specific atrophy and astrogliosis. D1-expressing cell number was reduced throughout the rostrocaudal extent of the dorsal striatum consistent with partial destruction of the striatonigral pathway. Additional striatal changes included up-regulated D2 and enkephalin mRNA, and an increased density of D2 and preproenkephalin-expressing projection neurons, and striatal neuropeptide Y and cholinergic interneurons. These data suggest that striatal D1-cell-ablation alone may account for the involuntary movements and locomotor, balance and orofacial deficits seen not only in HD but also in HD phenocopy syndromes with striatal atrophy. Therapeutic strategies would therefore need to target striatal D1 cells to ameliorate deficits especially when the clinical presentation is dominated by a bradykinetic/ataxic phenotype with involuntary movements.
Neurobiology of Disease 10/2013; · 5.62 Impact Factor
[show abstract][hide abstract] ABSTRACT: Modelling negative symptoms in any animal model, particularly in mice mutant for genes related to schizophrenia, is complicated by the absence of the following key elements that might assist in developing validation criteria: clinical clarity surrounding this symptom constellation; any clear association between negative symptoms and pathological signature(s) in the brain; and therapeutic strategies with material clinical efficacy against these symptoms. In this review, the application of mutant mouse models to the study of negative symptoms is subjected to critical evaluation, focussing on the following challenges: (a) conceptual issues relating to negative symptoms and their evaluation in mutant models; (b) measurement of negative symptoms in mice, in terms of social behaviour, motivational deficits/avolition and anhedonia; (c) studies in mutants with disruption of genes either regulating aspects of neurotransmission implicated in schizophrenia or associated with risk for psychotic illness; (d) the disaggregation of behavioural phenotypes into underlying pathobiological processes, as a key to the development of new therapeutic strategies for negative symptoms. Advances in genetic and molecular technologies are facilitating these processes, such that more accurate models of putative schizophrenia-linked genetic abnormalities are becoming feasible. This progress in terms of mimicking the genetic contribution to distinct domains of psychopathology associated with psychotic illness must be matched by advances in conceptual/clinical relevance and sensitivity/specificity of phenotypic assessments at the level of behaviour.
European neuropsychopharmacology: the journal of the European College of Neuropsychopharmacology 10/2013; · 3.68 Impact Factor
[show abstract][hide abstract] ABSTRACT: To investigate the role of glutamate receptor subtypes and γ-aminobutyric acid (GABA) in orofacial function, six individual topographies of orofacial movement, both spontaneous and induced by the dopamine D1-like receptor agonist SKF 83959, were quantified in mutant mice with deletion of (a) GluN2A, B or D receptors, and (b) the GABA synthesising enzyme, 65-kD isoform of glutamate decarboxylase (GAD65). In GluN2A mutants, habituation of head movements was disrupted and vibrissae movements were reduced, with an overall increase in locomotion; responsivity to SKF 83959 was unaltered. In GluN2B mutants, vertical and horizontal jaw movements and incisor chattering were increased, with an overall decrease in locomotion; under challenge with SKF 83959, head and vibrissae movements were reduced. In GluN2D mutants, horizontal jaw movements, incisor chattering and vibrissae movements were increased, with reduced tongue protrusions and no overall change in locomotion; under challenge with SKF 83959, horizontal jaw movements were increased. In GAD65 mutants, vertical jaw movements were increased, with disruption to habituation of locomotion; under challenge with SKF 83959, vertical and horizontal jaw movements and incisor chattering were decreased. Effects on orofacial movements differed from their effects on regulation of overall locomotor behaviour. These findings (a) indicate novel, differential roles for GluN2A, B and D receptors and for GAD65-mediated GABA in the regulation of individual topographies of orofacial movement and (b) reveal how these roles differ from and/or interact with the established role of D1-like receptors in pattern generators and effectors for such movements.
[show abstract][hide abstract] ABSTRACT: To investigate general practitioners' current knowledge of and attitudes towards psychosis and its management by Cavan-Monaghan Mental Health Service, Ireland, prior to their involvement in the introduction of an early intervention service.
