Although synaptic loss is thought to be core to the pathophysiology of schizophrenia, the nature, consistency and magnitude of synaptic protein and mRNA changes has not been systematically appraised. ...Our objective was thus to systematically review and meta-analyse findings. The entire PubMed database was searched for studies from inception date to the 1st of July 2017. We selected case-control postmortem studies in schizophrenia quantifying synaptic protein or mRNA levels in brain tissue. The difference in protein and mRNA levels between cases and controls was extracted and meta-analysis conducted. Among the results, we found a significant reduction in synaptophysin in schizophrenia in the hippocampus (effect size: -0.65, p < 0.01), frontal (effect size: -0.36, p = 0.04), and cingulate cortices (effect size: -0.54, p = 0.02), but no significant changes for synaptophysin in occipital and temporal cortices, and no changes for SNAP-25, PSD-95, VAMP, and syntaxin in frontal cortex. There were insufficient studies for meta-analysis of complexins, synapsins, rab3A and synaptotagmin and mRNA measures. Findings are summarised for these, which generally show reductions in SNAP-25, PSD-95, synapsin and rab3A protein levels in the hippocampus but inconsistency in other regions. Our findings of moderate-large reductions in synaptophysin in hippocampus and frontal cortical regions, and a tendency for reductions in other pre- and postsynaptic proteins in the hippocampus are consistent with models that implicate synaptic loss in schizophrenia. However, they also identify potential differences between regions and proteins, suggesting synaptic loss is not uniform in nature or extent.
Studies using positron emission tomography to image striatal dopamine function, have demonstrated that individuals with schizophrenia display increases in presynaptic function. Mesolimbic dysfunction ...specifically, has previously been suggested to underlie psychotic symptoms. This has not been directly tested in vivo, and the precise anatomical locus of dopamine dysfunction within the striatum remains unclear. The current article investigates the magnitude of dopaminergic abnormalities in individuals with schizophrenia, and determines how the magnitude of abnormality varies across functional subdivisions of the striatum.
EMBASE, PsychINFO, and MEDLINE were searched from January 1, 1960, to December 1, 2016. Inclusion criteria were molecular imaging studies that had measured presynaptic striatal dopamine functioning. Effects sizes for whole striatum and functional subdivisions were calculated separately. The magnitude of difference between functional subdivisions in patients and controls was meta-analyzed.
Twenty-one eligible studies were identified, including 269 patients and 313 controls. Individuals with schizophrenia (Hedges' g = 0.68, P < .001) demonstrated elevated presynaptic dopamine functioning compared to controls. Seven studies examined functional subdivisions. These demonstrated significant increases in patients compared to controls in associative (g = 0.73, P = .002) and sensorimotor (g = 0.54, P = .005) regions, but not limbic (g = 0.29, P = .09). The magnitude of the difference between associative and limbic subdivisions was significantly greater in patients compared to controls (g = 0.39, P = .003).
In individuals with schizophrenia dopaminergic dysfunction is greater in dorsal compared to limbic subdivisions of the striatum. This is inconsistent with the mesolimbic hypothesis and identifies the dorsal striatum as a target for novel treatment development.
Resistance to antipsychotic treatment is a significant clinical problem in patients with schizophrenia with approximately 1 in 3 showing limited or no response to repeated treatments with ...antipsychotic medication. The neurobiological basis for treatment resistance is unknown but recent evidence implicates glutamatergic function in the anterior cingulate cortex. We examined glutamate levels of chronically ill treatment-resistant patients directly compared to treatment-responsive patients.
We acquired proton magnetic resonance spectroscopy (1H-MRS) at 3 Tesla from 21 treatment-resistant and 20 treatment-responsive patients. All participants had a DSM-IV diagnosis of schizophrenia. Treatment-resistant patients were classified using the modified Kane criteria. The groups were matched for age, sex, smoking status, and illness duration.
Glutamate to creatine ratio levels were higher in treatment-resistant patients (Mean SD = 1.57 0.24) than in treatment-responsive patients (MeanSD = 1.38 0.23), (T35 = 2.34, P = .025, 2-tailed), with a large effect size of d = 0.76. A model assuming 2 populations showed a 25% improvement in the fit of the Akaike weights (0.55) over a model assuming 1 population (0.44), producing group values almost identical to actual group means.
