Publications by authors named "David Anthony"

450 Publications

W Alwyn Lishman.

Authors:
Anthony David

Lancet 2021 May;397(10286):1704

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http://dx.doi.org/10.1016/S0140-6736(21)00997-1DOI Listing
May 2021

Structural Covariance of Cortical Gyrification at Illness Onset in Treatment Resistance: A Longitudinal Study of First-Episode Psychoses.

Schizophr Bull 2021 Apr 14. Epub 2021 Apr 14.

Department of Psychosis Studies, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, UK.

Treatment resistance (TR) in patients with first-episode psychosis (FEP) is a major cause of disability and functional impairment, yet mechanisms underlying this severe disorder are poorly understood. As one view is that TR has neurodevelopmental roots, we investigated whether its emergence relates to disruptions in synchronized cortical maturation quantified using gyrification-based connectomes. Seventy patients with FEP evaluated at their first presentation to psychiatric services were followed up using clinical records for 4 years; of these, 17 (24.3%) met the definition of TR and 53 (75.7%) remained non-TR at 4 years. Structural MRI images were obtained within 5 weeks from first exposure to antipsychotics. Local gyrification indices were computed for 148 contiguous cortical regions using FreeSurfer; each subject's contribution to group-based structural covariance was quantified using a jack-knife procedure, providing a single deviation matrix for each subject. The latter was used to derive topological properties that were compared between TR and non-TR patients using a Functional Data Analysis approach. Compared to the non-TR patients, TR patients showed a significant reduction in small-worldness (Hedges's g = 2.09, P < .001) and a reduced clustering coefficient (Hedges's g = 1.07, P < .001) with increased length (Hedges's g = -2.17, P < .001), indicating a disruption in the organizing principles of cortical folding. The positive symptom burden was higher in patients with more pronounced small-worldness (r = .41, P = .001) across the entire sample. The trajectory of synchronized cortical development inferred from baseline MRI-based structural covariance highlights the possibility of identifying patients at high-risk of TR prospectively, based on individualized gyrification-based connectomes.
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http://dx.doi.org/10.1093/schbul/sbab035DOI Listing
April 2021

Employment and relationship outcomes in first-episode psychosis: A systematic review and meta-analysis of longitudinal studies.

Schizophr Res 2021 Apr 8;231:122-133. Epub 2021 Apr 8.

Department of Psychosis Studies, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, United Kingdom; Department of Psychiatry, Royal College of Surgeons in Ireland, Dublin, Ireland; Department of Psychiatry, St Vincent's Hospital Fairview, Dublin, Ireland.

As employment and relationship status are important long-term outcomes in individuals with a diagnosis of first episode psychosis (FEP) disorders, there is a need to elucidate more accurately the extent of these social deficits in people with FEP. This in turn can aid treatment planning and policy development ultimately ensuring more complete and sustainable recoveries. We carried out a systematic review and meta-analysis of longitudinal studies in FEP reporting on employment and relationship status during the illness course. Random effects meta-analyses and meta-regression analyses were employed. Seventy-four studies were included with a sample totalling 15,272 (range = 20-1724) FEP cases with an average follow-up duration of 8.3 years (SD = 7.2). 32.5% (95%CI = 28.5-36.9) of people with a diagnosis of FEP disorders were employed and 21.3% (95%CI = 16.5-27.1) were in a relationship at the end of follow-up. Studies from high-income countries and Europe had a higher proportion of people in employment at the end of follow-up compared to middle-income nations and non-European countries. The inverse was found for relationship status. The proportion of people with a diagnosis of FEP in employment decreased significantly with longer follow-up. Living with family, being in a relationship at first contact and Black and White ethnicities were identified as significant moderators of these outcomes. These findings highlight marked functional recovery deficits for people with FEP, although cultural factors need to be considered. They support the need for interventions to improve employment opportunities, and social functioning, both in early psychosis and during the longitudinal illness course.
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http://dx.doi.org/10.1016/j.schres.2021.03.013DOI Listing
April 2021

A longer look at COVID-19 and neuropsychiatric outcomes.

Lancet Psychiatry 2021 05 6;8(5):351-352. Epub 2021 Apr 6.

Institute of Mental Health, University College London, London, UK.

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http://dx.doi.org/10.1016/S2215-0366(21)00120-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8023693PMC
May 2021

Striatal dopamine D receptors in medication-naïve schizophrenia: an [I] IBZM SPECT study.

Psychol Med 2021 Mar 8:1-9. Epub 2021 Mar 8.

Mental Health Neurosciences Research Department, Division of Psychiatry, University College London, London, UK.

Background: The hyper-function of the striatal dopamine system has been suggested to underlie key pathophysiological mechanisms in schizophrenia. Moreover, patients have been observed to present a significant elevation of dopamine receptor availability compared to healthy controls. Although it is difficult to measure dopamine levels directly in humans, neurochemical imaging techniques such as single-photon emission computed tomography (SPECT) provide indirect indices of in vivo dopamine synthesis and release, and putative synaptic levels.

Methods: We focused on the role of dopamine postsynaptic regulation using [123I] iodobenzamide (IBZM) SPECT. We compared D2/3 receptor availability between 53 healthy controls and 21 medication-naive patients with recent-onset schizophrenia.

Result: The mean specific striatal binding showed no significant difference between patients and controls (estimated difference = 0.001; 95% CI -0.11 to 0.11; F = 0.00, df = 1, 69; p = 0.99). There was a highly significant effect of age whereby IBZM binding declined with advancing age [estimated change per decade of age = -0.01(binding ratio); 95% CI -0.01 to -0.004; F = 11.5, df = 1, 69; p = 0.001]. No significant correlations were found between the mean specific striatal binding and psychopathological or cognitive rating scores.

