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author:(William G honey)
1.  Impaired musical ability in people with schizophrenia 
Background
Assessment of the musical ability of people with schizophrenia has attracted little interest despite the diverse and substantive findings of impairments in sound perception and processing and the therapeutic effect of music in people with the illness. The present study investigated the musical ability of people with schizophrenia and the association with psychiatric symptoms and cognition.
Methods
We recruited patients with chronic schizophrenia and healthy controls for participation in our study. To measure musical ability and cognitive function, we used the Montreal Battery of Evaluation of Amusia (MBEA) and the Brief Assessment of Cognition in Schizophrenia (BACS). We carried out a mediation analysis to investigate a possible pathway to a deficit in musical ability.
Results
We enrolled 50 patients and 58 controls in the study. The MBEA global score in patients with schizophrenia was significantly lower than that in controls (p < 0.001), and was strongly associated with both the composite cognitive function score (r = 0.645, p < 0.001) and the negative symptom score (r = −0.504, p < 0.001). Further analyses revealed direct and indirect effects of negative symptoms on musical ability. The indirect effects were mediated through cognitive impairment.
Limitations
The relatively small sample size did not permit full evaluation of the possible effects of age, sex, education, medication and cultural influences on the results.
Conclusion
Examining the associations between musical deficits, negative symptoms and cognitive imapirment in patients with schizophrenia may identify shared biological mechanisms.
doi:10.1503/jpn.120207
PMCID: PMC3937280  PMID: 24119791
2.  The Hotel Study—Clinical and Health Service Effectiveness in a Cohort of Homeless or Marginally Housed Persons 
Objective:
The Hotel Study was initiated in Vancouver’s Downtown East Side (DTES) neighborhood to investigate multimorbidity in homeless or marginally housed people. We evaluated the clinical effectiveness of existing, illness-specific treatment strategies and assessed the effectiveness of health care delivery for multimorbid illnesses.
Method:
For context, we mapped the housing locations of patients presenting for 552,062 visits to the catchment hospital emergency department (2005-2013). Aggregate data on 22,519 apprehensions of mentally ill people were provided by the Vancouver Police Department (2009-2015). The primary strategy was a longitudinal cohort study of 375 people living in the DTES (2008-2015). We analysed mortality and evaluated the clinical and health service delivery effectiveness for infection with human immunodeficiency virus or hepatitis C virus, opioid dependence, and psychosis.
Results:
Mapping confirmed the association between poverty and greater number of emergency visits related to substance use and mental illness. The annual change in police apprehensions did not differ between the DTES and other policing districts. During 1581 person-years of cohort observation, the standardized mortality ratio was 8.43 (95% confidence interval, 6.19 to 11.50). Physician visits were common (84.3% of participants over 6 months). Clinical treatment effectiveness was highest for HIV/AIDS, intermediate for opioid dependence, and lowest for psychosis. Health service delivery mechanisms provided examples of poor access, poor treatment adherence, and little effect on multimorbid illnesses.
Conclusions:
Clinical effectiveness was variable, and illness-specific service delivery appeared to have little effect on multimorbidity. New models of care may need to be implemented.
doi:10.1177/0706743717693781
PMCID: PMC5528984  PMID: 28199798
psychosis; heroin; HIV; HCV; police; multimorbidity; mortality
3.  Mortality from treatable illnesses in marginally housed adults: a prospective cohort study 
BMJ Open  2015;5(8):e008876.
Objectives
Socially disadvantaged people experience greater risk for illnesses that may contribute to premature death. This study aimed to evaluate the impact of treatable illnesses on mortality among adults living in precarious housing.
Design
A prospective cohort based in a community sample.
Setting
A socially disadvantaged neighbourhood in Vancouver, Canada.
Participants
Adults (N=371) living in single room occupancy hotels or recruited from the Downtown Community Court and followed for median 3.8 years.
Main outcome measures
Participants were assessed for physical and mental illnesses for which treatment is currently available. We compared cohort mortality rates with 2009 Canadian rates. Left-truncated Cox proportional hazards modelling with age as the time scale was used to assess risk factors for earlier mortality.
