[Show abstract][Hide abstract]ABSTRACT: Major neuropsychiatric disorders are genetically complex but share overlapping etiology. Mice mutant for rare, highly penetrant risk variants can be useful in dissecting the molecular mechanisms involved. The gene disrupted in schizophrenia 1 (DISC1) has been associated with increased risk for neuropsychiatric conditions. Mice mutant for Disc1 display morphological, functional and behavioral deficits that are consistent with impairments observed across these disorders. Here we report that Disc1 L100P mutants are less able to reorganize cortical circuitry in response to stimulation in vivo. Molecular analysis reveals that the mutants have a reduced expression of PSD95 and pCREB in visual cortex and fail to adjust expression of such markers in response to altered stimulation. In vitro analysis shows that mutants have impaired functional reorganization of cortical neurons in response to selected forms of neuronal stimulation, but there is no altered basal expression of synaptic markers. These findings suggest that DISC1 has a critical role in the reorganization of cortical plasticity and that this phenotype becomes evident only under challenge, even at early postnatal stages. This result may represent an important etiological mechanism in the emergence of neuropsychiatric disorders.
Full-text · Article · Jan 2016 · Translational Psychiatry
[Show abstract][Hide abstract]ABSTRACT: Background Substance use is recognised as the most common co morbidity of psychosis, with cannabis the substance used most often. A recent 5 year follow-up study of individuals with a first episode psychosis demonstrated that those who continued to use cannabis experienced more psychotic symptoms and poorer functioning. Thirty two Randomised Controlled Trials have failed to support evidence for an effective intervention to improve outcomes, most experiencing difficulties in recruitment and engagement. Aim The aim of this study is to use a modified version of the Delphi method as an innovative way to consult with experts from various fields to gather their opinions through an iterative process and reach a consensus as to which interventions are most likely to engage and improve outcomes for people with early phase psychosis and comorbid cannabis abuse or dependence. Methodology Participants are selected through the use of purposive sampling based on their expert knowledge in the areas of psychosis and cannabis research, clinical service delivery, or through their experience as a carer or service user, to participate in at least three rounds of interview via telephone/skype/email. The research team compiles the outcome of reach round of interviews to inform a subsequent round until information saturation is reached. Results / Implications When a consensus of information is achieved the research team will develop an intervention manual based on the Delphi study findings to be utilized within a large scale RCT.
[Show abstract][Hide abstract]ABSTRACT: Schizophrenia is a highly heritable disorder. Genetic risk is conferred by a large number of alleles, including common alleles of small effect that might be detected by genome-wide association studies. Here we report a multi-stage schizophrenia genome-wide association study of up to 36,989 cases and 113,075 controls. We identify 128 independent associations spanning 108 conservatively defined loci that meet genome-wide significance, 83 of which have not been previously reported. Associations were enriched among genes expressed in brain, providing biological plausibility for the findings. Many findings have the potential to provide entirely new insights into aetiology, but associations at DRD2 and several genes involved in glutamatergic neurotransmission highlight molecules of known and potential therapeutic relevance to schizophrenia, and are consistent with leading pathophysiological hypotheses. Independent of genes expressed in brain, associations were enriched among genes expressed in tissues that have important roles in immunity, providing support for the speculated link between the immune system and schizophrenia.
[Show abstract][Hide abstract]ABSTRACT: Background:
Conducting research on the work outcomes of first episode psychosis (FEP) samples may extend our understanding of the factors associated with the work outcome of people with schizophrenia and other psychotic illnesses.
To conduct a detailed study of the work outcome of an FEP sample.
Members of a FEP cohort, who had completed a 12-year clinical outcome assessment, were invited to participate in an adjunctive work outcome study. Engagement in paid and non-paid work was first established and the relationship with potentially influential baseline characteristics investigated. Subsequently the influence of work outcome to participants' level of quality of life, mental health, recovery, and social inclusion were examined.
