Realising stratified psychiatry using multidimensional signatures and trajectories

BACKGROUND: Stratified or personalised medicine targets treatments for groups of individuals with a disorder based on individual heterogeneity and shared factors that influence the likelihood of response. Psychiatry has traditionally defined diagnoses by constellations of co-occurring signs and symptoms that are assigned a categorical label (e.g. schizophrenia). Trial methodology in psychiatry has evaluated interventions targeted at these categorical entities, with diagnoses being equated to disorders. Recent insights into both the nosology and neurobiology of psychiatric disorder reveal that traditional categorical diagnoses cannot be equated with disorders. We argue that current quantitative methodology (1) inherits these categorical assumptions, (2) allows only for the discovery of average treatment response, (3) relies on composite outcome measures and (4) sacrifices valuable predictive information for stratified and personalised treatment in psychiatry. METHODS AND FINDINGS: To achieve a truly ‘stratified psychiatry’ we propose and then operationalise two necessary steps: first, a formal multi-dimensional representation of disorder definition and clinical state, and second, the similar redefinition of outcomes as multidimensional constructs that can expose within- and between-patient differences in response. We use the categorical diagnosis of schizophrenia—conceptualised as a label for heterogeneous disorders—as a means of introducing operational definitions of stratified psychiatry using principles from multivariate analysis. We demonstrate this framework by application to the Clinical Antipsychotic Trials of Intervention Effectiveness dataset, showing heterogeneity in both patient clinical states and their trajectories after treatment that are lost in the traditional categorical approach with composite outcomes. We then systematically review a decade of registered clinical trials for cognitive deficits in schizophrenia highlighting existing assumptions of categorical diagnoses and aggregate outcomes while identifying a small number of trials that could be reanalysed using our proposal. CONCLUSION: We describe quantitative methods for the development of a multi-dimensional model of clinical state, disorders and trajectories which practically realises stratified psychiatry. We highlight the potential for recovering existing trial data, the implications for stratified psychiatry in trial design and clinical treatment and finally, describe different kinds of probabilistic reasoning tools necessary to implement stratification

Protein Tyrosine Phosphatase PTP1B is Involved in Hippocampal Synapse Formation and Learning

ER-bound PTP1B is expressed in hippocampal neurons, and accumulates among neurite contacts. PTP1B dephosphorylates ß-catenin in N-cadherin complexes ensuring cell-cell adhesion. Here we show that endogenous PTP1B, as well as expressed GFP-PTP1B, are present in dendritic spines of hippocampal neurons in culture. GFP-PTP1B overexpression does not affect filopodial density or length. In contrast, impairment of PTP1B function or genetic PTP1B-deficiency leads to increased filopodia-like dendritic spines and a reduction in mushroom-like spines, while spine density is unaffected. These morphological alterations are accompanied by a disorganization of pre- and post-synapses, as judged by decreased clustering of synapsin-1 and PSD-95, and suggest a dynamic synaptic phenotype. Notably, levels of ß-catenin-Tyr-654 phosphorylation increased ∼5-fold in the hippocampus of adult PTP1B−/− (KO) mice compared to wild type (WT) mice and this was accompanied by a reduction in the amount of ß-catenin associated with N-cadherin. To determine whether PTP1B-deficiency alters learning and memory, we generated mice lacking PTP1B in the hippocampus and cortex (PTP1Bfl/fl–Emx1-Cre). PTP1Bfl/fl–Emx1-Cre mice displayed improved performance in the Barnes maze (decreased time to find and enter target hole), utilized a more efficient strategy (cued), and had better recall compared to WT controls. Our results implicate PTP1B in structural plasticity within the hippocampus, likely through modulation of N-cadherin function by ensuring dephosphorylation of ß-catenin on Tyr-654. Disruption of hippocampal PTP1B function or expression leads to elongation of dendritic filopodia and improved learning and memory, demonstrating an exciting novel role for this phosphatase

The importance of pro-social processing, and ameliorating dysfunction in schizophrenia. An FMRI study of oxytocin

Schizophrenia is often a severe and debilitating mental illness, frequently associated with impairments in social cognition that hinder individuals' abilities to relate to others and integrate effectively in society. Oxytocin has emerged as a putative therapeutic agent for treating social deficits in schizophrenia, but the mode of action remains unclear. This placebo-controlled crossover study aimed to elucidate the neural underpinnings of oxytocin administration in patients with schizophrenia. 20 patients with schizophrenia were examined using functional magnetic resonance imaging under oxytocin (40 IU) or placebo nasal spray. Participants performed a stochastically rewarded decision-making task that incorporated elements of social valence provided by different facial expressions, i.e. happy, angry and neutral. Oxytocin attenuated the normal bias in selecting the happy face accompanied by reduced activation in a network of brain regions that support mentalising, processing of facial emotion, salience, aversion, uncertainty and ambiguity in social stimuli, including amygdala, temporo-parietal junction, posterior cingulate cortex, precuneus and insula. These pro-social effects may contribute to the facilitation of social engagement and social interactions in patients with schizophrenia and warrant further investigation in future clinical trials for social cognitive impairments in schizophrenia