Increased anterior cingulate glutamate level is associated with treatment-resistant schizophrenia. This appears to be a stable neurobiological trait of treatment-resistant patients. We discuss possible explanations for glutamatergic dysfunction playing a significant role in resistance to conventional antipsychotic treatments, which are all dopamine-2 receptor blockers. Our findings suggest that glutamatergic treatments may be particularly effective in resistant patients and that 1H-MRS glutamate indices can potentially have clinical use.
Purpose: This study was conducted to examine the comparative effectiveness of 2 different approaches, 1 domain-specific and the other domain-general, to language and attention rehabilitation in ...participants with stroke-induced aphasia. The domain-specific treatment consisted of language-specific attention treatment (L-SAT), and the domain-general treatment consisted of direct attention training (DAT) using the computerized exercises included in Attention Process Training-3 (Sohlberg & Mateer, 2010). Method: Four individuals with mild-moderate aphasia participated in this study. A randomized controlled cross-over single-subject design was used to assess the effectiveness of the 2 treatments administered in this study. Treatment outcomes were evaluated in terms of participants' task performance for each program, standardized language and attention measures, tests of functional abilities, and patient-reported outcomes. Results: Visual comparisons demonstrated linear improvements following L-SAT and variable patterns following DAT. Omnibus effect sizes were statistically significant for 9 of the 13 L-SAT tasks. The weighted standardized effect sizes for posttreatment changes following L-SAT ranged from small to large, with the exception of 1 task. The average group gain following DAT was 5%. The Western Aphasia Battery--Revised Aphasia Quotients (Kertesz, 2007) demonstrated reliable improvements for 3 of the 4 participants following L-SAT, whereas only 1 of the participants improved reliably following DAT. The margins of improvements in functional language were substantially larger following L-SAT than DAT. Performance on the Test of Everyday Attention improved significantly for 2 participants following L-SAT and for 1 participant following DAT on selected Test of Everyday Attention (Robertson, Ward, Ridgeway, & Nimmo-Smith, 1994) subtests. Patient-reported outcomes for communication and attention following treatment favored L-SAT compared to DAT. Conclusions: The results support the view that attention is allocated in ways that are particular to specific tasks rather than as a general resource that is allocated equivalently to all processing tasks. Domain-specific treatment for language deficits due to attentional impairment appears to be a suitable, if not preferable, approach for aphasia rehabilitation.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, ODKLJ, OILJ, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK, VSZLJ
Approximately 188 million people use cannabis yearly worldwide, and it has recently been legalised in 11 US states, Canada, and Uruguay for recreational use. The potential for increased cannabis use ...highlights the need to better understand its risks, including the acute induction of psychotic and other psychiatric symptoms. We aimed to investigate the effect of the cannabis constituent Δ9-tetrahydrocannabinol (THC) alone and in combination with cannabidiol (CBD) compared with placebo on psychiatric symptoms in healthy people.
In this systematic review and meta-analysis, we searched MEDLINE, Embase, and PsycINFO for studies published in English between database inception and May 21, 2019, with a within-person, crossover design. Inclusion criteria were studies reporting symptoms using psychiatric scales (the Brief Psychiatric Rating Scale BPRS and the Positive and Negative Syndrome Scale PANSS) following the acute administration of intravenous, oral, or nasal THC, CBD, and placebo in healthy participants, and presenting data that allowed calculation of standardised mean change (SMC) scores for positive (including delusions and hallucinations), negative (such as blunted affect and amotivation), and general (including depression and anxiety) symptoms. We did a random-effects meta-analysis to assess the main outcomes of the effect sizes for total, positive, and negative PANSS and BPRS scores measured in healthy participants following THC administration versus placebo. Because the number of studies to do a meta-analysis on CBD's moderating effects was insufficient, this outcome was only systematically reviewed. This study is registered with PROSPERO, CRD42019136674.
15 eligible studies involving the acute administration of THC and four studies on CBD plus THC administration were identified. Compared with placebo, THC significantly increased total symptom severity with a large effect size (assessed in nine studies, with ten independent samples, involving 196 participants: SMC 1·10 95% CI 0·92–1·28, p<0·0001); positive symptom severity (assessed in 14 studies, with 15 independent samples, involving 324 participants: SMC 0·91 95% CI 0·68–1·14, p<0·0001); and negative symptom severity with a large effect size (assessed in 12 studies, with 13 independent samples, involving 267 participants: SMC 0·78 95% CI 0·59–0·97, p<0·0001). In the systematic review, of the four studies evaluating CBD's effects on THC-induced symptoms, only one identified a significant reduction in symptoms.