Results
During 1269 person-years of observation, 31/371 (8%) of participants died. Compared with age-matched and sex-matched Canadians, the standardised mortality ratio was 8.29 (95% CI 5.83 to 11.79). Compared with those that had cleared the virus, active hepatitis C infection was a significant predictor for hepatic fibrosis adjusting for alcohol dependence and age (OR=2.96, CI 1.37 to 7.08). Among participants <55 years of age, psychosis (HR=8.12, CI 1.55 to 42.47) and hepatic fibrosis (HR=13.01, CI 3.56 to 47.57) were associated with earlier mortality. Treatment rates for these illnesses were low (psychosis: 32%, hepatitis C virus: 0%) compared with other common disorders (HIV: 57%, opioid dependence: 61%) in this population.
Conclusions
Hepatic fibrosis and psychosis are associated with increased mortality in people living in marginal conditions. Timely diagnosis and intervention could reduce the high mortality in marginalised inner city populations.
doi:10.1136/bmjopen-2015-008876
PMCID: PMC4550735  PMID: 26297373
PUBLIC HEALTH; INFECTIOUS DISEASES
4.  Structural brain imaging abnormalities associated with schizophrenia and partial trisomy of chromosome 5 
Psychological medicine  1992;22(2):519-524.
SYNOPSIS
Chromosomal abnormalities occurring in association with mental illness provide a unique opportunity to study the interaction of genetic abnormalities and the brain in mental illness. Four individuals from a family in which schizophrenia was found to cosegregate with a partial trisomy of chromosome 5 were studied with computed tomography and magnetic resonance imaging. Temporal lobe atrophy was found in the two trisomic males and in the asymptomatic balanced translocation female. In addition, a large cavum septum pellucidum and a cavum vergae were found in the older trisomic individual. Scans from the normal male were free of abnormalities. These results suggest that molecular studies of the translocation breakpoints in this chromosomal abnormality may be of interest, and encourage further studies of brain structure in other chromosomal abnormalities associated with psychosis.
PMCID: PMC3154172  PMID: 1615118 CAMSID: cams1823
5.  A translational research approach to poor treatment response in patients with schizophrenia: clozapine–antipsychotic polypharmacy 
Poor treatment response in patients with schizophrenia is an important clinical problem, and one possible strategy is concurrent treatment with more than one antipsychotic (polypharmacy). We analyzed the evidence base for this strategy using a translational research model focused on clozapine–antipsychotic polypharmacy (CAP). We considered 3 aspects of the existing knowledge base and translational research: the link between basic science and clinical studies of efficacy, the evidence for effectiveness in clinical research and the implications of research for the health care delivery system. Although a rationale for CAP can be developed from receptor pharmacology, there is little available preclinical research testing these concepts in animal models. Randomized clinical trials of CAP show minimal or no benefit for overall severity of symptoms. Most studies at the level of health services are limited to estimates of CAP prevalence and some suggestion of increased costs. Increasing use of antipsychotic polypharmacy in general may be a factor contributing to the under-utilization of clozapine and long delays in initiating clozapine monotherapy. Translational research models can be applied to clinical questions such as the value of CAP. Better linkage between the components of translational research may improve the appropriate use of medications such as clozapine in psychiatric practice.
PMCID: PMC2783434  PMID: 19949719
6.  Decreased cortical FADD protein is associated with clinical dementia and cognitive decline in an elderly community sample 
Background
FADD (Fas-associated death domain) adaptor is a crucial protein involved in the induction of cell death but also mediates non-apoptotic actions via a phosphorylated form (p-Ser194-FADD). This study investigated the possible association of FADD forms with age-related neuropathologies, cognitive function, and the odds of dementia in an elderly community sample.
Methods
FADD forms were quantified by western blot analysis in dorsolateral prefrontal cortex (DLPFC) samples from a large cohort of participants in a community-based aging study (Memory and Aging Project, MAP), experiencing no-(NCI, n = 51) or mild-(MCI, n = 42) cognitive impairment, or dementia (n = 57).