Conclusions: Medication-naïve patients with recent-onset schizophrenia have similar D2/3 receptor availability to healthy controls. We suggest that, rather than focusing exclusively on postsynaptic receptors, future treatments should target the presynaptic control of dopamine synthesis and release.
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http://dx.doi.org/10.1017/S0033291720005413DOI Listing
March 2021

Asymmetric Reductive Dicarbofunctionalization of Alkenes via Nickel Catalysis.

Synlett 2020 Jul;31(15):1443-1447

Department of Chemistry, New York University, 100 Washington Square E, New York, NY 10003, USA.

Alkenes are an appealing functional group that can be transformed into a variety of structures. Transition-metal catalyzed dicarbofunctionalization of alkenes can efficiently afford products with complex substitution patterns from simple substrates. Under reductive conditions, this transformation can be achieved while avoiding stoichiometric organometallic reagents. Asymmetric difunctionalization of alkenes has been underdeveloped, in spite of its potential synthetic utility. Herein, we present a summary of our efforts to control enantioselectivity for alkene diarylation with a nickel catalyst. This reaction is useful for preparing triarylethanes. The selectivity is enhanced by an -oxyl radical additive.
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http://dx.doi.org/10.1055/s-0040-1707900DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7935080PMC
July 2020

Longitudinal Structural MRI Findings in Individuals at Genetic and Clinical High Risk for Psychosis: A Systematic Review.

Front Psychiatry 2021 2;12:620401. Epub 2021 Feb 2.

Division of Psychiatry, Institute of Mental Health, University College London, London, United Kingdom.

Several cross-sectional studies report brain structure differences between healthy volunteers and subjects at genetic or clinical high risk of developing schizophrenia. However, longitudinal studies are important to determine whether altered trajectories of brain development precede psychosis onset. We conducted a systematic review to determine if brain trajectories differ between (i) those with psychotic experiences (PE), genetic (GHR) or clinical high risk (CHR), compared to healthy volunteers, and (ii) those who transition to psychosis compared to those who do not. Thirty-eight studies measured gray matter and 18 studies measured white matter in 2,473 high risk subjects and 990 healthy volunteers. GHR, CHR, and PE subjects show an accelerated decline in gray matter primarily in temporal, and also frontal, cingulate and parietal cortex. In those who remain symptomatic or transition to psychosis, gray matter loss is more pronounced in these brain regions. White matter volume and fractional anisotropy, which typically increase until early adulthood, did not change or reduced in high risk subjects in the cingulum, thalamic radiation, cerebellum, retrolenticular part of internal capsule, and hippocampal-thalamic tracts. In those who transitioned, white matter volume and fractional anisotropy reduced over time in the inferior and superior fronto-occipital fasciculus, corpus callosum, anterior limb of the internal capsule, superior corona radiate, and calcarine cortex. High risk subjects show deficits in white matter maturation and an accelerated decline in gray matter. Gray matter loss is more pronounced in those who transition to psychosis, but may normalize by early adulthood in remitters.
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http://dx.doi.org/10.3389/fpsyt.2021.620401DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7884337PMC
February 2021

Relationship Between Serum NMDA Receptor Antibodies and Response to Antipsychotic Treatment in First-Episode Psychosis.

Biol Psychiatry 2020 Nov 24. Epub 2020 Nov 24.

Department of Psychosis Studies, Institute of Psychiatry, Psychology and Neuroscience, King's Health Partners, King's College London, London, United Kingdom; South London and Maudsley NHS Foundation Trust, University College London, London, United Kingdom.

Background: When psychosis develops in NMDA receptor (NMDAR) antibody encephalitis, it usually has an acute or subacute onset, and antipsychotic treatment may be ineffective and associated with adverse effects. Serum NMDAR antibodies have been reported in a minority of patients with first-episode psychosis (FEP), but their role in psychosis onset and response to antipsychotic treatment is unclear.

Methods: Sera from 387 patients with FEP (duration of psychosis <2 years, minimally or never treated with antipsychotics) undergoing initial treatment with amisulpride as part of the OPTiMiSE (Optimization of Treatment and Management of Schizophrenia in Europe) trial (ClinicalTrials.gov number NCT01248195) were tested for NMDAR IgG antibodies using a live cell-based assay. Symptom severity was assessed using the Positive and Negative Syndrome Scale and the Clinical Global Impressions Scale at baseline and again after 4 weeks of treatment with amisulpride.

Results: At baseline, 15 patients were seropositive for NMDAR antibodies and 372 were seronegative. The seropositive patients had similar symptom profiles and demographic features to seronegative patients but a shorter duration of psychosis (median 1.5 vs. 4.0 months; p = .031). Eleven seropositive and 284 seronegative patients completed 4 weeks of amisulpride treatment: after treatment, there was no between-groups difference in improvement in Positive and Negative Syndrome Scale scores or in the frequency of adverse medication effects.

Conclusions: These data suggest that in FEP, NMDAR antibody seropositivity alone is not an indication for using immunotherapy instead of antipsychotic medications. Further studies are required to establish what proportion of patients with FEP who are NMDAR antibody seropositive have coexisting cerebrospinal fluid inflammatory changes or other paraclinical evidence suggestive of a likely benefit from immunotherapy.
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http://dx.doi.org/10.1016/j.biopsych.2020.11.014DOI Listing
November 2020

The Use of Neuroscience and Psychological Measurement in England's Court of Protection.

Front Psychiatry 2020 7;11:570709. Epub 2020 Dec 7.

Mental Health Ethics and Law Research Group, Department of Psychological Medicine, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, United Kingdom.

