Max Marshall’s research while affiliated with Lancashire Care NHS Foundation Trust and other places

Early psychosis is characterised by heterogeneity in illness trajectories, where outcomes remain poor for many. Understanding psychosis symptoms and their relation to illness outcomes, from a novel network perspective, may help to delineate psychopathology within early psychosis and identify pivotal targets for intervention. Using network modelling in first episode psychosis (FEP), this study aimed to identify: (a) key central and bridge symptoms most influential in symptom networks, and (b) examine the structure and stability of the networks at baseline and 12-month follow-up. Data on 1027 participants with FEP were taken from the National EDEN longitudinal study and used to create regularised partial correlation networks using the ‘EBICglasso’ algorithm for positive, negative, and depressive symptoms at baseline and at 12-months. Centrality and bridge estimations were computed using a permutation-based network comparison test. Depression featured as a central symptom in both the baseline and 12-month networks. Conceptual disorganisation, stereotyped thinking, along with hallucinations and suspiciousness featured as key bridge symptoms across the networks. The network comparison test revealed that the strength and bridge centralities did not differ significantly between the two networks (C = 0.096153; p = 0.22297). However, the network structure and connectedness differed significantly from baseline to follow-up (M = 0.16405, p = <0.0001; S = 0.74536, p = 0.02), with several associations between psychosis and depressive items differing significantly by 12 months. Depressive symptoms, in addition to symptoms of thought disturbance (e.g. conceptual disorganisation and stereotyped thinking), may be examples of important, under-recognized treatment targets in early psychosis, which may have the potential to lead to global symptom improvements and better recovery.

Background: Treatment resistance causes significant burden in psychosis. Clozapine is the only evidence-based pharmacologic intervention available for people with treatment-resistant schizophrenia; current guidelines recommend commencement after two unsuccessful trials of standard antipsychotics. Aims: This paper aims to explore the prevalence of treatment resistance and pathways to commencement of clozapine in UK early intervention in psychosis (EIP) services. Method: Data were taken from the National Evaluation of the Development and Impact of Early Intervention Services study (N = 1027) and included demographics, medication history and psychosis symptoms measured by the Positive and Negative Syndrome Scale (PANSS) at baseline, 6 months and 12 months. Prescribing patterns and pathways to clozapine were examined. We adopted a strict criterion for treatment resistance, defined as persistent elevated positive symptoms (a PANSS positive score ≥16, equating to at least two items of at least moderate severity), across three time points. Results: A total of 143 (18.1%) participants met the definition of treatment resistance of having continuous positive symptoms over 12 months, despite treatment in EIP services. Sixty-one (7.7%) participants were treatment resistant and eligible for clozapine, having had two trials of standard antipsychotics; however, only 25 (2.4%) were prescribed clozapine over the 12-month study period. Treatment-resistant participants were more likely to be prescribed additional antipsychotic medication and polypharmacy, instead of clozapine. Conclusions: Prevalent treatment resistance was observed in UK EIP services, but prescription of polypharmacy was much more common than clozapine. Significant delays in the commencement of clozapine may reflect a missed opportunity to promote recovery in this critical period.