As part of a continuing medical education programme for psychosis, delivered to all 32 general practitioners practising in this region, participants were asked to complete a 29-item questionnaire designed to assess their baseline knowledge and attitudes.
All 32 general practitioners participated in the study. Although 17% had received no previous psychiatric training, 93% described their knowledge of psychiatric disorders as average or above average. However, only 53% could correctly identify all of a set of psychiatric symptoms related to psychosis. Only 50% felt comfortable initiating treatment for psychotic symptoms. Whereas only 40% had heard of the early intervention model, 89% believed it to be advantageous. Easy accessibility to services and rapid assessment of patients referred were most commonly reported as helpful. However, concerns were expressed about the potential for associated increases in workload.
As 'gatekeepers-in-waiting', these general practitioners will have a vital role in effective implementation of the early intervention service for psychosis. However, their knowledge needs improvement, through regular educational sessions, and this service must be responsive to their needs. In addition, general practitioners' concerns regarding the potential for increased workload must be adequately addressed in order to maintain enthusiasm and collaboration at the interface between primary care and mental health services, particularly in the context of early intervention.
Early Intervention in Psychiatry 07/2013; · 1.65 Impact Factor
[show abstract][hide abstract] ABSTRACT: The challenge of modelling a complex and multifaceted disorder such as schizophrenia is epitomised by the considerable degree of phenotypic variability described in patients and by the absence of specific and consistent neuropathological biomarkers. The pattern and severity of a range of clinical features, including florid psychotic symptoms such as hallucinations and delusions, negative symptoms and cognitive dysfunction, together with age at onset, course of illness and other indices, can vary greatly between individual patients. The undefined nature of the relationship between diagnosis and underlying aetiology has complicated research in the field of clinical and preclinical neuroscience, thereby making it difficult to generate or evaluate appropriate disease models of schizophrenia. In the present review, we explore those conceptual and practical issues that relate specifically to the genetic modelling of schizophrenia and related disorders in rodents. Practical issues that impact on the robustness of endophenotypic findings and their translational relevance are discussed with reference to evidence from selective genetic models of candidate risk genes and copy number variants implicated in schizophrenia.
Cell and Tissue Research 05/2013; · 3.68 Impact Factor
[show abstract][hide abstract] ABSTRACT: 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.
[show abstract][hide abstract] ABSTRACT: Considerable topographic overlap exists between brain opioidergic and dopaminergic neurons. Pharmacological blockade of the dopamine D(1) receptor (Drd1a) reverses several behavioural phenomena elicited by opioids. The present study examines the effects of morphine in adult mutant (MUT) mice expressing the attenuated diphtheria toxin-176 gene in Drd1a-expressing cells, a mutant line shown previously to undergo post-natal striatal atrophy and loss of Drd1a-expression. MUT and wild-type mice were assessed behaviourally following acute administration of 10 mg/kg morphine. Treatment with morphine reduced locomotion and rearing similarly in both genotypes but reduced total grooming only in MUT mice. Morphine-induced Straub tail and stillness were heightened in MUT mice. Chewing and sifting were decreased in MUT mice and these effects were not modified by morphine. Loss of striatal Drd1-positive cells and up-regulated D(2)-expression, as reflected in down-regulated D(1)-like and up-regulated D(2)-like binding, respectively, is not uniform along the cranio-caudal extent in this model but appears to be greater in the caudal striatum. Preferential caudal loss of µ-opioid-expression, a marker for the striosomal compartment, was seen. These data indicate that Drd1a-positive cell loss modifies the exploratory behavioural response elicited by morphine, unmasking novel morphine-induced MUT-specific behaviours and generating a hypersensitivity to morphine for others.
Journal of Pharmacological Sciences 01/2013; 121(1):39-47. · 2.15 Impact Factor
[show abstract][hide abstract] ABSTRACT: BACKGROUND: 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. AIMS: 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. METHOD: 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, 3months and 1year. RESULTS: At 3month and 1year 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 3months and this effect was sustained at 1year. CONCLUSIONS: 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.