The 2005 Mental Capacity Act of England and Wales provides a description in statute law of a test determining if a person lacks "mental capacity" to take a particular decision and describes how the "best interests" of such a person should be determined. The Act established a new Court of Protection (CoP) to hear cases related to the Act and to rule on disputes over mental capacity. The court gathers a range of evidence, including reports from clinicians and experts. Human rights organisations and others have raised concerns about the nature of assessments for incapacity, including the role of brain investigations and psychometric tests. Describe use and interpretation of structured measures of psychological and brain function in CoP cases, to facilitate standardisation and improvement of practices, both in the courtroom and in non-legal settings. Quantitative review of case law using all CoP judgments published until 2019. The judgments ( = 408) were read to generate a subset referring to structured testing ( = 50). These were then examined in detail to extract the nature of the measurements, circumstances of their use and features of interpretation by the court. The 408 judgments contained 146 references to structured measurement of psychological or brain function, spread over 50 cases. 120/146 (82.2%) referred to "impairment of mind or brain," with this being part of assessment for incapacity in 58/146 (39.7%). Measurement referred on 25/146 (17.1%) occasions to "functional decision-making abilities." Structured measures were used most commonly by psychiatrists and psychologists. Psychological measurements comprised 66.4% of measures. Neuroimaging and electrophysiology were presented for diagnostic purposes only. A small number of behavioural measures were used for people with disorders of consciousness. When assessing incapacity, IQ and the Mini-Mental-State Examination were the commonest measures. A standardised measure of mental capacity itself was employed just once. Judges rarely integrated measurements in their capacity determinations. Structured testing of brain and psychological function is used in limited ways in the Court of Protection. Whilst there are challenges in creating measures of capacity, we highlight an opportunity for the neuroscience community to improve objectivity in assessment, inside and outside the courtroom.
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http://dx.doi.org/10.3389/fpsyt.2020.570709DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7750429PMC
December 2020

Clozapine Response in Schizophrenia and Hematological Changes.

J Clin Psychopharmacol 2021 Jan/Feb 01;41(1):19-24

From the Department of Psychosis Studies, Institute of Psychiatry, Psychology & Neuroscience, King's College London.

Background: Clozapine is the only effective medication for treatment-resistant schizophrenia; however, its mechanism of action remains unclear. The present study explored whether its effectiveness is related to changes in hematological measures after clozapine initiation.

Methods: Patients with treatment-resistant schizophrenia commenced on clozapine between January 2007 and December 2014 by the United Kingdom's largest mental health trust were identified from electronic patient records. Hematological data from these patients were obtained from a monitoring registry. White blood cell, neutrophil, and platelet count were assessed at baseline and during the early phase of clozapine treatment. Clozapine response at 3 months was defined as "much," or "very much" improved on the seven-point Clinical Global Impression-Improvement (CGI-I) subscale.

Results: In the total sample (n = 188), clozapine initiation was associated with a significant transient increase (peaking in weeks 3 to 4) in white blood cell, neutrophil, and platelet count (P < 0.001). There were 112 (59.6%) patients that responded to treatment; however, none of the hematological factors assessed at baseline, nor changes in these factors, were directly associated with treatment response.

Implications: Clozapine treatment is associated with transient hematological changes during the first month of treatment; however, there was no evidence that these were related to the therapeutic response.
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http://dx.doi.org/10.1097/JCP.0000000000001329DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7752217PMC
December 2020

Correction to: Integrated GP care for patients with persistent physical symptoms: feasibility cluster randomised trial.

BMC Fam Pract 2020 Nov 6;21(1):226. Epub 2020 Nov 6.

Department of Psychological Medicine, Institute of Psychiatry, Psychology and Neuroscience, King's College London, 16 De Crespigny Park, London, SE5 8AF, UK.

An amendment to this paper has been published and can be accessed via the original article.
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http://dx.doi.org/10.1186/s12875-020-01302-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7648267PMC
November 2020

Predicting onset of early- and late-treatment resistance in first-episode schizophrenia patients using advanced shrinkage statistical methods in a small sample.

Psychiatry Res 2020 12 21;294:113527. Epub 2020 Oct 21.

Department of Biostatistics & Health Informatics, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, United Kingdom.

Evidence suggests there are two treatment-resistant schizophrenia subtypes (i.e. early treatment resistant (E-TR) and late-treatment resistant (L-TR)). We aimed to develop prediction models for estimating individual risk for these outcomes by employing advanced statistical shrinkage methods. 239 first-episode schizophrenia (FES) patients were followed-up for approximately 5 years after first presentation to psychiatric services; of these, n=56 (25.2%) were defined as E-TR and n=24 (12.6%) were defined as L-TR. Using known risk factors for poor schizophrenia outcomes, we developed prediction models for E-TR and L-TR using LASSO and RIDGE logistic regression models. Models' internal validation was performed employing Harrell's optimism-correction with repeated cross-validation; their predictive accuracy was assessed through discrimination and calibration. Both LASSO and RIDGE models had high discrimination, good calibration. While LASSO had moderate sensitivity for estimating an individual risk for E-TR and L-TR, sensitivity estimated for RIDGE model for these outcomes was extremely low, which was due to having a very large estimated optimism. Although it was possible to discriminate with sufficient accuracy who would meet criteria for E-TR and L-TR during the 5-year follow-up after first contact with mental health services for schizophrenia, further work is necessary to improve sensitivity for these models.
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http://dx.doi.org/10.1016/j.psychres.2020.113527DOI Listing
December 2020

Origins and genetic legacy of prehistoric dogs.

Science 2020 10 29;370(6516):557-564. Epub 2020 Oct 29.

Sobolev Institute of Geology and Mineralogy of the Siberian Branch of Russian Academy of Sciences, Novosibirsk, Russian Federation.

Dogs were the first domestic animal, but little is known about their population history and to what extent it was linked to humans. We sequenced 27 ancient dog genomes and found that all dogs share a common ancestry distinct from present-day wolves, with limited gene flow from wolves since domestication but substantial dog-to-wolf gene flow. By 11,000 years ago, at least five major ancestry lineages had diversified, demonstrating a deep genetic history of dogs during the Paleolithic. Coanalysis with human genomes reveals aspects of dog population history that mirror humans, including Levant-related ancestry in Africa and early agricultural Europe. Other aspects differ, including the impacts of steppe pastoralist expansions in West and East Eurasia and a near-complete turnover of Neolithic European dog ancestry.
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http://dx.doi.org/10.1126/science.aba9572DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7116352PMC
October 2020

Clinical, cognitive and neuroanatomical associations of serum NMDAR autoantibodies in people at clinical high risk for psychosis.

