Future-Directed Thinking In First Episode Psychosis

Psychosis encompasses a constellation of symptoms that have far-reaching social, physical and functional consequences for sufferers. One of the key clinical concerns in the management of psychotic illnesses is the risk of suicide, which is greatest in the early stages of psychosis. Hopelessness is consistently associated with risk for suicide but as a concept it is not well defined and is not specific enough to be of use in prediction of suicide. Future-directed thinking, particularly regarding positive future events, constitutes an aspect of hopelessness that is closely associated with risk for suicide. This study employed the Future Thinking Task to investigate whether future-directed thinking in first episode psychosis is significantly different from that of matched controls in performance or content, and to clarify the nature of its association with suicide risk in this patient group. In addition, the association of future-directed thinking with the negative symptoms of psychosis was investigated. The results showed that individuals with psychosis were impaired in future-directed thinking globally, particularly with respect to the coming year. Specific deficits were shown in the domains of relations with other people and personal development and understanding. Associations were shown between future-directed thinking and suicide, and reduced positive future-directed thinking was shown to be strongly associated with increased severity of negative symptoms. The results suggest avenues for novel interventions to improve hopelessness, suicide risk and the severity of negative symptoms in psychotic illness, and thereby improve functional outcomes

Antipsychotic medication versus psychological intervention versus a combination of both in adolescents with first-episode psychosis (MAPS): a multicentre, three-arm, randomised controlled pilot and feasibility study

Background Evidence for the effectiveness of treatments in early-onset psychosis is sparse. Current guidance for the treatment of early-onset psychosis is mostly extrapolated from trials in adult populations. The UK National Institute for Health and Care Excellence has recommended evaluation of the clinical effectiveness and cost-effectiveness of antipsychotic drugs versus psychological intervention (cognitive behavioural therapy [CBT] and family intervention) versus the combination of these treatments for early-onset psychosis. The aim of this study was to establish the feasibility of a randomised controlled trial of antipsychotic monotherapy, psychological intervention monotherapy, and antipsychotics plus psychological intervention in adolescents with first-episode psychosis. Methods We did a multicentre pilot and feasibility trial according to a randomised, single-blind, three-arm, controlled design. We recruited participants from seven UK National Health Service Trust sites. Participants were aged 14–18 years; help-seeking; had presented with first-episode psychosis in the past year; were under the care of a psychiatrist; were showing current psychotic symptoms; and met ICD-10 criteria for schizophrenia, schizoaffective disorder, or delusional disorder, or met the entry criteria for an early intervention for psychosis service. Participants were assigned (1:1:1) to antipsychotics, psychological intervention (CBT with optional family intervention), or antipsychotics plus psychological intervention. Randomisation was via a web-based randomisation system, with permuted blocks of random size, stratified by centre and family contact. CBT incorporated up to 26 sessions over 6 months plus up to four booster sessions, and family intervention incorporated up to six sessions over 6 months. Choice and dose of antipsychotic were at the discretion of the treating consultant psychiatrist. Participants were followed up for a maximum of 12 months. The primary outcome was feasibility (ie, data on trial referral and recruitment, session attendance or medication adherence, retention, and treatment acceptability) and the proposed primary efficacy outcome was total score on the Positive and Negative Syndrome Scale (PANSS) at 6 months. Primary outcomes were analysed by intention to treat. Safety outcomes were reported according to as-treated status, for all patients who had received at least one session of CBT or family intervention, or at least one dose of antipsychotics. The study was prospectively registered with ISRCTN, ISRCTN80567433. Findings Of 101 patients referred to the study, 61 patients (mean age 16·3 years [SD 1·3]) were recruited from April 10, 2017, to Oct 31, 2018, 18 of whom were randomly assigned to psychological intervention, 22 to antipsychotics, and 21 to antipsychotics plus psychological intervention. The trial recruitment rate was 68% of our target sample size of 90 participants. The study had a low referral to recruitment ratio (around 2:1), a high rate of retention (51 [84%] participants retained at the 6-month primary endpoint), a high rate of adherence to psychological intervention (defined as six or more sessions of CBT; in 32 [82%] of 39 participants in the monotherapy and combined groups), and a moderate rate of adherence to antipsychotic medication (defined as at least 6 consecutive weeks of exposure to antipsychotics; in 28 [65%] of 43 participants in the monotherapy and combined groups). Mean scores for PANSS total at the 6-month primary endpoint were 68·6 (SD 17·3) for antipsychotic monotherapy (6·2 points lower than at randomisation), 59·8 (13·7) for psychological intervention (13·1 points lower than at randomisation), and 62·0 (15·9) for antipsychotics plus psychological intervention (13·9 points lower than at randomisation). A good clinical response at 6 months (defined as ≥50% improvement in PANSS total score) was achieved in four (22%) of 18 patients receiving antipsychotic monotherapy, five (31%) of 16 receiving psychological intervention, and five (29%) of 17 receiving antipsychotics plus psychological intervention. In as-treated groups, serious adverse events occurred in eight [35%] of 23 patients in the combined group, two [13%] of 15 in the antipsychotics group, four [24%] of 17 in the psychological intervention group, and four [80%] of five who did not receive any treatment. No serious adverse events were considered to be related to participation in the trial. Interpretation This trial is the first to show that a head-to-head clinical trial comparing psychological intervention, antipsychotics, and their combination is safe in young people with first-episode psychosis. However, the feasibility of a larger trial is unclear because of site-specific recruitment challenges, and amendments to trial design would be needed for an adequately powered clinical and cost-effectiveness trial that provides robust evidence