Among the 38 participants the mean percentage of time spent in work was 62% of which 50% was in paid work and 12% was in non-paid work. Being employed at inception was the only independent predictor of the duration of the follow-up period spent in work. Relationships between work outcome and all measures of wellbeing were found.CONCLUSION: The paid and non-paid work attained by people affected by a psychotic illness played an important role in the extent of their wellbeing, recovery, and social inclusion.
[Show abstract][Hide abstract]ABSTRACT: Background:
The boundaries of psychotic illness and the extent to which operational diagnostic categories are distinct in the long term remain poorly understood. Clarification of these issues requires prospective evaluation of diagnostic trajectory, interplay and convergence/divergence across psychotic illness, without a priori diagnostic or other restrictions.
The Cavan-Monaghan First Episode Psychosis Study (CAMFEPS), conducted using methods to attain the closest approximation to epidemiological completeness, incepts all 12 DSM-IV psychotic diagnoses. In this study we applied methodologies to achieve diagnostic reassessments on follow-up, at a mean of 6.4 years after first presentation, for 196 (97%) of the first 202 cases, with quantification of prospective and retrospective consistency.
Over 6 years, the 12 initial psychotic diagnoses were characterized by numerous transitions but only limited convergence towards a smaller number of more stable diagnostic nodes. In particular, for initial brief psychotic disorder (BrP), in 85% of cases this was the harbinger of long-term evolution to serious psychotic illness of diagnostic diversity; for initial major depressive disorder with psychotic features (MDDP), in 18% of cases this was associated with mortality of diverse causality; and for initial psychotic disorder not otherwise specified (PNOS), 31% of cases continued to defy DSM-IV criteria.
CAMFEPS methodology revealed, on an individual case basis, a diversity of stabilities in, and transitions between, all 12 DSM-IV psychotic diagnoses over 6 years; thus, psychotic illness showed longitudinal disrespect to current nosology and may be better accommodated by a dimensional model. In particular, a first episode of BrP or MDDP may benefit from more vigorous, sustained interventions.
No preview · Article · Mar 2013 · Psychological Medicine
[Show abstract][Hide abstract]ABSTRACT: Drugs that induce psychosis, such as D-amphetamine (AMP), and those that alleviate it, such as antipsychotics, are suggested to exert behavioral effects via dopamine receptor D2 (D2). All antipsychotic drugs are D2 antagonists, but D2 antagonism underlies the severe and debilitating side effects of these drugs; it is therefore important to know whether D2 is necessary for their behavioral effects. Using
D2-null mice (Drd2/), we first investigated whether D2 is required for AMP disruption of latent inhibition (LI). LI is a process of learning to ignore irrelevant stimuli. Disruption of LI by AMP models impaired attention and abnormal salience allocation consequent to dysregulated dopamine relevant to schizophrenia. AMP disruption of LI was seen in both wild-type (WT) and Drd2/. This was in
contrast to AMP-induced locomotor hyperactivity, which was reduced in Drd2/. AMP disruption of LI was attenuated in mice lacking dopamine receptor D1 (Drd1/), suggesting that D1 may play a role in AMP disruption of LI. Further supporting this possibility, we found that D1 antagonist SKF83566 attenuated AMP disruption of LI in WT. Remarkably, both haloperidol and clozapine attenuated AMP disruption of LI in Drd2/. This demonstrates that antipsychotic drugs can attenuate AMP disruption of learning to ignore irrelevant stimuli in the absence of D2 receptors. Data suggest that D2 is not essential either for AMP to disrupt or for antipsychotic drugs to reverse AMP disruption of learning to ignore irrelevant stimuli and further that D1 merits investigation in the mediation of AMP disruption of these processes.
Full-text · Article · Feb 2013 · Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology
[Show abstract][Hide abstract]ABSTRACT: Objective:
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.