Mol Psychiatry 2020 Oct 19. Epub 2020 Oct 19.

Department of Psychosis Studies, Institute of Psychiatry, Psychology and Neuroscience, King's Health Partners, King's College London, London, UK.

Serum neuronal autoantibodies, such as those to the NMDA receptor (NMDAR), are detectable in a subgroup of patients with psychotic disorders. It is not known if they are present before the onset of psychosis or whether they are associated with particular clinical features or outcomes. In a case-control study, sera from 254 subjects at clinical high risk (CHR) for psychosis and 116 healthy volunteers were tested for antibodies against multiple neuronal antigens implicated in CNS autoimmune disorders, using fixed and live cell-based assays (CBAs). Within the CHR group, the relationship between NMDAR antibodies and symptoms, cognitive function and clinical outcomes over 24 month follow-up was examined. CHR subjects were not more frequently seropositive for neuronal autoantibodies than controls (8.3% vs. 5.2%; OR = 1.50; 95% CI: 0.58-3.90). The NMDAR was the most common target antigen and NMDAR IgGs were more sensitively detected with live versus fixed CBAs (p < 0.001). Preliminary phenotypic analyses revealed that within the CHR sample, the NMDAR antibody seropositive subjects had higher levels of current depression, performed worse on the Rey Auditory Verbal Learning Task (p < 0.05), and had a markedly lower IQ (p < 0.01). NMDAR IgGs were not more frequent in subjects who later became psychotic than those who did not. NMDAR antibody serostatus and titre was associated with poorer levels of functioning at follow-up (p < 0.05) and the presence of a neuronal autoantibody was associated with larger amygdala volumes (p < 0.05). Altogether, these findings demonstrate that NMDAR autoantibodies are detectable in a subgroup of CHR subjects at equal rates to controls. In the CHR group, they are associated with affective psychopathology, impairments in verbal memory, and overall cognitive function: these findings are qualitatively and individually similar to core features of autoimmune encephalitis and/or animal models of NMDAR antibody-mediated CNS disease. Overall the current work supports further evaluation of NMDAR autoantibodies as a possible prognostic biomarker and aetiological factor in a subset of people already meeting CHR criteria.
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http://dx.doi.org/10.1038/s41380-020-00899-wDOI Listing
October 2020

Can metacognitive interventions improve insight in schizophrenia spectrum disorders? A systematic review and meta-analysis.

Psychol Med 2020 10 14;50(14):2289-2301. Epub 2020 Oct 14.

Institute of Mental Health, University College London, London, UK.

Background: Patients with schizophrenia spectrum disorders (SSD) tend to lack insight, which is linked to poor outcomes. The effect size of previous treatments on insight changes in SSD has been small. Metacognitive interventions may improve insight in SSD, although this remains unproved.

Methods: We carried out a systematic review and meta-analysis of randomized controlled trials (RCTs) to examine the effects of metacognitive interventions designed for SSD, namely Metacognitive Training (MCT) and Metacognitive Reflection and Insight Therapy (MERIT), on changes in cognitive and clinical insight at post-treatment and at follow-up.

Results: Twelve RCTs, including 10 MCT RCTs (n = 717 participants) and two MERIT trials (n = 90), were selected, totalling N = 807 participants. Regarding cognitive insight six RCTs (n = 443) highlighted a medium effect of MCT on self-reflectiveness at post-treatment, d = 0.46, p < 0.01, and at follow-up, d = 0.30, p < 0.01. There was a small effect of MCT on self-certainty at post-treatment, d = -0.23, p = 0.03, but not at follow-up. MCT was superior to controls on an overall Composite Index of cognitive insight at post-treatment, d = 1.11, p < 0.01, and at follow-up, d = 0.86, p = 0.03, although we found evidence of heterogeneity. Of five MCT trials on clinical insight (n = 244 participants), which could not be meta-analysed, four of them favoured MCT compared v. control. The two MERIT trials reported conflicting results.

Conclusions: Metacognitive interventions, particularly Metacognitive Training, appear to improve insight in patients with SSD, especially cognitive insight shortly after treatment. Further long-term RCTs are needed to establish whether these metacognitive interventions-related insight changes are sustained over a longer time period and result in better outcomes.
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http://dx.doi.org/10.1017/S0033291720003384DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7610184PMC
October 2020

Population neuroimaging: generation of a comprehensive data resource within the ALSPAC pregnancy and birth cohort.

Wellcome Open Res 2020 28;5:203. Epub 2020 Aug 28.

MRC Integrative Epidemiology Unit, Population Health Sciences, University of Bristol, Bristol, BS8 2BN, UK.

Neuroimaging offers a valuable insight into human brain development by allowing assessment of structure, connectivity and function. Multimodal neuroimaging data have been obtained as part of three sub-studies within the Avon Longitudinal Study of Parents and Children, a prospective multigenerational pregnancy and birth cohort based in the United Kingdom. Brain imaging data were acquired when offspring were between 18 and 24 years of age, and included acquisition of structural, functional and magnetization transfer magnetic resonance, diffusion tensor, and magnetoencephalography imaging. This resource provides a unique opportunity to combine neuroimaging data with extensive phenotypic and genotypic measures from participants, their mothers, and fathers.
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http://dx.doi.org/10.12688/wellcomeopenres.16060.1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7531050PMC
August 2020

Trial Of Neurostimulation In Conversion Symptoms (TONICS): a feasibility randomised controlled trial of transcranial magnetic stimulation for functional limb weakness.

BMJ Open 2020 10 6;10(10):e037198. Epub 2020 Oct 6.

