26 research outputs found
sj-docx-1-jop-10.1177_02698811231177287 – Supplemental material for The histamine system and cognitive function: An in vivo H3 receptor PET imaging study in healthy volunteers and patients with schizophrenia
No full textSupplemental material, sj-docx-1-jop-10.1177_02698811231177287 for The histamine system and cognitive function: An in vivo H3 receptor PET imaging study in healthy volunteers and patients with schizophrenia by Atheeshaan Arumuham, Matthew M Nour, Mattia Veronese, Ellis Chika Onwordi, Eugenii A Rabiner and Oliver D Howes in Journal of Psychopharmacology</p
In vivo synaptic imaging in schizophrenia
No full textSynaptic deficits are hypothesised to play a role in schizophrenia pathogenesis, but this has not yet been tested directly in vivo. In this thesis, I use positron emission tomography with novel radioligand [11C]UCB-J in patients with schizophrenia and healthy volunteers to investigate levels of synaptic vesicle glycoprotein 2A (SV2A), a marker of presynaptic terminal density. First, I demonstrate that levels of SV2A are significantly lower in the frontal and anterior cingulate cortices in chronic schizophrenia subjects compared to healthy volunteers, and that antipsychotic drug exposure is not significantly associated with SV2A levels in patients. Then, indexing glutamate levels using proton magnetic resonance spectroscopy, I show that SV2A and glutamate levels are significantly positively correlated in the anterior cingulate cortex and hippocampus in healthy volunteers, but not in schizophrenia. Finally, I report that deficits in SV2A levels are not present in the early course of schizophrenia compared to healthy controls. Collectively, these findings provide the first direct evidence that presynaptic terminal protein levels are lower in schizophrenia in vivo, and that lower levels are unlikely to be directly accounted for by antipsychotic drug treatment. They indicate that lower presynaptic terminal protein levels arise after illness onset, and may be due to lower levels of glutamatergic synapses and/or a lower proportion of glutamatergic synapses in schizophrenia.Open Acces
Effects of Sustained D2 Receptors Blockade on Brain Structure and Function in Healthy Volunteers
No full textTBackground
The effect of D2 Receptor (D2R) blockade, exerted by antipsychotics, on brain structure and function is still under debate. Studies in patients reported mixed results with difficulties in separating disease and treatment effects. Single-dose studies in healthy volunteers (HV) have shown no change or reduction in striatal volumes, increased striatal cerebral blood flow (CBF) and reduced cortico-striatal functional connectivity (FC). However, it remains unclear whether these effects are stable after prolonged D2R blockade and how do they relate to extrapyramidal symptoms (EPS).
Methods
A total of 37 HV (15 females) entered a double-blinded, randomized, crossover, placebo-controlled study. Participants received either amisulpride 400mg or placebo daily for seven days. T1-maps and brain volume estimation were derived from MP2RAGE sequence. PCASL and resting-state multi-echo fMRI sequences were used to assess CBF and FC respectively. Voxel-wise permutation-based paired t-test as in FSL randomise was used to test drug effects (TFCE correction). We tested the association between drug effects and EPS (ESRS scale) using Spearman correlation. Analyses were performed on all subjects with available data.
Results
We did not find voxel-wise differences between amisulpride and placebo in both T1-maps and brain volumes. Amisulpride increased CBF in the striatum and reduced FC between its sensorimotor subdivision and the primary motor cortex as compared with placebo. Greater reduction in functional connectivity was associated with greater EPS (R2= 0.33, p= 0.018).