Results
Cortical FADD was lower in subjects with dementia and lower FADD was associated with a greater load of amyloid-β pathology, fewer presynaptic terminal markers, poorer cognitive function and increased odds of dementia. Together with the observations of FADD redistribution into tangles and dystrophic neurites within plaques in Alzheimer’s disease brains, and its reduction in APP23 mouse cortex, the results suggest this multifunctional protein might participate in the mechanisms linking amyloid and tau pathologies during the course of the illness.
Conclusions
The present data suggests FADD as a putative biomarker for pathological processes associated with the course of clinical dementia.
Electronic supplementary material
The online version of this article (doi:10.1186/s13024-017-0168-x) contains supplementary material, which is available to authorized users.
doi:10.1186/s13024-017-0168-x
PMCID: PMC5360099  PMID: 28320441
Alzheimer’s disease; Aging; Neurotoxicity; Neuroplasticity; Apoptosis
7.  Increased SNARE Protein-Protein Interactions in Orbitofrontal and Anterior Cingulate Cortices in Schizophrenia 
Biological psychiatry  2014;78(6):361-373.
Background
Synaptic dysfunction in schizophrenia may be associated with abnormal expression or function of SNARE proteins (syntaxin, SNAP25, VAMP), forming the molecular complex underlying neurosecretion. The impact of such abnormalities on efficient SNARE heterotrimer formation is poorly understood. We investigated putative SNARE dysfunction, along with possible roles for the SNARE binding partners Munc18-1, complexins (Cplx) 1/2 and synaptotagmin, in brains from autopsies of individuals with and without schizophrenia.
Methods
Postmortem samples were obtained from orbitofrontal (OFC) and/or anterior cingulate (ACC) cortices from two separate cohorts (n = 15+15 schizophrenia cases, n = 13+15 controls). SNARE interactions were studied by immunoprecipitation and one- or two-dimensional blue native electrophoresis (BN-PAGE).
Results
In the first cohort, syntaxin, Munc18-1 and Cplx1, but not VAMP, Cplx2 or synaptotagmin, were two-fold enriched in SNAP25-immunoprecipitated products from schizophrenia OFC in the absence of any alterations in total tissue homogenate levels of these proteins. In BN-PAGE, the SNARE heterotrimer was identified as a 150-kDa complex, increased in schizophrenia samples from Cohort 1 (OFC: +45%; ACC: +44%) and Cohort 2 (OFC: +40%), with lower 70-kDa SNAP25-VAMP dimer (−37%) in the OFC. Upregulated 200-kDa SNARE-Cplx1 (+65%), and downregulated 550-kDa Cplx1-containing oligomers (−24%) in schizophrenia OFC were identified by BN-PAGE. These findings were not explained by postmortem interval, antipsychotic medication, or other potentially confounding variables.
Conclusions
The findings support the hypothesis of upregulated SNARE complex formation in schizophrenia OFC, possibly favored by enhanced affinity for Munc18-1 and/or Cplx1. These alterations offer new therapeutic targets for schizophrenia.
doi:10.1016/j.biopsych.2014.12.012
PMCID: PMC4474796  PMID: 25662103
schizophrenia; postmortem human brain; SNARE; complexin; Munc18-1; blue native PAGE
8.  SNAP-25 is a promising novel cerebrospinal fluid biomarker for synapse degeneration in Alzheimer’s disease 
Background
Synaptic degeneration is an early pathogenic event in Alzheimer’s disease, associated with cognitive impairment and disease progression. Cerebrospinal fluid biomarkers reflecting synaptic integrity would be highly valuable tools to monitor synaptic degeneration directly in patients. We previously showed that synaptic proteins such as synaptotagmin and synaptosomal-associated protein 25 (SNAP-25) could be detected in pooled samples of cerebrospinal fluid, however these assays were not sensitive enough for individual samples.