Background Delayed treatment for first episodes of psychosis predicts worse outcomes. We hypothesised that delaying treatment makes all symptoms more refractory, with harm worsening first quickly, then more slowly. We also hypothesised that although delay impairs treatment response, worse symptoms hasten treatment, which at presentation mitigates the detrimental effect of treatment delay on symptoms. Methods In this longitudinal analysis and modelling study, we included two longitudinal cohorts of patients with first-episode psychosis presenting to English early intervention services from defined catchments: NEDEN (recruiting 1003 patients aged 14–35 years from 14 services between Aug 1, 2005, and April 1, 2009) and Outlook (recruiting 399 patients aged 16–35 years from 11 services between April 1, 2006, and Feb 28, 2009). Patients were assessed at baseline, 6 months, and 12 months with the Positive and Negative Symptom Scale (PANSS), Calgary Depression Scale for Schizophrenia, Mania Rating Scale, Insight Scale, and Social and Occupational Functioning Assessment Scale. Regression was used to compare different models of the relationship between duration of untreated psychosis (DUP) and total symptoms at 6 months. Growth curve models of symptom subscales tested predictions arising from our hypotheses. Findings We included 948 patients from the NEDEN study and 332 patients from the Outlook study who completed baseline assessments and were prescribed dopamine antagonist antipsychotics. For both cohorts, the best-fitting models were logarithmic, describing a curvilinear relationship of DUP to symptom severity: longer DUP predicted reduced treatment response, but response worsened more slowly as DUP lengthened. Increasing DUP by ten times predicted reduced improvement in total symptoms (ie, PANSS total) by 7·339 (95% CI 5·762 to 8·916; p<0·0001) in NEDEN data and 3·846 (1·689 to 6·003; p=0·0005) in Outlook data. This was true of treatment response for all symptom types. Nevertheless, longer DUP was not associated with worse presentation for any symptoms except depression in NEDEN (coefficients 0·099 [95% CI 0·033 to 0·164]; p=0·0028 in NEDEN and 0·007 [−0·081 to 0·095]; p=0·88 in Outlook). Interpretation Long DUP was associated with reduced treatment response across subscales, consistent with a harmful process upstream of individual symptoms' mechanisms; response appeared to worsen quickly at first, then more slowly. These associations underscore the importance of rapid access to a comprehensive range of treatments, especially in the first weeks after psychosis onset. Funding UK Department of Health, National Institute of Health Research, and Medical Research Council.

Background: Previous evidence suggests that delusional disorder has a later onset and better functional outcomes compared to schizophrenia. However, studies have not examined longitudinal outcomes in a first episode population, where confounding factors may be adjusted for. Methods: A nested case control study was designed within the National EDEN study; a cohort of 1027 first episode psychosis patients. Patients with a baseline diagnosis of delusional disorder (n = 48) were compared with schizophrenia (n = 262) at 6 and 12 months with respect to symptomatic and functional outcomes. Regression analysis was used to adjust for possible confounders. Results: Delusional disorder patients had a shorter duration of untreated psychosis compared to schizophrenia but were similar in other baseline characteristics. At baseline, delusional disorder patients had lower symptom scores but higher function scores compared to those with schizophrenia. At 12 months the differences persisted for symptoms scores but not overall function scores. After adjusting for baseline score, age and duration of untreated psychosis, differences between the groups remained significant only for Positive and Negative Syndrome Scale (PANNS) negative, general and total scores and recovery rates. There were no differences in changes in outcomes scores. Conclusions: Delusional disorder in a first episode psychosis population presents with less severe symptoms, higher recovery rates and better functioning than schizophrenia, but at 12 months differences are ameliorated when adjusting for baseline differences.

Background Depending on the nature of their items factor analyses of different scales impose different structures on the underlying psychopathological dimensions, so a broader range of scale items should be more revealing. Few studies repeat analyses over successive interviews to investigate whether psychopathology has a consistent structure or evolves, especially after first presentations when the illness is most plastic and cohorts are unselected by chronicity. Methods A cohort was recruited from consecutive presentations aged 16–35 to NHS Early Intervention in Psychosis services from 14 catchments over 5 years during the National EDEN project. All met DSM IV-R criteria for schizophrenia spectrum psychoses, brief or substance induced psychoses, mania or severe depression with psychosis. At recruitment, after 6 and 12 months each was assessed with Positive and Negative Symptom Scale (PANSS), Calgary Depression Scale (CDS), Young’s Mania Rating Scale (MRS) and Birchwood’s Insight Scale (IS). At each point principal axis factoring with oblique (Promax) rotation included all scale items simultaneously, apart from using total scores for IS. Items below communality thresholds were excluded and the analyses repeated until stable solutions were achieved with fit metrics meeting conventional thresholds. Factor solutions were selected using breaks in the scree plot and eigenvalues>1.0. Results 1003 met diagnostic criteria and 948 provided data. Each time point produced 6 factors featuring consistent items: psychosis (PANSS delusions, hallucinations, suspicion, stereotyped thinking & bizarre ideation; MRS grandiose content); excitement/mania/disorganisation (PANSS agitation; MRS elation, overactivity, pressured and disorganised speech); hostility/suspiciousness (PANSS hostility, uncooperativeness & impulsive irritability; MRS irritability & aggression); depression/anxiety (PANSS anxiety, guilt, depression; CDS subjective & objective depression, guilt & guilty ideas of reference, hopelessness, self-depreciation, suicidality, early waking); negative symptoms (PANSS blunting, emotional & social withdrawal, poor rapport, poverty of speech, retardation and avolition), and poor insight (PANSS insight, MRS insight, IS total). Depression explained 29–32% of variance at different stages, Psychosis 28–29%, Negative 25–26%, Excitement 19–24%, Hostility 16–23% and Poor Insight 16–23%. Discussion The cohort, recruited from consecutive presentations, included a full range of psychoses in sufficient numbers to factor analyse the scales’ 51 parameters. There was evidence for 6 factors slightly different from the traditional 3 SAPS/SANS (Scales for the Assessment of Positive and Negative Symptoms) or 5 PANSS factors derived using chronically unwell samples with non-affective psychosis. There was more consistency than in previous first episode follow-up studies and affective and insight dimensions were more clearly defined.