Conclusions
Our results indicate that functional alteration in the striatum persist after sustained D2R blockade without structural changes and could potentially serve as a biomarker for EPS
Antipsychotics cause reversible structural brain changes within one week
No full text: Determining the effects of antipsychotics on MRI brain structural metrics without the potential confounding effects related to the natural course of a psychotic illness is challenging. However, it is crucial to understand these effects to interpret the results of cross-sectional and longitudinal studies in medicated patients and, ultimately, to understand better the biological mechanisms driving antipsychotics' effects. In this work, we aim to determine whether exposure to antipsychotics is associated with alterations in brain MRI structural metrics in the absence of disease effects. A randomized, double-blind, counter-balanced order, crossover, placebo-controlled study in healthy volunteers was performed. The study comprised two arms. Within arms, participants were randomized to receive daily doses of either the active compound (Arm 1= amisulpride 400 mg/day, N = 24; Arm 2= aripiprazole 10 mg/day, N = 24) for one week, followed by placebo or vice versa. We found increased MRI volume estimates in the left putamen and in the right caudate in the amisulpride condition as compared to placebo and increased right putamen volume estimates after aripiprazole compared to placebo. No other effects were found in cortical volume estimates, cortical thickness, cortical surface area, and T1-relaxation time. Striatal changes reversed within weeks of drug withdrawal. Short-term exposure to either one of two different antipsychotics results in a transient increase in striatal volume measured with T1-weighted MRI that normalizes rapidly on stopping treatment without cortical changes. Our findings suggest that striatal volumetric MRI differences detected in people with schizophrenia taking antipsychotics are, at least in part, attributable to pharmacological effects
Neurofunctional correlates of glutamate and GABA imbalance in psychosis: a systematic review
No full textGlutamatergic and GABAergic dysfunction are implicated in the pathophysiology of schizophrenia. Previous work has shown relationships between glutamate, GABA, and brain activity in healthy volunteers. We conducted a systematic review to evaluate whether these relationships are disrupted in psychosis. Primary outcomes were the relationship between metabolite levels and fMRI BOLD response in psychosis relative to healthy volunteers. 17 case-control studies met inclusion criteria (594 patients and 538 healthy volunteers). Replicated findings included that in psychosis, positive associations between ACC glutamate levels and brain activity are reduced during resting state conditions and increased during cognitive control tasks, and negative relationships between GABA and local activation in the ACC are reduced. There was evidence that antipsychotic medication may alter the relationship between glutamate levels and brain activity. Emerging literature is providing insights into disrupted relationships between neurometabolites and brain activity in psychosis. Future studies determining a link to clinical variables may develop this approach for biomarker applications, including development or targeting novel therapeutics
Proton Magnetic Resonance Spectroscopy of N-acetyl Aspartate in Chronic Schizophrenia, First Episode of Psychosis and High-Risk of Psychosis:A Systematic Review and Meta-Analysis
No full textN-acetyl-aspartate (NAA) is a readily measured marker of neuronal metabolism. Previous analyses in schizophrenia have shown NAA levels are low in frontal, temporal and thalamic regions, but may be underpowered to detect effects in other regions, in high-risk states and in first episode psychosis. We searched for magnetic resonance spectroscopy studies comparing NAA in chronic schizophrenia, first episode psychosis and high risk of psychosis to controls. 182 studies were included and meta-analysed using a random-effects model for each region and illness stage. NAA levels were significantly lower than controls in the frontal lobe [Hedge's g = -0.36, p < 0.001], hippocampus [-0.52, p < 0.001], temporal lobe [-0.35, p = 0.031], thalamus [-0.32, p = 0.012] and parietal lobe [-0.25, p = 0.028] in chronic schizophrenia, and lower than controls in the frontal lobe [-0.26, p = 0.002], anterior cingulate cortex [-0.24, p = 0.016] and thalamus [-0.28, p = 0.028] in first episode psychosis. NAA was lower in high-risk of psychosis in the hippocampus [-0.20, p = 0.049]. In schizophrenia, NAA alterations appear to begin in hippocampus, frontal cortex and thalamus, and extend later to many other regions.</p
The histamine system and cognitive function: An in vivo H3 receptor PET imaging study in healthy volunteers and patients with schizophrenia