A single THC administration induces psychotic, negative, and other psychiatric symptoms with large effect sizes. There is no consistent evidence that CBD induces symptoms or moderates the effects of THC. These findings highlight the potential risks associated with the use of cannabis and other cannabinoids that contain THC for recreational or therapeutic purposes.
UK Medical Research Council, Maudsley Charity, Brain and Behavior Research Foundation, Wellcome Trust, and the UK National Institute for Health Research.
Rationale
While cannabis-based medicinal products have been shown to be effective for numerous neurological and psychiatric disorders, the evidence base regarding their adverse cognitive effects is ...poorly understood. The cannabinoid 1 receptor modulates memory performance via intracellular and extracellular mechanisms that alter synaptic transmission and plasticity. While previous literature has consistently shown that chronic cannabis users exhibit marked cognitive impairments, mixed findings have been reported in the context of placebo-controlled experimental trials. It is therefore unclear whether these compounds inherently alter cognitive processes or whether individuals who are genetically predisposed to use cannabis may have underlying cognitive deficits.
Objective
We conducted a meta-analysis to investigate the effects of full and partial cannabinoid 1 receptor (CB1R) agonists, antagonists, and negative allosteric modulators on non-spatial and spatial memory.
Methods
In accordance with the PRISMA guidelines, the EMBASE, MEDLINE, and PsycINFO databases were systematically searched for studies examining the effects of CB1R agonists, antagonists, and negative allosteric modulators on memory performance.
Results
We systematically reviewed 195 studies investigating the effects of cannabinoid compounds on memory. In humans (
N
= 35 studies, comprising
N
= 782 subjects), delta-9-tetrahydrocannabinol (THC) (1.5–5 mg/kg) relative to placebo impaired performance on non-spatial memory tests, whereas only high THC doses (67 mg/kg) impaired spatial memory. Similarly, THC (0.2–4 mg/kg) significantly impaired visuospatial memory in monkeys and non-human primates (
N
= 8 studies, comprising
N
= 71 subjects). However, acute THC (0.002–10 mg/kg) had no effect on non-spatial (
N
= 6 studies, comprising 117 subjects;
g
= 1.72, 95% confidence interval (CI) − 0.18 to 3.63,
p
= 0.08) or spatial memory (9 studies, comprising 206 subjects;
g
= 0.75, 95% confidence interval (CI) − 1.09 to 2.58,
p
= 0.43). However, acute, full CB1R agonists significantly impaired non-spatial memory (
N
= 23 studies, 519 subjects;
g
= − 1.39, 95% CI − 2.72 to − 0.06,
p
= 0.03). By contrast, the chronic administration of CB1R agonists had no effect on non-spatial memory (
N
= 5 studies, comprising 146 subjects;
g
= − 0.05, 95% confidence interval (CI) − 1.32 to 1.22,
p
= 0.94). Moreover, the acute administration of CB1R antagonists had no effect on non-spatial memory in rodents (
N
= 9 studies,
N
= 149 subjects;
g
= 0.40, 95% CI − 0.11 to 0.92,
p
= 0.12).
Conclusions
The acute administration of THC, partial CB1R agonist, significantly impaired non-spatial memory in humans, monkeys, and non-human primates but not rodents. However, full CB1R agonists significantly impaired non-spatial memory in a dose-dependent manner but CB1R antagonists had no effect on non-spatial memory in rodents. Moreover, chronic THC administration did not significantly impair spatial or non-spatial memory in rodents, and there is inconclusive evidence on this in humans. Our findings highlight species differences in the effects of cannabinoid compounds on memory.
Background:
Treatment-resistant schizophrenia (TRS) is a major cause of disability. Clozapine is currently the only antipsychotic medication licensed for its treatment. However, the rate of treatment ...resistance among outpatients with schizophrenia or other psychoses, and the rate of use of clozapine among them, is not known.
Aims:
The aims of this study are (a) to determine the point prevalence of treatment-resistant psychosis in a community sample, and (b) to determine the number of patients with TRS who have never had a clozapine trial.
Method:
Clinico-demographic data were extracted from the case notes for 202 patients from two community mental-health teams.