Institute of Psychiatry Psychology and Neuroscience, King's College London, London, UK

Objectives: Transcranial magnetic stimulation (TMS) has been used therapeutically for functional (conversion) motor symptoms but there is limited evidence for its efficacy and the optimal protocol. We examined the feasibility of a novel randomised controlled trial (RCT) protocol of TMS to treat functional limb weakness.

Design: A double-blind (patient, outcome assessor) two parallel-arm, controlled RCT.

Setting: Specialist neurology and neuropsychiatry services at a large National Health Service Foundation Trust in London, UK.

Participants: Patients with a diagnosis of functional limb weakness (Diagnostic and Statistical Manual of Mental Disorders - Fifth Edition). Exclusion criteria included comorbid neurological or major psychiatric disorder, contraindications to TMS or previous TMS treatment.

Interventions: Patients were randomised to receive either active (single-pulse TMS to primary motor cortex (M1) above resting motor threshold) or inactive treatment (single-pulse TMS to M1 below resting motor threshold). Both groups received two TMS sessions, 4 weeks apart.

Outcome Measures: We assessed recruitment, randomisation and retention rates. The primary outcome was patient-rated symptom change (Clinical Global Impression-Improvement scale, CGI-I). Secondary outcomes included clinician-rated symptom change, psychosocial functioning and disability. Outcomes were assessed at baseline, both TMS visits and at 3-month follow-up.

Results: Twenty-two patients were recruited and 21 (96%) were successfully randomised (active=10; inactive=11). Nineteen (91%) patients were included at follow-up (active=9; inactive=10). Completion rates for most outcomes were good (80%-100%). Most patients were satisfied/very satisfied with the trial in both groups, although ratings were higher in the inactive arm (active=60%, inactive=92%). Adverse events were not more common for the active treatment. Treatment effect sizes for patient-rated CGI-I scores were small-moderate (Cliff's delta=-0.1-0.3, CIs-0.79 to 0.28), reflecting a more positive outcome for the active treatment (67% and 44% of active arm-rated symptoms as 'much improved' at session 2 and follow-up, respectively, vs 20% inactive group). Effect sizes for secondary outcomes were variable.

Conclusions: Our protocol is feasible. The findings suggest that supramotor threshold TMS of M1 is safe, acceptable and potentially beneficial as a treatment for functional limb weakness. A larger RCT is warranted.

Trial Registration Number: ISRCTN51225587.
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http://dx.doi.org/10.1136/bmjopen-2020-037198DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7539585PMC
October 2020

BMC family practice integrated GP care for patients with persistent physical symptoms: feasibility cluster randomised trial.

BMC Fam Pract 2020 10 7;21(1):207. Epub 2020 Oct 7.

Department of Psychological Medicine, Institute of Psychiatry, Psychology and Neuroscience, King's College London, 16 De Crespigny Park, London, SE5 8AF, UK.

Background: Patients continue to suffer from medically unexplained symptoms otherwise referred to as persistent physical symptoms (PPS). General practitioners (GPs) play a key role in the management of PPS and require further training. Patients are often frustrated with the care they receive. This study aims to assess the acceptability of an 'integrated GP care' approach which consists of offering self-help materials to patients with PPS and offering their GPs training on how to utilise cognitive behavioural skills within their consultations, as well as assessing the feasibility of conducting a future trial in primary care to evaluate its benefit.

Methods: A feasibility cluster randomised controlled trial was conducted in primary care, South London, UK. GP practices (clusters) were randomly allocated to 'integrated GP care plus treatment as usual' or 'treatment as usual'. Patients with PPS were recruited from participating GP practices before randomisation. Feasibility parameters, process variables and potential outcome measures were collected at pre-randomisation and at 12- and 24-weeks post-randomisation at cluster and individual participant level.

Results: Two thousand nine hundred seventy-eight patients were identified from 18 GP practices. Out of the 424 patients who responded with interest in the study, 164 fully met the eligibility criteria. One hundred sixty-one patients provided baseline data before cluster randomisation and therefore were able to participate in the study. Most feasibility parameters indicated that the intervention was acceptable and a future trial feasible. 50 GPs from 8 GP practices (randomised to intervention) attended the offer of training and provided positive feedback. Scores in GP knowledge and confidence increased post-training. Follow-up rate of patients at 24 weeks was 87%. However estimated effect sizes on potential clinical outcomes were small.

Conclusions: It was feasible to identify and recruit patients with PPS. Retention rates of participants up to 24 weeks were high. A wide range of health services were used. The intervention was relatively low cost and low risk. This complex intervention should be further developed to improve patients'/GPs' utilisation of audio/visual and training resources before proceeding to a full trial evaluation.

Trial Registration: NCT02444520  (ClinicalTrials.gov).
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http://dx.doi.org/10.1186/s12875-020-01269-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7542765PMC
October 2020

Influence of theta-burst transcranial magnetic stimulation over the dorsolateral prefrontal cortex on emotion processing in healthy volunteers.

Cogn Affect Behav Neurosci 2020 12 30;20(6):1278-1293. Epub 2020 Sep 30.

Division of Psychiatry, University College London, Maple House, 6th Floor, 149 Tottenham Court Rd, Fitzrovia, London, W1T 7BN, UK.

Repetitive transcranial magnetic stimulation is a potential treatment option for depression, with the newer intermittent theta-burst stimulation (iTBS) protocols providing brief intervention. However, their mechanism of action remains unclear. We investigated the hypothesis that iTBS influences brain circuits involved in emotion processing that are also affected by antidepressants. We predicted that iTBS would lead to changes in performance on emotion-processing tasks. We investigated the effects of intermittent TBS (iTBS) over the left dorsolateral prefrontal cortex (DLPFC) on the processing of emotional information (word recall and categorization, facial emotion recognition, and decision-making) in 28 healthy volunteers by contrasting these effects with those of sham stimulation. Each volunteer received iTBS and sham stimulation in a blinded crossover design and completed the emotion-processing tasks before and after stimulation. Compared to sham stimulation, iTBS increased positive affective processing for word recall, yet had an unexpected effect on facial emotion recognition for happy and sad faces. There was no evidence of an effect on decision-making or word categorization. We found support for our hypothesis that iTBS influences emotion processing, though some changes were not in the expected direction. These findings suggest a possible common mechanism of action between iTBS and antidepressants, and a complex neural circuitry involved in emotion processing that could potentially be tapped into via brain stimulation. Future research should investigate the neural correlates of emotion processing more closely to inform future iTBS protocols.
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http://dx.doi.org/10.3758/s13415-020-00834-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7716858PMC
December 2020

G-CSF mediated neutrophil augmentation in a unique case of comorbid idiopathic Parkinson's disease and treatment-resistant schizophrenia on clozapine.