Outcomes in treatment-resistant schizophrenia: symptoms, function and clozapine plasma concentrations

Background: Clozapine is the only medication licenced for treating patients with treatment-refractory schizophrenia. However, there are no evidence-based guidelines as to the optimal plasma level of clozapine to aim for, and their association with clinical and functional outcome. Objective: We assessed the relationship between clinical and functional outcome measures and blood concentrations of clozapine among patients with treatment-refractory psychosis. Methods: Data were reviewed in 82 patients with treatment-refractory psychosis admitted to a specialised tertiary-level service and treated with clozapine. Analysis focussed on the relationship between clozapine and norclozapine plasma concentrations and the patient’s clinical symptoms and functional status. Results: Clinical symptom improvement was positively correlated with norclozapine plasma concentrations and inversely correlated with clozapine to norclozapine plasma concentrations ratio. Clozapine concentrations showed a bimodal association with clinical improvement (peaks around 350 and 660 ng/ml). Clinical symptom improvement correlated with functional outcomes, although there was no significant correlation between the latter and clozapine or norclozapine plasma concentrations. Conclusion: Clozapine treatment was associated with optimal clinical improvement at two different peak plasma concentrations around 350 and 650 ng/ml. Clinical improvement was associated with functional outcome; however, functionality was not directly associated with clozapine concentrations. A subset of patients may require higher clozapine plasma concentrations to achieve clinical improvement

Post graduate clinical placements: evaluating benefits and challenges with a mixed methods cross sectional design

Abstract Background Systematic evaluations of clinical placements are rare, especially when offered alongside academic postgraduate courses. An evidence-based approach is important to allow pedagogically-driven provision, rather than that solely governed by opinion or market demand. Our evaluation assessed a voluntary clinical placement scheme allied to a mental health course. Methods Data were collected over academic years 2010/11– 2013/14, from participating students (n = 20 to 58) and clinician supervisors (n = 10–12), using a mixed-methods cross-sectional design. Quantitative evaluation captured information on uptake, dropout, resource use, attitudes and experience, using standardized (the Placement Evaluation Questionnaire; the Scale To Assess the Therapeutic Relationship – Clinical version and the University of Toronto Placement Supervisor Evaluation) and bespoke questionnaires and audit data. Qualitative evaluation comprised two focus groups (5 clinicians, 5 students), to investigate attitudes, experience, perceived benefits, disadvantages and desired future developments. Data were analysed using framework analysis to identify a priori and emergent themes. Results High uptake (around 70 placements per annum), low dropout (2–3 students per annum; 5 %) and positive focus group comments suggested placements successfully provided added value and catered sufficiently to student demand. Students’ responses confirmed that placements met expectations and the perception of benefit remained after completion with 70 % (n = 14) reporting an overall positive experience, 75 % (n = 15) reporting a pleasant learning experience, 60 % (n = 12) feeling that their clinical skills were enhanced and 85 % (n = 17) believing that it would benefit other students. Placements contributed the equivalent of seven full time unskilled posts per annum to local health care services. While qualitative data revealed perceived ‘mutual benefit’ for both students and clinicians, this was qualified by the inherent limitations of students’ time and expertise. Areas for development included fostering learning around professionalism and students’ confidence on placement. Conclusions The addition of healthcare placements to academic postgraduate taught courses can improve their attractiveness to applicants, benefit healthcare services and enhance students’ perception of their learning experiences. Well-positioned and supported placement learning opportunities could become a key differentiator for academic courses, over potential competitors. However, the actual implications for student employability and achievement remain to be established

Post graduate clinical placements: evaluating benefits and challenges with a mixed methods cross sectional design.

BACKGROUND: Systematic evaluations of clinical placements are rare, especially when offered alongside academic postgraduate courses. An evidence-based approach is important to allow pedagogically-driven provision, rather than that solely governed by opinion or market demand. Our evaluation assessed a voluntary clinical placement scheme allied to a mental health course. METHODS: Data were collected over academic years 2010/11- 2013/14, from participating students (n = 20 to 58) and clinician supervisors (n = 10-12), using a mixed-methods cross-sectional design. Quantitative evaluation captured information on uptake, dropout, resource use, attitudes and experience, using standardized (the Placement Evaluation Questionnaire; the Scale To Assess the Therapeutic Relationship - Clinical version and the University of Toronto Placement Supervisor Evaluation) and bespoke questionnaires and audit data. Qualitative evaluation comprised two focus groups (5 clinicians, 5 students), to investigate attitudes, experience, perceived benefits, disadvantages and desired future developments. Data were analysed using framework analysis to identify a priori and emergent themes. RESULTS: High uptake (around 70 placements per annum), low dropout (2-3 students per annum; 5 %) and positive focus group comments suggested placements successfully provided added value and catered sufficiently to student demand. Students' responses confirmed that placements met expectations and the perception of benefit remained after completion with 70 % (n = 14) reporting an overall positive experience, 75 % (n = 15) reporting a pleasant learning experience, 60 % (n = 12) feeling that their clinical skills were enhanced and 85 % (n = 17) believing that it would benefit other students. Placements contributed the equivalent of seven full time unskilled posts per annum to local health care services. While qualitative data revealed perceived 'mutual benefit' for both students and clinicians, this was qualified by the inherent limitations of students' time and expertise. Areas for development included fostering learning around professionalism and students' confidence on placement. CONCLUSIONS: The addition of healthcare placements to academic postgraduate taught courses can improve their attractiveness to applicants, benefit healthcare services and enhance students' perception of their learning experiences. Well-positioned and supported placement learning opportunities could become a key differentiator for academic courses, over potential competitors. However, the actual implications for student employability and achievement remain to be established

Integrated care in mental health: next steps after the NHS Long Term Plan.