Schizophrenia Research 11/2012; · 4.59 Impact Factor
[show abstract][hide abstract] ABSTRACT: The vague relationship between diagnosis, underlying etiology and a rudimentary understanding of the pathophysiology of psychosis, particularly schizophrenia, has made it difficult to develop and validate suitable disease models for such disorders. Despite recent technological advancements, animal models have yet to yield a revolutionary treatment for schizophrenia. Refinement and standardization of assessment methods in the preclinical domain and streamlining of concepts from which animal models are generated are required, particularly in relation to models that recapitulate cognitive and negative symptoms of schizophrenia. In this review, caveats of current treatments for schizophrenia and current animal modeling strategies are examined in the context of their validity and potential for discovery of novel therapies, and finally, future prospects for the field are considered.
Expert Review of Clinical Pharmacology 11/2012; 5(6):667-76.
[show abstract][hide abstract] ABSTRACT: Among numerous mechanisms implicated in the regulation of orofacial movements, dopamine-containing neurons have received the most extensive study. Here we review the effects of a) constitutive knockout of D(1-5) dopamine receptors and b) conditional mutations with progressive ablation of D(1) receptor-expressing cells, on the topography of spontaneous and D(1)-like agonist-induced orofacial movements. In constitutive knockouts, D(1) and D(2) exert primary roles in regulating horizontal and vertical jaw movements, respectively, in opposite directions; in contrast, both D(1) and D(2) receptors regulate tongue protrusions and incisor chattering, in the same direction. D(3) and D(5) receptors play more subtle roles in regulating orofacial movements, while D(4) receptors do not play any material role. Progressive loss of forebrain D(1) receptor-expressing cells in CamKIIa/Cre D(1)Tox mutants is associated primarily with decreases in head and vibrissae movements, while progressive loss of striatal D(1) receptor-expressing cells in DARPP-32/Cre D(1)Tox mutants is associated primarily with reductions in jaw movements and tongue protrusions but increases in head and vibrissae movements. Further application of constitutive and particularly conditional mutants may clarify further not only dopaminergic regulation of orofacial movements but also the pathophysiology of orofacial dysfunction in Huntington's disease and Parkinson's disease.
Journal of Pharmacological Sciences 07/2012; 119(4):297-301. · 2.15 Impact Factor
[show abstract][hide abstract] ABSTRACT: 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.
Nature medicine 06/2012; 18(7):1087-94. · 27.14 Impact Factor
[show abstract][hide abstract] ABSTRACT: Current antipsychotic drugs lack material efficacy against the negative symptoms and cognitive deficits of schizophrenia. There is considerable uncertainty regarding the optimal pharmacotherapeutic strategy for treating these and other aspects of psychotic illness. The present review summarises clinical, mutant, and psychopharmacological data related to catechol-O-methyltransferase (COMT), an enzyme involved in the catabolism of catecholamine neurotransmitters, with a view to establishing the antipsychotic potential of compounds targeting the action of this enzyme. The review examines clinical and preclinical genetic data linking COMT gene variation with risk for schizophrenia or specific symptoms or disease endophenotypes. We then summarise data concerning the behavioural effects of COMT inhibitors. These genetic and pharmacological data relating to COMT as a therapeutic target have implications for the development of individualised treatments for treatment-resistant symptoms of schizophrenia, including cognitive dysfunction and, potentially, negative symptoms.
[show abstract][hide abstract] ABSTRACT: 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.
Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology 03/2012; 37(7):1773-83. · 6.99 Impact Factor
[show abstract][hide abstract] ABSTRACT: 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.
