Meta-analysis of Positive and Negative Symptoms Reveals Schizophrenia Modifier Genes

BACKGROUND: Evidence suggests that genetic factors may influence both schizophrenia (Scz) and its clinical presentation. In recent years, genome-wide association studies (GWAS) have demonstrated considerable success in identifying risk loci. Detection of "modifier loci" has the potential to further elucidate underlying disease processes.

METHODS: We performed GWAS of empirically derived positive and negative symptom scales in Irish cases from multiply affected pedigrees and a larger, independent case-control sample, subsequently combining these into a large Irish meta-analysis. In addition to single-SNP associations, we considered gene-based and pathway analyses to better capture convergent genetic effects, and to facilitate biological interpretation of these findings. Replication and testing of aggregate genetic effects was conducted using an independent European-American sample.

RESULTS: Though no single marker met the genome-wide significance threshold, genes and ontologies/pathways were significantly associated with negative and positive symptoms; notably, NKAIN2 and NRG1, respectively. We observed limited overlap in ontologies/pathways associated with different symptom profiles, with immune-related categories over-represented for negative symptoms, and addiction-related categories for positive symptoms. Replication analyses suggested that genes associated with clinical presentation are generalizable to non-Irish samples.

CONCLUSIONS: These findings strongly support the hypothesis that modifier loci contribute to the etiology of distinct Scz symptom profiles. The finding that previously implicated "risk loci" actually influence particular symptom dimensions has the potential to better delineate the roles of these genes in Scz etiology. Furthermore, the over-representation of distinct gene ontologies/pathways across symptom profiles suggests that the clinical heterogeneity of Scz is due in part to complex and diverse genetic factors.

mGluR5 Positive Allosteric Modulators Facilitate both Hippocampal LTP and LTD and Enhance Spatial Learning

Highly selective positive allosteric modulators (PAMs) of metabotropic glutamate receptor subtype 5 (mGluR5) have emerged as a potential approach to treat positive symptoms associated with schizophrenia. mGluR5 plays an important role in both long-term potentiation (LTP) and long-term depression (LTD), suggesting that mGluR5 PAMs may also have utility in improving impaired cognitive function. However, if mGluR5 PAMs shift the balance of LTP and LTD or induce a state in which afferent activity induces lasting changes in synaptic function that are not appropriate for a given pattern of activity, this could disrupt rather than enhance cognitive function. We determined the effect of selective mGluR5 PAMs on the induction of LTP and LTD at the Schaffer collateral-CA1 synapse in the hippocampus. mGluR5-selective PAMs significantly enhanced threshold theta-burst stimulation (TBS)-induced LTP. In addition, mGluR5 PAMs enhanced both DHPG-induced LTD and LTD induced by the delivery of paired-pulse low-frequency stimulation. Selective potentiation of mGluR5 had no effect on LTP induced by suprathreshold TBS or saturated LTP. The finding that potentiation of mGluR5-mediated responses to stimulation of glutamatergic afferents enhances both LTP and LTD and supports the hypothesis that the activation of mGluR5 by endogenous glutamate contributes to both forms of plasticity. Furthermore, two systemically active mGluR5 PAMs enhanced performance in the Morris water maze, a measure of hippocampus-dependent spatial learning. Discovery of small molecules that enhance both LTP and LTD in an activity-appropriate manner shows a unique action on synaptic plasticity that may provide a novel approach for the treatment of impaired cognitive function. Neuropsychopharmacology (2009) 34, 2057-2071; doi:10.1038/npp.2009.30; published online 18 March 2009

Predictors of PTSD Symptoms in Response to Psychosis and Psychiatric Admission

The experiences of psychosis and psychiatric admission have the potential to act as events precipitating posttraumatic stress disorder (PTSD) symptoms. Known risk factors for the development of PTSD symptoms in adults were identified. These included childhood trauma, current psychiatric symptoms, perceived coercion, and relationships with mental health service providers. These factors were analyzed to determine if they were important in the development of PTSD symptoms in response to psychosis and admission. We used a cross-sectional design with a sample of 47 participants recruited from a service in Northern Ireland who had experienced psychosis and been discharged from inpatient treatment within 12 months of data collection. The main outcome measure was the impact of events scale-revised. Data was subject to correlation analyses. A cut-off point of r = +/- 0.25 was used to select variables for inclusion in hierarchical regression analyses. Forty-five percent and 31% of the sample had moderate to severe PTSD symptoms related to psychosis and admission, respectively. The majority of participants identified positive symptoms and the first admission as the most distressing aspects of psychosis and admission. Childhood sexual and physical traumas were significant predictors of some PTSD symptoms. Strong association was found between current affective symptoms and PTSD symptoms. A reduced sense of availability of mental health service providers was also associated with PTSD symptoms and depression. Awareness of risk factors for the development of PTSD symptoms in response to admission and psychosis raises important issues for services and has implications for interventions provided.