Results
We report a new strategy to study synaptic pathology by using affinity purification and mass spectrometry to measure the levels of the presynaptic protein SNAP-25 in cerebrospinal fluid. By applying this novel affinity mass spectrometry strategy on three separate cohorts of patients, the value of SNAP-25 as a cerebrospinal fluid biomarker for synaptic integrity in Alzheimer’s disease was assessed for the first time. We found significantly higher levels of cerebrospinal fluid SNAP-25 fragments in Alzheimer’s disease, even in the very early stages, in three separate cohorts. Cerebrospinal fluid SNAP-25 differentiated Alzheimer’s disease from controls with area under the curve of 0.901 (P < 0.0001).
Conclusions
We developed a sensitive method to analyze SNAP-25 levels in individual CSF samples that to our knowledge was not possible previously. Our results support the notion that synaptic biomarkers may be important tools for early diagnosis, assessment of disease progression, and to monitor drug effects in treatment trials.
Electronic supplementary material
The online version of this article (doi:10.1186/1750-1326-9-53) contains supplementary material, which is available to authorized users.
doi:10.1186/1750-1326-9-53
PMCID: PMC4253625  PMID: 25418885
Alzheimer’s disease; Biomarker; Cerebrospinal fluid; SNAP-25; SNARE proteins; Mass spectrometry; Immunopurification; Selected reaction monitoring
9.  Metabolic abnormalities in fronto-striatal-thalamic white matter tracts in schizophrenia 
Schizophrenia research  2009;109(0):159-166.
The anterior limb of the internal capsule (ALIC) is the major white matter tract providing reciprocal connections between the frontal cortex, striatum and thalamus. Mounting evidence suggests that this tract may be affected in schizophrenia, with brain imaging studies reporting reductions in white matter volume and density, changes in fractional anisotropy and reduced asymmetry. However, the molecular correlates of these deficits are currently unknown. The aim of this study was to identify alterations in protein and metabolite levels in the ALIC in schizophrenia. Samples were obtained post-mortem from individuals with schizophrenia (n=15) and non-psychiatric controls (n=13). Immunoreactivity for the myelin-associated protein myelin basic protein (MBP), and the axonal-associated proteins phosphorylated neurofilament and SNAP-25 was measured by enzyme-linked immunoadsorbant assay (ELISA). Metabolite concentrations were quantified by proton nuclear magnetic resonance (1H NMR) spectroscopy. Levels of myelin- or axonal-associated proteins did not differ between groups. Overall differences in metabolite concentrations were observed between the two groups (MANOVA F=2.685, p=0.036), with post-hoc tests revealing lower lactate (19%) and alanine (24%) levels in the schizophrenia group relative to controls. Observed changes in lactate and alanine levels indicate metabolic abnormalities within the ALIC in schizophrenia.
doi:10.1016/j.schres.2009.01.017
PMCID: PMC4169119  PMID: 19272755
myelin; axon; metabolite; internal capsule; lactate
10.  Psychopharmacology for the Clinician 
doi:10.1503/jpn.130288
PMCID: PMC3997610  PMID: 24758945
11.  Temporal Lobe Abnormalities in Multigenerational Families with Schizophrenia 
Biological psychiatry  1994;36(11):737-743.
Brain structure in familial schizophrenia was studied with computerized tomography in 42 individuals from six multigenerational families. Sulcal enlargement in the lateral temporal cortex, and ventricular and cisternal enlargement in the medial temporal region were observed in psychotic individuals compared to unaffected family members. Genetic factors in familial schizophrenia may exert part of their effect through determining or altering temporal lobe structure.
PMCID: PMC3160970  PMID: 7858069 CAMSID: cams1917
Sylvian fissure; CT scan; schizophrenia genetics
13.  White matter deficits assessed by diffusion tensor imaging and cognitive dysfunction in psychostimulant users with comorbid human immunodeficiency virus infection 
BMC Research Notes  2015;8:515.
Background
Psychostimulant drug use is commonly associated with drug-related infection, including the human immunodeficiency virus (HIV). Both psychostimulant use and HIV infection are known to damage brain white matter and impair cognition. To date, no study has examined white matter integrity using magnetic resonance imaging (MRI) diffusion tensor imaging (DTI) in chronic psychostimulant users with comorbid HIV infection, and determined the relationship of white matter integrity to cognitive function.