Ther Adv Psychopharmacol 2020 16;10:2045125320956414. Epub 2020 Sep 16.

South London and Maudsley NHS Foundation Trust, 1st Floor, Cheyne Wing, King's College Hospital, London, SE5 9RS, UK.

Treatment of psychosis in Parkinson's disease (PD) is challenging; pharmacological options are limited, with clozapine considered most effective. The risk of agranulocytosis restricts the use of clozapine, but, where this occurs, cautious re-challenge with granulocyte stimulating factor can be successful. We present a unique case of a patient who developed early-onset PD on a background of antecedent treatment-resistant schizophrenia, who had been treated effectively with clozapine for over 15 years with no adverse events. However, during a hospital admission intended to optimise her Parkinsonian medications, she developed persistent neutropenia necessitating clozapine discontinuation. Numerous attempts to re-challenge with clozapine failed until augmentation with lithium and G-CSF was trialled. Two doses of G-CSF led to a sustained increase in the neutrophil count, allowing the continuation of clozapine therapy in the 1 year of follow up. This illustrates the potential for G-CSF to be used to facilitate clozapine use in a patient population not described previously. Neutrophil augmentation allowed the sustained continuation of this effective therapy, treating her psychotic symptoms without detriment to her movement disorder. We suggest that G-CSF might be considered as a treatment option in other cases where clozapine-associated neutropenia obstructs its use.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7498832PMC
September 2020

The evolving picture of SARS-CoV-2 and COVID-19 in children: critical knowledge gaps.

BMJ Glob Health 2020 09;5(9)

Research Programme, Elizabeth Glaser Pediatric AIDS Foundation, Washington DC, District of Columbia, USA.

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http://dx.doi.org/10.1136/bmjgh-2020-003454DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7496567PMC
September 2020

Prevention of psychosis: moving on from the at-risk mental state to universal primary prevention.

Psychol Med 2021 Jan 7;51(2):223-227. Epub 2020 Sep 7.

Department of Biostatistics & Health Informatics, Institute of Psychiatry, Psychology & Neuroscience, King's College London, University of London, London, UK.

The value of services for those with the 'At Risk Mental State for Psychosis' (ARMS) continues to be disputed. ARMS services have provided a valuable stimulus to academic research into the transition into psychosis. Furthermore, there is currently a welcome trend to transform such clinics into youth mental health services catering for the broader clientele of young people suffering from anxiety and depression, who already constitute the bulk of those seen at ARMS clinics. However, such services are never likely to make major inroads into preventing psychosis because they only reach a small proportion of those at risk. Evidence from medicine shows that avoiding exposure to factors which increase the risk of disease (e.g. poor nutrition, transmission of infection, tobacco smoking), produces greater public benefit than focussing efforts on individuals with, or about to develop, disease. We consider that the most productive approach for psychosis prevention is avoiding exposure to risk-increasing factors. The best-established risk factors for psychosis are obstetric events, childhood abuse, migration, city living, adverse life events and cannabis use. Some as city living, are likely proxies for an unknown causal factor(s) while preventing others such as childhood abuse is currently beyond our powers. The risk factor for psychosis which is most readily open to this approach is the use of cannabis. Therefore, as an initial step towards a strategy for universal primary prevention, we advocate public health campaigns to educate young people about the harms of regular use of high potency cannabis.
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http://dx.doi.org/10.1017/S003329172000313XDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7893507PMC
January 2021

Experiences and Illness Perceptions of Patients with Functional Symptoms Admitted to Hyperacute Stroke Wards: A Mixed-Method Study.

Neuropsychiatr Dis Treat 2020 24;16:1795-1805. Epub 2020 Jul 24.

UCL Institute of Mental Health, University College London, London, UK.

Introduction: A proportion of patients admitted to acute-stroke settings have not had a stroke, but have conditions mimicking a stroke. Approximately 25% of suspected stroke cases are "stroke mimics" and 2% are patients with functional symptoms - "functional stroke mimics". This study aimed to explore experiences and illness perceptions of patients with functional symptoms admitted to hyperacute stroke wards.

Methods: This study used mixed methods. Patients with functional stroke symptoms participated in semistructured qualitative interviews immediately after admission to one of two acute-stroke units in London and again 2 months after hospital discharge. Qualitative data were assessed using thematic analysis. The Brief Illness Perception Questionnaire (Brief-IPQ) measured illness perceptions at admission and at 2-month follow-up.

Results: A total of 36 participants completed baseline interviews and 25 completed follow-up. Six themes emerged: physical symptom experience, emotional and coping responses, symptom causes, hospital experiences, views on the future, and uncertainty after hospital discharge. Mean Brief-IPQ score at admission was 49.3 (SD: 9.9), indicating a moderate-high level of perceived illness threat. Participants presented with a range of functional symptoms. At baseline, participants were highly concerned about their symptoms, but this had decreased at 2-month follow-up. Two months later, many were confused as to the cause of their admission.