Impact of persistent substance misuse on 1-year outcome in first-episode psychosis

Background: Substance misuse is a common comorbid problem in people presenting with first-episode psychosis and is associated with a poor short-term outcome.

Aims: The aim of this study is to examine differences in baseline characteristics and 1-year outcome between individuals with first-episode psychosis who have never misused substances, those who stop misusing substances after initial presentation and those who persistently misuse substances over the 1-year assessment period.

Method: Patients were recruited to the Northern Ireland First Episode Psychosis Study (n=272). Clinical assessments were performed at baseline and at 1 year (n=194) and data were collected from the case notes.

Results: Individuals with persistent substance misuse had more severe depression, more positive symptoms, poorer functional outcome and greater rates of relapse at 1 year than those who stopped and those who had never misused substances. There were no differences in outcome between people who had never misused substances and those who stopped misusing after presentation.

Conclusions: These results support assertive intervention targeted at comorbid substance misuse in individuals with first-episode psychosis.

Does chronic illness place constraints on positive constructions of identity? Temporal comparisons and self-evaluations in people with schizophrenia

It is often suggested that people in potentially threatening situations might engage in self-enhancing temporal comparisons that allow them to view themselves and their experience in a more positive light. Data from semistructured interviews with 12 individuals in the UK diagnosed as having schizophrenia were content analyzed to explore patterns of temporal comparison. The study found that the onset of schizophrenic symptoms created a new baseline in participants' representations of their past, with different types of temporal comparisons occurring before and after this point. Although comparisons with past selves after onset supported the suggestion that people may select and construct their past in such a manner that permits them to see their present circumstances more positively and envisage a better future, comparisons with past selves before onset were more negative. The findings suggest that the Theory of Temporal Self-Appraisals (Ross I Wilson, 2000) needs to be elaborated to include people who have experienced major life changes. (c) 2004 Elsevier Ltd. All rights reserved.

A prospective randomised trial of a "test and treat" policy versus endoscopy based management in young Helicobacter pylori positive patients with ulcer-like dyspepsia, referred to a hospital clinic

Management of dyspepsia remains a controversial area. Although the European Helicobacter pylori study group has advised empirical eradication therapy without oesophagogastroduodenoscopy (OGD) in young H pylori positive dyspeptic patients who do not exhibit alarm symptoms, this strategy has not been subjected to clinical trial.

Double blind cross-over placebo controlled study of omeprazole in the treatment of patients with reflux symptoms and physiological levels of acid reflux--the "sensitive oesophagus"

At least 10-15% of patients with reflux symptoms have a normal endoscopy and physiological levels of acid reflux on pH monitoring. Such patients with 50% or more of symptoms associated with acid reflux episodes have "a positive symptom index" (SI), and it has been proposed that this defines the "sensitive oesophagus".

Mood congruent psychotic symptoms and specific cognitive deficits in carriers of the novel schizophrenia risk variant at MIR-137

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. Method: 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). Results: 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. Conclusion: 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. © 2012 Elsevier Ireland Ltd.

Agreement between self-report and medical records on signs and symptoms of respiratory illness

Background: Information on patient symptoms can be obtained by patient self-report or medical records review. Both methods have limitations. Aims: To assess the agreement between self-report and documentation in the medical records of signs/symptoms of respiratory illness (fever, cough, runny nose, sore throat, headache, sinus problems, muscle aches, fatigue, earache, and chills). Methods: Respondents were 176 research participants in the Hutterite Influenza Prevention Study during the 2008-2009 influenza season with information about the presence or absence of signs/symptoms from both self-report and primary care medical records. Results: Compared with medical records, lower proportions of self-reported fever, sore throat, earache, cough, and sinus problems were found. Total agreements between self-report and medical report of symptoms ranged from 61% (for sore throat) to 88% (for muscle aches and earache), with kappa estimates varying from 0.05 (for chills) to 0.41 (for cough) and 0.51 (for earache). Negative agreement was considerably higher (from 68% for sore throat to 93% for muscle aches and earache) than positive agreement (from 13% for chills to 58% for earache) for each symptom except cough where positive agreement (77%) was higher than negative agreement (64%). Agreements varied by age group. We found better agreement for earache (kappa=0.62) and lower agreements for headache, sinus problems, muscle aches, fatigue, and chills in older children (aged =5 years) and adults. Conclusions: Agreements were variable depending on the specific symptom. Contrary to research in other patient populations which suggests that clinicians report fewer symptoms than patients, we found that the medical record captured more symptoms than selfreport. Symptom agreement and disagreement may be affected by the perspectives of the person experiencing them, the observer, the symptoms themselves, measurement error, the setting in which the symptoms were observed and recorded, and the broader community and cultural context of patients. © 2012 Primary Care Respiratory Society UK. All rights reserved.