Methods
Twenty-one subjects (mean age 37.5 ± 9.0 years) with a history of heavy psychostimulant use and HIV infection (8.7 ± 4.3 years) and 22 matched controls were scanned on a 3T MRI. Fractional anisotropy (FA) values were calculated with DTI software. Four regions of interest were manually segmented, including the genu of the corpus callosum, left and right anterior limbs of the internal capsule, and the anterior commissure. Subjects also completed a neurocognitive battery and questionnaires about physical and mental health.
Results
The psychostimulant using, HIV positive group displayed decreased white matter integrity, with significantly lower FA values for all white matter tracts (p < 0.05). This group also exhibited decreased cognitive performance on tasks that assessed cognitive set-shifting, fine motor speed and verbal memory. FA values for the white matter tracts correlated with cognitive performance on many of the neurocognitive tests.
Conclusions
White matter integrity was thus impaired in subjects with psychostimulant use and comorbid HIV infection, which predicted worsened cognitive performance on a range of tests. Further study on this medical comorbidity is required.
doi:10.1186/s13104-015-1501-5
PMCID: PMC4590729  PMID: 26423806
Comorbidity; Diffusion tensor imaging; Human immunodeficiency virus; Magnetic resonance imaging; Neurocognitive; Psychostimulant
14.  Assessing the machinery of mind: synapses in neuropsychiatric disorders. 
Neural connectivity in postmortem human brain can now be studied with the use of antibodies that react with synapse-enriched proteins. Using a range of antibody-based techniques, the authors observed abnormalities in connectivity in Alzheimer's disease, temporal lobe epilepsy, and schizophrenia. They also found disease-related differences in the individual protein markers affected and in the anatomical distribution of differences from controls. Molecular and cellular abnormalities in neural connectivity may underlie functional abnormalities observed in vivo using positron emission tomography or functional magnetic resonance imaging.
Images
PMCID: PMC1188991  PMID: 10212553
15.  Brain Tocopherols Related to Alzheimer Disease Neuropathology in Humans 
Randomized trials of α-tocopherol supplements on cognitive decline are negative whereas studies of dietary tocopherols show benefit. We investigated these inconsistencies by analyzing the relations of α- and γ-tocopherol brain concentrations to Alzheimer disease (AD) neuropathology among 115 deceased participants of the prospective Rush Memory and Aging Project. Associations of amyloid load and neurofibrillary tangle severity with brain tocopherol concentrations were examined in separate adjusted linear regression models. γ-tocopherol concentrations were associated with lower amyloid load (β= −2.10; p=.002) and lower neurofibrillary tangle severity (β= −1.16; p=0.02). Concentrations of α-tocopherol were not associated with AD neuropathology except as modified by γ-tocopherol: high α-tocopherol was associated with higher amyloid load when γ-tocopherol levels were low and with lower amyloid levels when γ-tocopherol levels were high (P for interaction=0.03). Brain concentrations of γ- and α-tocopherols may be associated with AD neuropathology in interrelated, complex ways. Randomized trials should consider the contribution of γ-tocopherol.
doi:10.1016/j.jalz.2013.12.015
PMCID: PMC4148466  PMID: 24589434
Nutritional; Alzheimer disease; Cohort studies; α-tocopherol = alpha tocopherol; γ-tocopherol=gamma tocopherol; δ-tocopherol=delta tocopherol; β= beta coefficient; r=Pearson’s r coefficient
16.  Loss of Munc18-1 long splice variant in GABAergic terminals is associated with cognitive decline and increased risk of dementia in a community sample 
Background
Presynaptic terminals contribute to cognitive reserve, balancing the effects of age-related pathologies on cognitive function in the elderly. The presynaptic protein Munc18-1, alternatively spliced into long (M18L) or short (M18S) isoforms, is a critical modulator of neurotransmission. While subtle alterations in Munc18-1 have been shown to cause severe neuropsychiatric disorders with cognitive impairment, little information is known regarding the specific roles of Munc18-1 splice variants. We first investigated functional and anatomical features evidencing the divergent roles of M18L and M18S, and then evaluated their contribution to the full range of age-related cognitive impairment in the dorsolateral prefrontal cortex of a large sample of participants from a community-based aging study, including subjects with no-(NCI, n = 90), or mild-(MCI, n = 86) cognitive impairment, or with clinical dementia (n = 132). Finally, we used APP23 mutant mice to study the association between M18L/S and the time-dependent accumulation of common Alzheimer’s disease pathology.