Conclusion: This is the first study to examine functional stroke patients' experiences of acute-stroke admission. At admission, patients expressed confusion regarding their diagnosis, experienced high levels of emotional distress, and were concerned they were perceived as time wasting by stroke clinicians. While most participants experienced symptom recovery, there was a significant subgroup for whom symptoms persisted or worsened. A lack of care guidelines on the management of functional stroke patients may perpetuate functional symptoms.
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http://dx.doi.org/10.2147/NDT.S251328DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7399446PMC
July 2020

Correction to: Persistent physical symptoms reduction intervention: a system change and evaluation in secondary care (PRINCE secondary) - a CBT-based transdiagnostic approach: study protocol for a randomised controlled trial.

BMC Psychiatry 2020 Aug 12;20(1):403. Epub 2020 Aug 12.

Department of Biostatistics and Health Informatics, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.

An amendment to this paper has been published and can be accessed via the original article.
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http://dx.doi.org/10.1186/s12888-020-02811-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7422523PMC
August 2020

Development and characterization of a human Th17-driven ex vivo skin inflammation model.

Exp Dermatol 2020 10 25;29(10):993-1003. Epub 2020 Aug 25.

Skin Research, LEO Pharma A/S, Ballerup, Denmark.

Skin models mimicking features of psoriasis-related inflammation are needed to support the development of new drugs in dermatology. Reconstructed skin models lack tissue complexity, including a fully competent skin barrier, and presence and/or diversity of immune cells. Here, we describe InflammaSkin®, a novel human Th17-driven ex vivo skin inflammation model. In this model, skin-resident T cells are in situ activated by intradermal injection of anti-CD3 and anti-CD28 antibodies and Th17 cell polarization is sustained by culture in a chemically defined medium supplemented with IL-1β, IL-23 and TGF-β for seven days. The acquired Th17 signature is demonstrated by the sustained secretion of IL-17A, IL-17AF, IL-17F, IL-22, IFN-γ, and to some degree IL-15 and TNF-α observed in the activated ex vivo skin inflammation model compared with the non-activated skin model control. Furthermore, expression of S100A7 and Keratin-16 by keratinocytes and loss of epidermal structure integrity occur subsequently to in situ Th17cell activation, demonstrating cellular crosstalk between Th17 cells and keratinocytes. Finally, we demonstrate the use of this model to investigate the modulation of the IL-23/IL-17 immune axis by topically applied anti-inflammatory compounds. Taken together, we show that by in situ activation of skin-resident Th17 cells, the InflammaSkin® model reproduces aspects of inflammatory responses observed in psoriatic lesions and could be used as a translational tool to assess efficacy of test compounds.
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http://dx.doi.org/10.1111/exd.14160DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7693225PMC
October 2020

Development and validation of the schedule for the assessment of insight in eating disorders (SAI-ED).

Psychiatry Res 2020 10 16;292:113308. Epub 2020 Jul 16.

UCL Institute of Mental Health, Division of Psychiatry, University College London, UK.

This study examined the reliability, validity and internal structure of the newly developed, interview-based Schedule for the Assessment of Insight in Eating Disorders (SAI-ED) and the relationships of insight with demographic and clinical characteristics in EDs. Ninety-four female patients - 44 with anorexia nervosa (AN) and 50 with bulimia nervosa (BN) - were assessed with SAI-ED. The Brown Assessment of Beliefs Scale was used to evaluate convergent validity of SAI-ED. Hierarchical cluster analysis and multidimensional scaling were used to identify insight components and assess their inter-relationships. The final 8-item SAI-ED demonstrated good psychometric properties. Inter-rater and test-retest reliabilities were high. Three subscales of SAI-ED were identified which measure major insight components: awareness of illness, awareness of symptoms, and treatment engagement. Patients with AN had significant lower score on SAI-ED than patients with BN. Impaired insight was associated with: (a) lower current and lowest lifetime BMI and more severe dietary restrain in AN, (b) illness duration, severity of overall ED symptoms, body-related concerns and obsessionality in BN. Insight is a multidimensional construct in EDs associated with different clinical aspects in AN and BN. The SAI-ED is a valid and reliable tool for the assessment of insight in EDs patients.
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http://dx.doi.org/10.1016/j.psychres.2020.113308DOI Listing
October 2020

Psychiatric and neuropsychiatric presentations associated with severe coronavirus infections: a systematic review and meta-analysis with comparison to the COVID-19 pandemic.

Lancet Psychiatry 2020 07 18;7(7):611-627. Epub 2020 May 18.

UCL Institute of Mental Health, University College London, London, UK.

Background: Before the COVID-19 pandemic, coronaviruses caused two noteworthy outbreaks: severe acute respiratory syndrome (SARS), starting in 2002, and Middle East respiratory syndrome (MERS), starting in 2012. We aimed to assess the psychiatric and neuropsychiatric presentations of SARS, MERS, and COVID-19.

Methods: In this systematic review and meta-analysis, MEDLINE, Embase, PsycINFO, and the Cumulative Index to Nursing and Allied Health Literature databases (from their inception until March 18, 2020), and medRxiv, bioRxiv, and PsyArXiv (between Jan 1, 2020, and April 10, 2020) were searched by two independent researchers for all English-language studies or preprints reporting data on the psychiatric and neuropsychiatric presentations of individuals with suspected or laboratory-confirmed coronavirus infection (SARS coronavirus, MERS coronavirus, or SARS coronavirus 2). We excluded studies limited to neurological complications without specified neuropsychiatric presentations and those investigating the indirect effects of coronavirus infections on the mental health of people who are not infected, such as those mediated through physical distancing measures such as self-isolation or quarantine. Outcomes were psychiatric signs or symptoms; symptom severity; diagnoses based on ICD-10, DSM-IV, or the Chinese Classification of Mental Disorders (third edition) or psychometric scales; quality of life; and employment. Both the systematic review and the meta-analysis stratified outcomes across illness stages (acute vs post-illness) for SARS and MERS. We used a random-effects model for the meta-analysis, and the meta-analytical effect size was prevalence for relevant outcomes, I statistics, and assessment of study quality.