Positive aspects and challenges associated with caring for a dying relative at home

Research has consistently shown that family caregivers have a variety of unmet needs, despite comprehensive professional support for caregivers being a central aim of palliative care. This sub-study of a larger randomized controlled trial sought feedback from 47 primary family caregivers of advanced cancer patients who had recently commenced home palliative care. During semi-structured interviews in their homes, family caregivers were asked to comment on the key challenges associated with their role and whether they could identify challenges. These were associated with their own ill health, family circumstances, insufficient skills to manage patient symptoms, limited time for themselves and inadequate support from health professionals. Despite these challenges, 60% of family caregivers were readily able to identify positive aspects of the role. Previous research has tended to focus on the negative impact of caregiving. The extent to which the positive aspects buffer the negative aspects of the role warrants further exploration, as does the long-term impact of the caregiver role on those who are unable to recognize positive elements.

Self and identity in women with symptoms of borderline personality: A qualitative study

Identity disturbance has been suggested to be a core feature of borderline personality disorder (BPD). However, there is little known about the identity of individuals with symptoms of BPD from the participant’s perspective. This study availed of in-depth lightly structured life story interviews with five female participants. Thematic analysis was utilized to derive three themes of identity: connection, distance between us, and hurt and healing. Results provided support for multiple and flexible conceptualizations of identity in comparison to the idea of a unitary self/identity. Results also suggested that participants were able to establish differing connections to others ranging from disconnection to intimacy and care. Participants reported that their identities were impacted upon by historical and current family/relationship dysfunction, but life stories also illustrated the positive impact of healing relationship experiences. Findings provide support for psychological theories that consider a multiple and relational self/identity and the empowerment of healthy aspects of the self in BPD recovery. Studies that assess the association between insight and change may further our knowledge into this complex population.

Do Individual Differences in Emotion Regulation Mediate the Relationship Between Mental Toughness and Symptoms of Depression?

Mental Toughness (MT) provides crucial psychological capacities for achievement in sports,
education, and work settings. Previous research examined the role of MT in the domain of
mental health and showed that MT is negatively associated with and predictive of fewer
depressive symptoms in non-clinical populations. The present study aimed at 1) investigating
to what extent mentally tough individuals use two emotion regulation strategies: cognitive
reappraisal and expressive suppression; 2) exploring whether individual differences in
emotion regulation strategy use mediate the relationship between MT and depressive
symptoms. Three hundred sixty-four participants (M = 24.31 years, SD = 9.16) provided
self-reports of their levels of MT, depressive symptoms, and their habitual use of cognitive
reappraisal and expressive suppression. The results showed a statistically significant
correlation between MT and two commonly used measures of depressive symptoms. A small
statistically significant positive correlation between MT and the habitual use of cognitive
reappraisal was also observed. The correlation between MT and the habitual use of
expressive suppression was statistically significant, but the size of the effect was small. A
statistical mediation model indicated that individual differences in the habitual use of
expressive suppression mediate the relationship between MT and depressive symptoms. No
such effect was found for the habitual use of cognitive reappraisal. Implications of these
findings and possible avenues for future research are discussed.

Completely positive non-Markovian decoherence

We propose an effective Hamiltonian approach to investigate decoherence of a quantum system in a non-Markovian reservoir, naturally imposing the complete positivity on the reduced dynamics of the system. The formalism is based on the notion of an effective reservoir, i.e., certain collective degrees of freedom in the reservoir that are responsible for the decoherence. As examples for completely positive decoherence, we present three typical decoherence processes for a qubit such as dephasing, depolarizing, and amplitude damping. The effects of the non-Markovian decoherence are compared to the Markovian decoherence.

A cross-sectional study of neuropsychiatric symptoms in 435 patients with Alzheimer's disease

OBJECTIVES: The behavioral and psychological symptoms of Alzheimer's disease (AD) are associated with significant patient and caregiver distress and increased likelihood of institutionalization. We attempted to characterize in detail these symptoms and the distress they cause to caregivers. METHODS: Patients with probable AD were assessed with the Mini-Mental State Exam (MMSE), Functional Assessment Staging (FAST), and the Neuropsychiatric Inventory With Caregiver Distress (NPI-D). RESULTS: Four hundred and thirty-five patients were recruited. Neuropsychiatric symptoms of all types were highly prevalent. The most common and most persistent symptom was apathy (75%). Delusional symptoms were the least persistent. Depressive and apathetic symptoms were the earliest to appear, and hallucinations, elation/euphoria, and aberrant motor behavior were the latest symptoms to emerge. Hallucinations were significantly more common in severe dementia. Symptoms of irritability were most prevalent in early disease. Total Neuropsychiatric Symptom score was significantly correlated with MMSE and FAST score. Caregivers rated their own emotional distress levels as moderate or severe for 10 out of 12 symptom domains. The sum total of caregiver distress was strongly correlated with total NPI-D but not cognition or functional state. Distress levels did not vary when analyzed according to the patients' place of residence. CONCLUSIONS: Potentially treatable neuropsychiatric symptoms are common in AD and represent a major source of distress among caregivers. The extent of neuropsychiatric symptomatology is seen to correlate with the level of functional and cognitive disability although some symptoms are variably persistent and related to disease stage.