Health and social care face growing and conflicting pressures: mounting complex needs of an ageing population, restricted funding and a workforce recruitment and retention crisis. In response, in the UK the NHS Long Term Plan promises increased investment and an emphasis on better 'integrated' care. We describe key aspects of integration that need addressing.Declaration of interestD.K.T. and S.S.S. are on the editorial board of the British Journal of Psychiatry and executives of the Academic Faculty at the Royal College of Psychiatrists. A.J.B.J., H.P. and Z.M. have roles at the Royal College of Psychiatrists that include evaluation of integrated care systems. A.J.B.J. is married to Dr Sarah Wollaston, Member of Parliament for Totnes and Chair of the Health Select Committee

Outcomes in treatment-resistant schizophrenia: symptoms, function and clozapine plasma concentrations

Background: Clozapine is the only medication licenced for treating patients with treatment-refractory schizophrenia. However, there are no evidence-based guidelines as to the optimal plasma level of clozapine to aim for, and their association with clinical and functional outcome. Objective: We assessed the relationship between clinical and functional outcome measures and blood concentrations of clozapine among patients with treatment-refractory psychosis. Methods: Data were reviewed in 82 patients with treatment-refractory psychosis admitted to a specialised tertiary-level service and treated with clozapine. Analysis focussed on the relationship between clozapine and norclozapine plasma concentrations and the patient’s clinical symptoms and functional status. Results: Clinical symptom improvement was positively correlated with norclozapine plasma concentrations and inversely correlated with clozapine to norclozapine plasma concentrations ratio. Clozapine concentrations showed a bimodal association with clinical improvement (peaks around 350 and 660 ng/ml). Clinical symptom improvement correlated with functional outcomes, although there was no significant correlation between the latter and clozapine or norclozapine plasma concentrations. Conclusion: Clozapine treatment was associated with optimal clinical improvement at two different peak plasma concentrations around 350 and 650 ng/ml. Clinical improvement was associated with functional outcome; however, functionality was not directly associated with clozapine concentrations. A subset of patients may require higher clozapine plasma concentrations to achieve clinical improvement

The importance of pro-social processing, and ameliorating dysfunction in schizophrenia. An FMRI study of oxytocin

Schizophrenia is often a severe and debilitating mental illness, frequently associated with impairments in social cognition that hinder individuals' abilities to relate to others and integrate effectively in society. Oxytocin has emerged as a putative therapeutic agent for treating social deficits in schizophrenia, but the mode of action remains unclear. This placebo-controlled crossover study aimed to elucidate the neural underpinnings of oxytocin administration in patients with schizophrenia. 20 patients with schizophrenia were examined using functional magnetic resonance imaging under oxytocin (40 IU) or placebo nasal spray. Participants performed a stochastically rewarded decision-making task that incorporated elements of social valence provided by different facial expressions, i.e. happy, angry and neutral. Oxytocin attenuated the normal bias in selecting the happy face accompanied by reduced activation in a network of brain regions that support mentalising, processing of facial emotion, salience, aversion, uncertainty and ambiguity in social stimuli, including amygdala, temporo-parietal junction, posterior cingulate cortex, precuneus and insula. These pro-social effects may contribute to the facilitation of social engagement and social interactions in patients with schizophrenia and warrant further investigation in future clinical trials for social cognitive impairments in schizophrenia

It's not what you say but the way that you say it: an fMRI study of differential lexical and non-lexical prosodic pitch processing

<p>Abstract</p> <p>Background</p> <p>This study aims to identify the neural substrate involved in prosodic pitch processing. Functional magnetic resonance imaging was used to test the premise that prosody pitch processing is primarily subserved by the right cortical hemisphere.</p> <p>Two experimental paradigms were used, firstly pairs of spoken sentences, where the only variation was a single internal phrase pitch change, and secondly, a matched condition utilizing pitch changes within analogous tone-sequence phrases. This removed the potential confounder of lexical evaluation. fMRI images were obtained using these paradigms.</p> <p>Results</p> <p>Activation was significantly greater within the right frontal and temporal cortices during the tone-sequence stimuli relative to the sentence stimuli.</p> <p>Conclusion</p> <p>This study showed that pitch changes, stripped of lexical information, are mainly processed by the right cerebral hemisphere, whilst the processing of analogous, matched, lexical pitch change is preferentially left sided. These findings, showing hemispherical differentiation of processing based on stimulus complexity, are in accord with a 'task dependent' hypothesis of pitch processing.</p