Aim Exploring how negative symptoms are experienced and understood by individuals with lived experience of psychosis has the potential to offer insights into the complex psychosocial processes underlying negative symptom presentations. The aim of the current study was to investigate lived experiences of negative symptoms through secondary analysis of interviews conducted with individuals recovering from first‐episode psychosis. Method Transcripts of in‐depth interviews with participants (n = 24) recruited from Early Intervention in Psychosis services were analysed thematically with a focus on participants' experiences and personal understandings of features corresponding to the negative symptoms construct. Results Descriptions of reductions in expression, motivation and sociability were common features of participants' accounts. Several participants described the experience of having difficulty interacting as like being a “zombie”. Some participants experienced diminished capacity for emotion, thought or drive as underlying these experiences. However, participants typically attributed reductions in expression, motivation and sociability to medication side‐effects, lack of confidence or active avoidance intended to protect them from rejection or ridicule, sometimes linked to internalized stigma. Conclusions Personal accounts of experiences of reduced expression, motivation and sociability during first‐episode psychosis highlight the personal meaningfulness and role of agency in these features, challenging the framing of negative symptoms as passive manifestations of diminished capacity.

Aim Exploring how negative symptoms are experienced and understood by individuals with lived experience of psychosis has the potential to offer insights into the complex psychosocial processes underlying negative symptom presentations. The aim of the current study was to investigate lived experiences of negative symptoms through secondary analysis of interviews conducted with individuals recovering from first‐episode psychosis. Method Transcripts of in‐depth interviews with participants (n = 24) recruited from Early Intervention in Psychosis services were analysed thematically with a focus on participants' experiences and personal understandings of features corresponding to the negative symptoms construct. Results Descriptions of reductions in expression, motivation and sociability were common features of participants' accounts. Several participants described the experience of having difficulty interacting as like being a “zombie”. Some participants experienced diminished capacity for emotion, thought or drive as underlying these experiences. However, participants typically attributed reductions in expression, motivation and sociability to medication side‐effects, lack of confidence or active avoidance intended to protect them from rejection or ridicule, sometimes linked to internalized stigma. Conclusions Personal accounts of experiences of reduced expression, motivation and sociability during first‐episode psychosis highlight the personal meaningfulness and role of agency in these features, challenging the framing of negative symptoms as passive manifestations of diminished capacity.

Background: We conducted a randomised controlled trial to evaluate the efficacy of enhancing social recovery from First Episode Psychosis (FEP) by augmenting Early Intervention Service (EIS) provision with Social Recovery Therapy (SRT). The primary hypothesis was that SRT plus EIS would lead to improvements in social recovery. Methods: SUPEREDEN3 was an assessor blind randomised controlled trial. It was conducted at 4 specialist Early Intervention Services across the UK. Participants had (a) been clients of Early Intervention Services for 12-30 months; and (b) showed persistent and severe social disability defined as engaged in less than 30 hours per week of structured activity. Participants were randomised 1:1. Assessment of outcomes was conducted at baseline, 9 months (post intervention) and 15 month follow up. The primary outcome was time spent in structured activity at 9 months. The trial is registered (ISRCTN61621571). Findings: 75 (49%) of 154 participants were assigned to SRT plus EIS and 79 (51%) were assigned to EIS alone. At 9 months 143 participants (93%) provided data on the primary outcome. Randomisation to SRT plus EIS was associated with an increase in structured activity of 8.1 hours greater than EIS alone (95% CI 2.5 to 13.6; p = 0.0050). Jointly modelling loss to follow up and secondary outcomes provided supportive evidence of continued effects of SRT plus EIS. Interpretation: The findings show a clinically important benefit of enhanced social recovery for the SRT plus EIS group on the primary outcome of structured activity. Funding: National Institute for Health Research (NIHR).