Results
Using isoform-specific antibodies, M18L was localized to the synaptosomal fraction, with a distribution matching lipid raft microdomains. M18S was found widely across cytosolic and synaptosomal compartments. Immunocytochemical studies identified M18L in perisomatic, GABAergic terminals, while M18S was broadly distributed in GABAergic and glutamatergic terminals. Using regression models taking into account multiple age-related pathologies, age, education and sex, global cognitive function was associated with the level of M18L (p = 0.006) but not M18S (p = 0.88). Mean M18L in dementia cases was 51 % lower than in NCI cases (p < 0.001), and each unit of M18L was associated with a lower likelihood of dementia (odds ratio = 0.68, 95 % confidence interval = 0.50–0.90, p = 0.008). In contrast, M18S balanced across clinical and pathologically diagnosed groups. M18L loss may not be caused by age-related amyloid pathology, since APP23 mice (12- and 22-months of age) had unchanged cortical levels of M18L/S compared with wild-type animals.
Conclusions
M18L was localized to presynaptic inhibitory terminals, and was associated with cognitive function and protection from dementia in an elderly, community-based cohort. Lower M18L in inhibitory presynaptic terminals may be an early, independent contributor to cognitive decline.
Electronic supplementary material
The online version of this article (doi:10.1186/s13024-015-0061-4) contains supplementary material, which is available to authorized users.
doi:10.1186/s13024-015-0061-4
PMCID: PMC4667524  PMID: 26628003
Syntaxin-binding protein; SNARE; Protein-protein interactions; VGAT; VGLUT1; Human postmortem brain; Aging study; Mild cognitive impairment; Synaptic pathology; Alzheimer’s disease
17.  A Novel Mechanism and Treatment Target for Presynaptic Abnormalities in Specific Striatal Regions in Schizophrenia 
Neuropsychopharmacology  2010;35(5):1226-1238.
Abnormalities of amount and function of presynaptic terminals may have an important role in the mechanism of illness in schizophrenia. The SNARE proteins (SNAP-25, syntaxin, and VAMP) are enriched in presynaptic terminals, where they interact to form a functional complex to facilitate vesicle fusion. SNARE protein amounts are altered in the cortical regions in schizophrenia, but studies of protein–protein interactions are limited. We extended these investigations to the striatal regions (such as the nucleus accumbens, ventromedial caudate (VMC), and dorsal caudate) relevant to disease symptoms. In addition to measuring SNARE protein levels, we studied SNARE protein–protein interactions using a novel ELISA method. The possible effect of antipsychotic treatment was investigated in parallel in the striatum of rodents that were administered haloperidol and clozapine. In schizophrenia samples, compared with controls, SNAP-25 was 32% lower (P=0.015) and syntaxin was 26% lower (P=0.006) in the VMC. In contrast, in the same region, SNARE protein–protein interactions were higher in schizophrenia (P=0.008). Confocal microscopy of schizophrenia and control VMC showed qualitatively similar SNARE protein immunostaining. Haloperidol treatment of rats increased levels of SNAP-25 (mean 24%, P=0.003), syntaxin (mean 18%, P=0.010), and VAMP (mean 16%, P=0.001), whereas clozapine increased only the VAMP level (mean 13%, P=0.004). Neither drug altered SNARE protein–protein interactions. These results indicate abnormalities of amount and interactions of proteins directly related to presynaptic function in the VMC in schizophrenia. SNARE proteins and their interactions may be a novel target for the development of therapeutics.
doi:10.1038/npp.2009.228
PMCID: PMC3055413  PMID: 20072114
SNAREs; schizophrenia; striatum; postmortem; protein interactions; SNAP-25; Schizophrenia/Antipsychotics; Plasticity; Neurochemistry; Neuropharmacology; SNARE proteins
18.  A comprehensive method of assessing routine CT scans in schizophrenia 
Acta psychiatrica Scandinavica  1997;96(5):395-401.