[Show abstract][Hide abstract]ABSTRACT: Disrupted-in-schizophrenia-1 (DISC1) is a gene that has been functionally linked with neurodevelopmental processes and structural plasticity in the brain. Clinical genetic investigations have implicated DISC1 as a genetic risk factor for schizophrenia and related psychoses. Studies using mutant mouse models of DISC1 gene function have demonstrated schizophrenia-related anatomical and behavioral endophenotypes. In the present study, ethologically based assessment of exploratory and habituation behavior in the open field was conducted in DISC1 (L100P), wild-type (WT), heterozygous (HET), and homozygous (HOM) mutant mice of both sexes. Ethological assessment was conducted in an open-field environment to explore specific topographies of murine exploratory behavior across the extended course of interaction from initial exploration through subsequent habituation (the ethogram). During initial exploration, HET and HOM DISC1 mutants evidenced increased levels of locomotion and rearing to wall compared with WT. A HOM-specific increase in total rearing and a HET-specific increase in sifting behavior and reduction in rearing seated were also observed. Over subsequent habituation, locomotion, sniffing, total rearing, rearing to wall, rearing free, and rearing seated were increased in HET and HOM mutants vs. WT. Overall, grooming was increased in HOM relative to other genotypes. HET mice displayed a selective decrease in habituation of sifting behavior. These data demonstrate impairment in both initial exploratory and habituation of exploration in a novel environment in mice with mutation of DISC1. This is discussed in the context of the functional role of the gene vis à vis a schizophrenia phenotype as well as the value of ethologically based approaches to behavioral phenotyping.
No preview · Article · Jul 2012 · Journal of Neuroscience Research
[Show abstract][Hide abstract]ABSTRACT: Impaired insight is commonly seen in psychosis and some studies have proposed that is a biologically based deficit. Support for this view comes from the excess of neurological soft signs (NSS) observed in patients with psychoses and their neural correlates which demonstrate a degree of overlap with the regions of interest implicated in neuroimaging studies of insight. The aim was to examine the relationship between NSS and insight in a sample of 241 first-episode psychosis patients.
Total scores and subscale scores from three insight measures and two NSS scales were correlated in addition to factors representing overall insight and NSS which we created using principal component analysis.
There were only four significant associations when we controlled for symptoms. "Softer" condensed neurological evaluation (CNE) signs were associated with our overall insight factor (r = 0.19, P = 0.02), with total Birchwood (r = -0.24, P < 0.01), and the Birchwood subscales; recognition of mental illness (r = -0.24, P < 0.01) and need for treatment (r = -0.18, P = 0.02). Total neurological evaluation scale (NES) and recognition of the achieved effects of medication were also weakly correlated (r = 0.14, P = 0.04).
This study does not support a direct link between neurological dysfunction and insight in psychosis. Our understanding of insight as a concept remains in its infancy.
No preview · Article · Mar 2011 · European Psychiatry
[Show abstract][Hide abstract]ABSTRACT: The recent impact of new drugs acting selectively on D-1 dopamine receptors is reviewed. 1-pheny1-1H-3-benzazepines, typified by SCH 23390, SK&F 83566 and SK&F 38393, represent the major class of drugs with such properties. Contrary to previous theoretical schemes, which attributed a prepotent role to the D 2 receptor in the regulation of behaviour, selective D-1 agents are active in a wide variety of behavioural paradigms. However, they can show pharmacological profiles sometimes similar to and sometimes distinct from those of selective D-2 agents. Their effects can be different after lesions or transmitter depletions, in comparison with the whole animal, but are generally suggestive of functional interactions between D-1 and D-2 receptor systems at an integrative level. These behavioural actions of selective D-1 agents are sometimes complemented, but often contradicted, by their effects in neurophysiological and neurochemical studies. After a period of considerable neglect, the D-1 receptor has begun to find its functional role, and there will be intense speculation as to its clinical and therapeutic significance.
No preview · Article · Jan 2011 · Reviews in the neurosciences