Background: Provision of early intervention services has increased the rate of social recovery in patients with first-episode psychosis; however, many individuals have continuing severe and persistent problems with social functioning. We aimed to assess the efficacy of early intervention services augmented with social recovery therapy in patients with first-episode psychosis. The primary hypothesis was that social recovery therapy plus early intervention services would lead to improvements in social recovery. Methods: We did this single-blind, phase 2, randomised controlled trial (SUPEREDEN3) at four specialist early intervention services in the UK. We included participants who were aged 16-35 years, had non-affective psychosis, had been clients of early intervention services for 12-30 months, and had persistent and severe social disability, defined as engagement in less than 30 h per week of structured activity. Participants were randomly assigned (1:1), via computer-generated randomisation with permuted blocks (sizes of four to six), to receive social recovery therapy plus early intervention services or early intervention services alone. Randomisation was stratified by sex and recruitment centre (Norfolk, Birmingham, Lancashire, and Sussex). By necessity, participants were not masked to group allocation, but allocation was concealed from outcome assessors. The primary outcome was time spent in structured activity at 9 months, as measured by the Time Use Survey. Analysis was by intention to treat. This trial is registered with ISRCTN, number ISRCTN61621571. Findings: Between Oct 1, 2012, and June 20, 2014, we randomly assigned 155 participants to receive social recovery therapy plus early intervention services (n=76) or early intervention services alone (n=79); the intention-to-treat population comprised 154 patients. At 9 months, 143 (93%) participants had data for the primary outcome. Social recovery therapy plus early intervention services was associated with an increase in structured activity of 8·1 h (95% CI 2·5-13·6; p=0·0050) compared with early intervention services alone. No adverse events were deemed attributable to study therapy. Interpretation: Our findings show a clinically important benefit of enhanced social recovery on structured activity in patients with first-episode psychosis who received social recovery therapy plus early intervention services. Social recovery therapy might be useful in improving functional outcomes in people with first-episode psychosis, particularly in individuals not motivated to engage in existing psychosocial interventions targeting functioning, or who have comorbid difficulties preventing them from doing so. Funding: National Institute for Health Research.

Aim Duration of untreated psychosis (DUP) is considered as a key prognostic variable in psychosis. Yet, it is unclear whether a longer DUP causes worse outcomes or whether reported associations have alternative explanations. Methods Data from 2 cohorts of patients with first episode psychosis were used (n = 2134). Measures of DUP were assessed at baseline and outcomes at 12 months. Regression models were used to investigate the associations between DUP and outcomes. We also investigated whether any associations were replicated using instrumental variables (IV) analysis to reduce the effect of residual confounding and measurement bias. Results There were associations between DUP per 1‐year increase and positive psychotic symptoms (7.0% in symptom score increase 95% confidence interval (CI) 4.0%, 10.0%, P < .001), worse recovery (risk difference [RD] 0.78, 95%, CI 0.68, 0.83, P < .001) and worse global functioning (0.62 decrease in functioning score 95% CI −1.19, −0.04, P = .035). There was no evidence of an association with negative psychotic symptoms (1.0%, 95%, CI −2.0%, 5.0%, P = .455). The IV analysis showed weaker evidence of associations in the same direction between DUP per 1‐year increase and positive psychotic symptoms, recovery and global functioning. However, there was evidence of an inverse association with negative psychotic symptoms (decrease of 15.0% in symptom score 95% CI −26.0%, −3.0%, P = .016). Conclusions We have confirmed previous findings of a positive association between positive psychotic symptoms, global functioning and recovery and DUP using regression analysis. IV analysis shows some support for these findings. Future investigation using IV analysis should be repeated in large data sets.