Morphological brain abnormalities are common in schizophrenia, although the aetiological and clinical significance of these findings is largely unknown. Substantial between-subject variability suggests that large samples are needed to study the full implications of brain pathomorphology. Computerized tomography (CT) is frequently used routinely in schizophrenia, and large numbers of scans are available for study. This article describes the development and statistical properties of a rapid and simple method of assessing CT scans. The CT Rating Scale for Schizophrenia (CTRSS) is minimally affected by variability in scanning procedures, is reliable, and accurately estimates area and volumetric measures of brain spaces. By promoting the comprehensive assessment of large numbers of routinely obtained scans, the CTRSS would allow the investigation of variables that may systematically affect results (e.g. gender and age) and variables with low prevalence. The CTRSS provides a useful adjunct to technologically more sophisticated methods of assessment such as magnetic resonance imaging (MRI).
PMCID: PMC3169641  PMID: 9395159 CAMSID: cams1933
computerized tomography; brain morphology; schizophrenia
19.  A case study of temporal lobe development in familial schizophrenia 
Psychological medicine  1996;26(1):191-195.
SYNOPSIS
Case studies of patients with familial schizophrenia may help to define the pathophysiology of this illness and indicate potential candidate genes for genetic linkage studies. In this regard, the clinical, radiological and pathological assessments of a 39-year-old affected man from a pedigree with familial schizophrenia are presented. Brain imaging with CT indicated moderate cortical atrophy, particularly of the temporal lobes. Neuropathological examination revealed granular ependymitis, indicating possible past ventricular pathology. Granular ependymitis was reported to occur in genetic developmental disorders with neuronal migration abnormalities. In the present case, heterotopic clusters of neurons were visualized in the entorhinal cortex, suggesting that temporal lobe development was not entirely normal. This case study suggests that genetic factors could be investigated further as one possible aetiology of certain neurodevelopmental abnormalities observed in schizophrenia.
PMCID: PMC3169646  PMID: 8643758 CAMSID: cams1943
20.  A Genotype-Phenotype Research Strategy for Schizophrenia 
A research strategy which integrates known biological aspects of schizophrenia is proposed. The strategy includes genotype and phenotype components and emphasizes interactions. Its central feature is the comprehensive diagnostic assessment of patients with schizophrenia. Clinical and laboratory based methodologies are applied within the genotype and phenotype components of the strategy. Examples of research from each area and the potential interactions with other aspects of the strategy are presented. The expectation is that a greater understanding of the pathophysiology of schizophrenia will result from the application of the genotype-phenotype strategy and that consequently more efficacious treatments will ultimately be developed.
PMCID: PMC3176297  PMID: 2282633 CAMSID: cams1956
21.  Clinical features of schizophrenia in a woman with hyperandrogenism. 
Ample evidence supports sex differences in the clinical features of schizophrenia. In this regard, estrogen may contribute to later onset and less severe course of illness in women. Direct investigation of hormonal status in schizophrenia is extremely difficult. The present report documents the clinical features of schizophrenia in a young woman with long-standing hyperandrogenism related to polycystic ovarian disease. We postulate that hyperandrogenism contributed to a relatively early onset, olfactory dysfunction, and other clinical features of schizophrenia more commonly associated with men. Additionally, acute estrogen depletion following cessation of oral contraceptives may have precipitated psychosis, while recommencement of oral contraceptives could have contributed to subsequent improvement in symptoms.
PMCID: PMC1188817  PMID: 9002393
23.  The Positive and Negative Syndrome Scale (PANSS): A Three-Factor Model of Psychopathology in Marginally Housed Persons with Substance Dependence and Psychiatric Illness 
PLoS ONE  2016;11(3):e0151648.