Findings: 1963 studies and 87 preprints were identified by the systematic search, of which 65 peer-reviewed studies and seven preprints met inclusion criteria. The number of coronavirus cases of the included studies was 3559, ranging from 1 to 997, and the mean age of participants in studies ranged from 12·2 years (SD 4·1) to 68·0 years (single case report). Studies were from China, Hong Kong, South Korea, Canada, Saudi Arabia, France, Japan, Singapore, the UK, and the USA. Follow-up time for the post-illness studies varied between 60 days and 12 years. The systematic review revealed that during the acute illness, common symptoms among patients admitted to hospital for SARS or MERS included confusion (36 [27·9%; 95% CI 20·5-36·0] of 129 patients), depressed mood (42 [32·6%; 24·7-40·9] of 129), anxiety (46 [35·7%; 27·6-44·2] of 129), impaired memory (44 [34·1%; 26·2-42·5] of 129), and insomnia (54 [41·9%; 22·5-50·5] of 129). Steroid-induced mania and psychosis were reported in 13 (0·7%) of 1744 patients with SARS in the acute stage in one study. In the post-illness stage, depressed mood (35 [10·5%; 95% CI 7·5-14·1] of 332 patients), insomnia (34 [12·1%; 8·6-16·3] of 280), anxiety (21 [12·3%; 7·7-17·7] of 171), irritability (28 [12·8%; 8·7-17·6] of 218), memory impairment (44 [18·9%; 14·1-24·2] of 233), fatigue (61 [19·3%; 15·1-23·9] of 316), and in one study traumatic memories (55 [30·4%; 23·9-37·3] of 181) and sleep disorder (14 [100·0%; 88·0-100·0] of 14) were frequently reported. The meta-analysis indicated that in the post-illness stage the point prevalence of post-traumatic stress disorder was 32·2% (95% CI 23·7-42·0; 121 of 402 cases from four studies), that of depression was 14·9% (12·1-18·2; 77 of 517 cases from five studies), and that of anxiety disorders was 14·8% (11·1-19·4; 42 of 284 cases from three studies). 446 (76·9%; 95% CI 68·1-84·6) of 580 patients from six studies had returned to work at a mean follow-up time of 35·3 months (SD 40·1). When data for patients with COVID-19 were examined (including preprint data), there was evidence for delirium (confusion in 26 [65%] of 40 intensive care unit patients and agitation in 40 [69%] of 58 intensive care unit patients in one study, and altered consciousness in 17 [21%] of 82 patients who subsequently died in another study). At discharge, 15 (33%) of 45 patients with COVID-19 who were assessed had a dysexecutive syndrome in one study. At the time of writing, there were two reports of hypoxic encephalopathy and one report of encephalitis. 68 (94%) of the 72 studies were of either low or medium quality.

Interpretation: If infection with SARS-CoV-2 follows a similar course to that with SARS-CoV or MERS-CoV, most patients should recover without experiencing mental illness. SARS-CoV-2 might cause delirium in a significant proportion of patients in the acute stage. Clinicians should be aware of the possibility of depression, anxiety, fatigue, post-traumatic stress disorder, and rarer neuropsychiatric syndromes in the longer term.

Funding: Wellcome Trust, UK National Institute for Health Research (NIHR), UK Medical Research Council, NIHR Biomedical Research Centre at University College London Hospitals NHS Foundation Trust and University College London.
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http://dx.doi.org/10.1016/S2215-0366(20)30203-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7234781PMC
July 2020

Psychiatric Morbidity and Its Prognosis in Posterior Reversible Encephalopathy Syndrome.

J Neuropsychiatry Clin Neurosci 2020 14;32(4):385-388. Epub 2020 Apr 14.

Department of Health Service and Population Research, Section of Women's Mental Health, Institute of Psychiatry, Psychology and Neuroscience, King's College London (Keynejad); and UCL Institute of Mental Health, Division of Psychiatry, Faculty of Brain Sciences, University College London, London (David).

Posterior reversible encephalopathy syndrome (PRES) is a clinically and radiologically diagnosed disorder distinguished by subcortical vasogenic cerebral edema. To date, its presentation has been described through summarized neurological categories, such as seizures, headaches, "confusion," and "altered mental function." This retrospective case series identified all cases of clinically confirmed, radiologically diagnosed PRES resulting in treatment in a large teaching hospital from 2010 to 2019. The authors conducted a search for the term "reversible encephalopathy" in the hospital clinical radiology information system, followed by an audit of scan reports and clinical records. The most common reasons for psychiatric referral were addictions, acute psychosis, depression, suicidality, and treatment refusal. Multidisciplinary staff should consider PRES as a rare, organic differential diagnosis for acute mental state changes. Physicians should be aware of elevated rates of post-PRES psychiatric symptoms and consider whether psychiatric consultation may enhance recovery.
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http://dx.doi.org/10.1176/appi.neuropsych.19080184DOI Listing
April 2020

Insight is a useful construct in clinical assessments if used wisely.

J Med Ethics 2020 Apr 9. Epub 2020 Apr 9.

Department of Psychological Medicine, Institute of Psychiatry Psychology and Neuroscience, London, UK.

Medical ethicist, Guidry-Grimes has critically reviewed the concept of insight, voicing concerns that it lacks consensus as to its components and that it undermines patient perspectives. We respond by briefly summarising research over the last 30 years that she overlooks which has helped establish the clinical validity of the construct. This includes the adoption of standardised assessment tools-at least in research-and longitudinal and cross-sectional studies quantifying associations with psychopathological, clinical and cognitive measures. We also make the distinction between the current standards for assessing decision-making capacity leading to, where appropriate, involuntary treatment in clinical and medico-legal settings which in most legislations do not include insight assessments, and anecdotal reports of the use and misuse of 'lack of insight' as a proxy for more comprehensive evaluation. We conclude by encouraging a broader view of insight akin to self-knowledge.
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http://dx.doi.org/10.1136/medethics-2020-106128DOI Listing
April 2020