No full textBACKGROUND: The histamine-3 receptor (H3R) is an auto- and heteroreceptor that inhibits the release of histamine and other neurotransmitters. Post-mortem evidence has found altered H3R expression in patients with psychotic disorders, which may underlie cognitive impairment associated with schizophrenia (CIAS). AIMS: We used positron emission tomography (PET) imaging to compare brain uptake of an H3R selective tracer between patients with schizophrenia and matched controls (healthy individuals). Regions of interest included the dorsolateral prefrontal cortex (DLPFC) and striatum. We explored correlations between tracer uptake and symptoms, including cognitive domains. METHODS: A total of 12 patients and 12 matched controls were recruited to the study and were assessed with psychiatric and cognitive rating scales. They received a PET scan using the H3R-specific radioligand [11C]MK-8278 to determine H3R availability. RESULTS: There was no statistically significant difference in tracer uptake between patients and controls in the DLPFC (t19 = 0.79, p = 0.44) or striatum (t21 = 1.18, p = 0.25). An exploratory analysis found evidence for lower volume of distribution in the left cuneus (pFWE-corrected = 0.01). DLPFC tracer uptake was strongly correlated with cognition in controls (trail making test (TMT) A: r = 0.77, p = 0.006; TMT B: rho = 0.74, p = 0.01), but not in patients (TMT A: r = -0.18, p = 0.62; TMT B: rho = -0.06, p = 0.81). CONCLUSIONS: These findings indicate H3R in the DLPFC might play a role in executive function and this is disrupted in schizophrenia in the absence of major alterations in H3R availability as assessed using a selective radiotracer for H3R. This provides further evidence for the role of H3R in CIAS
The clinical significance of duration of untreated psychosis: an umbrella review and random‐effects meta‐analysis
No full textThe idea that a longer duration of untreated psychosis (DUP) leads to poorer outcomes has contributed to extensive changes in mental health services worldwide and has attracted considerable research interest over the past 30 years. However, the strength of the evidence underlying this notion is unclear. To address this issue, we conducted an umbrella review of available meta-analyses and performed a random-effects meta-analysis of primary studies. MEDLINE, Web of Science, PsycINFO and EMBASE were searched from inception to September 3, 2020 to identify relevant meta-analyses of studies including patients with schizophrenia spectrum disorders, first-episode psychosis, or affective and non-affective psychosis. Thirteen meta-analyses were included, corresponding to 129 individual studies with a total sample size of 25,657 patients. We detected potential violations of statistical assumptions in some of these meta-analyses. We therefore conducted a new random-effects meta-analysis of primary studies. The association between DUP and each outcome was graded according to a standardized classification into convincing, highly suggestive, suggestive, weak, or non-significant. At first presentation, there was suggestive evidence for a relationship between longer DUP and more severe negative symptoms (beta=–0.07, p=3.6×10–5) and higher chance of previous self-harm (odds ratio, OR=1.89, p=1.1×10–5). At follow-up, there was highly suggestive evidence for a relationship between longer DUP and more severe positive symptoms (beta=–0.16, p=4.5×10–8), more severe negative symptoms (beta=–0.11, p=3.5×10–10) and lower chance of remission (OR=2.16, p=3.0×10–10), and suggestive evidence for a relationship between longer DUP and poorer overall functioning (beta=–0.11, p=2.2×10–6) and more severe global psychopathology (beta=–0.16, p=4.7×10–6). Results were unchanged when analysis was restricted to prospective studies. These effect sizes are clinically meaningful, with a DUP of four weeks predicting >20% more severe symptoms at follow-up relative to a DUP of one week. We conclude that DUP is an important prognostic factor at first presentation and predicts clinically relevant outcomes over the course of illness. We discuss conceptual issues in DUP research and methodological limitations of current evidence, and provide recommendations for future research
Histamine-3 receptor availability and glutamate levels in the brain: A PET-<sup>1</sup>H-MRS study of patients with schizophrenia and healthy controls
No full textBackgroundThe histamine-3 receptor (H3R) may have a role in cognitive processes through its action as a presynaptic heteroreceptor inhibiting the release of glutamate in the brain. To explore this, we examined anterior cingulate cortex (ACC) and striatum H3R availability in patients with schizophrenia and characterized their relationships with glutamate levels in corresponding brain regions. MethodsWe employed a cross-sectional study, recruiting 12 patients with schizophrenia and 12 healthy volunteers. Participants underwent positron emission tomography using the H3R-specific radio ligand [11C]MK-8278, followed by proton magnetic resonance spectroscopy to measure glutamate levels, recorded as Glu and Glx. Based on existing literature, the ACC and striatum were selected as regions of interest. ResultsWe found significant inverse relationships between tracer uptake and Glu (r = -0.66, P =. 02) and Glx (r = -0.62, P =. 04) levels in the ACC of patients, which were absent in healthy volunteers (Glu: r = -0.19, P =. 56, Glx: r = 0.10, P =. 75). We also found a significant difference in striatal (F1,20 = 6.00, P =. 02) and ACC (F1,19 = 4.75, P =. 04) Glx levels between groups. ConclusionsThese results provide evidence of a regionally specific relationship between H3Rs and glutamate levels, which builds on existing preclinical literature. Our findings add to a growing literature indicating H3Rs may be a promising treatment target in schizophrenia, particularly for cognitive impairment, which has been associated with altered glutamate signaling.</p