Rates of psychopathology are elevated in marginalized and unstably housed persons, underscoring the need for applicable clinical measures for these populations. The Positive and Negative Syndrome Scale (PANSS) is a clinical instrument principally developed for use in schizophrenia to identify the presence and severity of psychopathology symptoms. The current study investigates whether a reliable and valid PANSS factor structure emerges in a marginally housed, heterogeneous sample recruited from the Downtown Eastside of Vancouver where substance use disorders and psychiatric illness are pervasive. Participants (n = 270) underwent structured clinical assessments including the PANSS and then were randomly assigned to either exploratory (EFA) or confirmatory factor analytic (CFA) subsamples. EFA pointed to a novel three factor PANSS. This solution was supported by CFA. All retained items (28 out of 30) load significantly upon hypothesized factors and model goodness of fit analyses are in the acceptable to good range. Each of the three first-order factor constructs, labeled Psychosis/Disorganized, Negative Symptoms/Hostility, and Insight/Awareness, contributed significantly to measurement of a higher-order psychopathology construct. Further, the latent structure of this 3-factor solution appears temporally consistent over one-year. This PANSS factor structure appears valid and reliable for use in persons with multimorbidity, including substance use disorders. The structure is somewhat distinct from existing solutions likely due to the unique characteristics of this marginally housed sample.
doi:10.1371/journal.pone.0151648
PMCID: PMC4801385  PMID: 26999280
24.  Personalized Risk Assessment of Drug-Related Harm Is Associated with Health Outcomes 
PLoS ONE  2013;8(11):e79754.
Background
The Independent Scientific Committee on Drugs (ISCD) assigned quantitative scores for harm to 20 drugs. We hypothesized that a personalized, ISCD-based Composite Harm Score (CHS) would be associated with poor health outcomes in polysubstance users.
Methods
A prospective community sample (n=293) of adults living in marginal housing was assessed for substance use. The CHS was calculated based on the ISCD index, and the personal substance use characteristics over four weeks. Regression models estimated the association between CHS and physical, psychological, and social health outcomes.
Results
Polysubstance use was pervasive (95.8%), as was multimorbid illness (median 3, possible range 0–12). The median CHS was 2845 (interquartile range 1865–3977). Adjusting for age and sex, every 1000-unit CHS increase was associated with greater mortality (odds ratio [OR] 1.47, 95% confidence interval [CI] 1.07–2.01, p = 0.02), and persistent hepatitis C infection (OR 1.29, 95% CI 1.02–1.67, p = 0.04). The likelihood of substance-induced psychosis increased 1.39-fold (95% CI 1.13–1.67, p = 0.001). The amount spent on drugs increased 1.51-fold (1.40–1.62, p < 0.001) and the odds of having committed a crime increased 1.74-fold (1.46–2.10, p < 0.001). Multimorbid illness increased 1.43-fold (95% CI 1.26–1.63, p < 0.001).
Conclusions
Greater CHS predicts poorer physical, psychological, and social health, and may be a useful quantitative, personalized measure of risk for drug-related harm.
doi:10.1371/journal.pone.0079754
PMCID: PMC3819243  PMID: 24223192
25.  The need for speed: an update on methamphetamine addiction 
The psychostimulant methamphetamine (MA) is a highly addictive drug that has surged in popularity over the last decade in North America. A burgeoning number of clandestine drug laboratories has led to dramatic increases in MA production, which have resulted in significant public health, legal and environmental problems. Current evidence indicates that exposure to MA is neurotoxic, and neuroimaging studies confirm that long-term use in humans may lead to extensive neural damage. These physiological changes are commonly associated with persistent forms of cognitive impairment, including deficits in attention, memory and executive function. In the present review, we provide a comprehensive description of the factors relating to MA use and the major health-related consequences, with an emphasis on MA-induced psychosis. It is hoped that increased knowledge of MA abuse will provide the basis for future treatment strategies.
PMCID: PMC1557685  PMID: 16951733
substance use disorders; animal models; brain imaging (MRI); psychoses; methamphetamine

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