Results:
We found that 56% (99/176) had a diagnosis of TRS, and 52% (51/99) of these patients had never been treated with clozapine. Patients of non-white ethnicity were less likely to have had a clozapine trial (p=0.009). The point prevalence of treatment resistance within the bipolar affective disorder sample was 19% (5/26).
Conclusion:
These findings suggest that TRS is common in the community mental-health team, and a large proportion of these patients have not received clozapine. These findings indicate that identifying and treating treatment resistance should be a focus of community services for schizophrenia.
The need for a specific, language-based treatment approach to aphasic impairments associated with attentional deficits is well documented. We describe language-specific attention treatment, a ...specific skill-based approach for aphasia that exploits increasingly complex linguistic tasks that focus attention. The program consists of eight tasks, some with multiple phases, to assess and treat lexical and sentence processing. Validation results demonstrate that these tasks load on six attentional domains: (1) executive attention; (2) attentional switching; (3) visual selective attention/processing speed; (4) sustained attention; (5) auditory-verbal working memory; and (6) auditory processing speed. The program demonstrates excellent inter- and intrarater reliability and adequate test-retest reliability. Two of four people with aphasia exposed to this program demonstrated good language recovery whereas three of the four participants showed improvements in auditory-verbal working memory. The results provide support for this treatment program in patients with aphasia having no greater than a moderate degree of attentional impairment.
N-methyl-D-aspartate receptor (NMDAR) hypofunction is hypothesised to underlie psychosis but this has not been tested early in illness. To address this, we studied 40 volunteers (21 patients with ...first-episode psychosis and 19 matched healthy controls) using PET imaging with an NMDAR selective ligand,
FGE-179, that binds to the ketamine binding site to index its distribution volume ratio (DVR) and volume of distribution (V
). Hippocampal DVR, but not V
, was significantly lower in patients relative to controls (p = 0.02, Cohen's d = 0.81; p = 0.15, Cohen's d = 0.49), and negatively associated with total (rho = -0.47, p = 0.04), depressive (rho = -0.67, p = 0.002), and general symptom severity (rho = -0.74, p < 0.001). Exploratory analyses found no significant differences in other brain regions (anterior cingulate cortex, thalamus, striatum and temporal cortex). These findings are consistent with the NMDAR hypofunction hypothesis and identify the hippocampus as a key locus for relative NMDAR hypofunction, although further studies should test specificity and causality.
Background: Multiple language problems have been attributed to attentional impairments in people with aphasia. As a result, a number of investigations have examined the effectiveness of attentional ...treatments for improving impaired language processing. With few exceptions, all of the studies have used domain-general (nonspecific) attention training with nonlinguistic tasks as the therapeutic modality. Unfortunately, despite the well-documented associations between language and attention, these treatments have not yielded substantial improvements in language outcomes. It may be that the lack of specificity in these approaches for recruiting language-related attentional processes is a contributing factor. To address this issue, a Language-Specific Attention Treatment (L-SAT) (Peach, 2012) was proposed using language tasks that are purported to recruit attention for language processing. Further investigation into the attentional requirements of these tasks is needed. Aims: To establish the construct validity and reliability of the baseline and probe tasks (hereafter, probe tasks) used in L-SAT in a group of healthy participants as well as to determine the external validity of these tasks in participants with aphasia. Methods & Procedures: Twenty healthy participants and six participants with aphasia were assessed using standardized language and attention tests and an experimental battery of eight language-specific attention tasks that serve as the probe measures for this program. Correlational analyses were performed to examine the construct and external validity of the experimental tasks as well as their reliability. Outcomes & Results: All of these language tasks were found to be independent of one another in healthy participants and to correlate strongly with at least one attention measure, with the exception of one task, which showed moderate correlations with several attention measures. Examination of the correlations among the probe tasks and the attention measures revealed a highly interpretable pattern that is consistent with the processing requirements of each task. i.e., the attentional demands suggested by these findings are reasonable and consistent with the language tasks themselves. Excellent inter- and intra-rater reliability were found for these tasks in both healthy participants and the PWA. Acceptable test-retest reliability was found in both groups for all but three of the tasks. Conclusions: The results suggest that these probe tasks provide a valid method for recruiting language-directed attentional abilities, and therefore, may be effective for indexing attentional processing in participants with aphasia. L-SAT, which incorporates these tasks into a hierarchically organized treatment program, may offer a promising approach to treating aphasic impairments associated with attentional deficits.
PDF