Brain Behavior and Immunity 03/2012; 26(4):660-71. · 5.61 Impact Factor
[show abstract][hide abstract] ABSTRACT: Schizophrenia is characterised by a multifactorial aetiology that involves genetic liability interacting with epigenetic and environmental factors to increase risk for developing the disorder. A consensus view is that the genetic component involves several common risk alleles of small effect and/or rare but penetrant copy number variations. Furthermore, there is increasing evidence for broader, overlapping genetic-phenotypic relationships in psychosis; for example, the same susceptibility genes also confer risk for bipolar disorder. Phenotypic characterisation of genetic models of candidate risk genes and/or putative pathophysiological processes implicated in schizophrenia, as well as examination of epidemiologically relevant gene × environment interactions in these models, can illuminate molecular and pathobiological mechanisms involved in schizophrenia. The present chapter outlines both the evidence from phenotypic studies in mutant mouse models related to schizophrenia and recently described mutant models addressing such gene × environment interactions. Emphasis is placed on evaluating the extent to which mutant phenotypes recapitulate the totality of the disease phenotype or model selective endophenotypes. We also discuss new developments and trends in relation to the functional genomics of psychosis which might help to inform on the construct validity of mutant models of schizophrenia and highlight methodological challenges in phenotypic evaluation that relate to such models.
Current topics in behavioral neurosciences. 02/2012; 12:209-50.
[show abstract][hide abstract] ABSTRACT: While motor disturbance in Parkinson's disease can affect innate, programmed processes, such as masticatory mandibular movements, the pathophysiology of such abnormalities remains unclear. This study applies digital analysis by high-speed video signal processing that tracks three dots placed around the mouth for recording masticatory movements in unilateral 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated monkeys. The system analyzes displacement, velocity and cycle duration of the topography of mandibular movement during mastication of sweet potato slices. In monkeys receiving MPTP into the right carotid artery (n = 3), positron emission tomography indicated significant reduction in the binding of (E)-N-(3-iodoprop-2-enyl)-2β-carbo[(11)C]methoxy-3β-(4-methylphenyl)nortropane ([(11)C]PE2I) to the dopamine transporter in the right caudate, putamen, nucleus accumbens and substantia nigra relative to the contralateral hemisphere. These monkeys showed hypokinesia of the left forelimbs and hindlimbs. During mastication, MPTP-treated monkeys chewed preferentially on the left side, while untreated monkeys (n = 3) showed no preference for chewing side. The amplitude of vertical opening and closing movements was reduced in MPTP-treated monkeys, with a slight but significant increase in the lateral component of mandibular movements. The velocity of all phases of horizontal mandibular movements was reduced. In consequence, duration of the occlusal phase was increased, while duration of the closing phase was decreased in MPTP-treated monkeys. These findings indicate that during masticatory movements MPTP-treated monkeys chew preferentially on the side contralateral to loss of dopamine neurons, with reduced amplitude and velocity of mandibular movements. High-speed digital movement analysis is able to define and quantify abnormalities of orofacial movement topography as a sign of parkinsonism.
Journal of Neural Transmission 02/2012; 119(8):933-41. · 3.05 Impact Factor
[show abstract][hide abstract] ABSTRACT: In this review we consider the application of mutant mouse phenotypes to the study of psychotic illness in general and schizophrenia in particular, as they relate to behavioral, psychopharmacological, and cellular phenotypes of putative import for antipsychotic drug development. Mutant models appear to be heuristic at two main levels; firstly, by indicating the functional roles of neuronal components thought to be of relevance to the putative pathobiology of psychotic illness, they help resolve overt behavioral and underlying cellular processes regulated by those neuronal components; secondly, by indicating the functional roles of genes associated with risk for psychotic illness, they help resolve overt behavioral and underlying cellular processes regulated by those risk genes. We focus initially on models of dopaminergic and glutamatergic dysfunction. Then, we consider advances in the genetics of schizophrenia and mutant models relating to replicable risk genes. Lastly, we extend this discussion by exemplifying two new variant approaches in mutant mice that may serve as prototypes for advancing antipsychotic drug development. There is continuing need not only to address numerous technical challenges but also to develop more "real-world" paradigms that reflect the milieu of gene × environment and gene × gene interactions that characterize psychotic illness and its response to antipsychotic drugs.