A three-arm feasibility randomised controlled trial comparing antipsychotic medication to psychological intervention to a combined treatment in adolescents with first episode psychosis: The Managing Adolescent first episode Psychosis Study (MAPS)

Background: The evidence base for treatments for early-onset psychosis (EOP) is limited and of low quality. Current guidance for the treatment of EOP is mostly extrapolated from trials in adult populations. NICE, in the United Kingdom (UK), make a specific research recommendation for the evaluation of clinical and cost-effectiveness of antipsychotics (AP), versus psychological intervention (cognitive behaviour therapy [CBT] and family intervention), versus combination treatment for EOP. The National Institute for Health Research (NIHR) in the UK commissioned this research to establish feasibility and acceptability of a definitive trial examining these three treatment options. Methods: We conducted a multi-site, Prospective Randomised Open Blinded Evaluation (PROBE) design, feasibility randomised controlled trial (RCT) comparing AP monotherapy with psychological intervention monotherapy (PI) plus a combination of these treatments in 14-18-year olds with a first episode of psychosis. We recruited participants from seven United Kingdom sites. Participants were followed-up at six and 12 months. Cognitive behavioural therapy incorporated up to 26 sessions over 6 months plus up to four booster sessions. Family intervention included up to six sessions over 6 months. Choice and dose of antipsychotic were at the discretion of the treating consultant psychiatrist. The primary outcome was feasibility data (recruitment, retention, acceptability) and the main effectiveness outcome was the Positive and Negative Syndrome Scale (PANSS) total score at 6 months. We conducted a repeated-measures analysis of the proposed primary outcome (PANSS) and the secondary outcome, the Questionnaire about the Process of Recovery (QPR) using a mixed effects model to account for the discrete timing of the follow-up assessments and adjusted for site. Safety outcomes were reported on the basis of as treated status defined as any one session of CBT or any one dose of APs; descriptive statistics are reported for safety outcomes. The study was prospectively registered on 27th February 2017, http://www.isrctn.com/ISRCTN80567433. Findings: 61 patients (aged 14-18 years; mean 16.3, SD 1.3) were recruited from 1st April 2017 to 31st October 2018, 18 were assigned to psychological intervention, 22 to antipsychotics and 21 to the combination. The feasibility of recruitment was unclear, since the trial only recruited 61 of a target of 90 participants. The study had a low referral: randomisation ratio (101:61), high rates of retention (>80%), high rates of adherence for psychological intervention (82.1%) defined as 6 or more sessions of CBT, and moderate rates of adherence for antipsychotic medication (65.1%), defined as 6 or more consecutive weeks of APs. The median number of sessions for CBT for those in the PI arm was 14 (IQR 9, 23) and 15 in the combined arm (IQR 9, 17). Of those in receipt of APs the mean duration that the participant remained on the medication was 31.5 weeks (SD 14.6, minimum 8.7 and maximum 52). There were no serious adverse events considered to be related to the trial. Interpretation: This is the first trial to show that it is safe to conduct a head-to-head clinical trial comparing psychological intervention with antipsychotics and the combination in people in young people with a first-episode psychosis. However, feasibility is unclear due to not meeting the recruitment progression criteria, so amendments to trial design are required in order to conduct an adequately powered clinical and cost effectiveness trial to provide robust evidence

Enhancing future-directed thinking in people with first-episode psychosis using a guided imagery intervention

Background and objectives Future-directed thinking (FDT) is associated with goal directed behaviour and may differ in people with psychosis compared to non-clinical controls. This study investigated whether guided imagery could enhance positive FDT in people with psychosis. Method Participants were 44 people experiencing a first episode of psychosis. They were assessed for negative and positive symptoms, FDT on the Future Thinking Task (FTT), depression, anxiety, autobiographical memory, verbal fluency and spontaneous use of imagery. They were randomised to either a positive or neutral imagery condition, before being retested on the FTT. Outcomes on the FTT were number of events generated, anticipated likelihood, anticipated affect and a composite score. Results Participants in the positive imagery condition generated significantly more positive events on the FTT compared with those in the neutral (F (1, 42) = 19.916, p < .001, ηp2 = 0.322). In both imagery conditions, likelihood ratings of positive events increased post-intervention. Positive and negative events were both perceived as less likely to occur the further into the future they were, and positive events were anticipated to be more positive and negative events more negative, the further into the future they were. Limitations The participants in this study experienced relatively low levels of symptoms, and therefore caution should be used when applying these results to people with greater symptomatology. Conclusions Positive guided imagery shows promise for enhancing positive FDT in people with first-episode psychosis. This intervention may offer a simple and effective method of enhancing engagement with the future, with potential implications for goal-directed behaviour

Functional dysconnectivity of corticostriatal circuitry as a risk phenotype for psychosis

IMPORTANCE: Dysregulation of corticostriatal circuitry has long been thought to be critical in the etiology of psychotic disorders, although the differential roles played by dorsal and ventral systems in mediating risk for psychosis have been contentious. OBJECTIVE: To use resting-state functional magnetic resonance imaging to characterize disease-related, risk-related, and symptom-related changes of corticostriatal functional circuitry in patients with first-episode psychosis and their unaffected first-degree relatives. DESIGN, SETTING, AND PARTICIPANTS: This case-control cross-sectional study was conducted at a specialist early psychosis clinic, GlaxoSmithKline Clinical Unit, and magnetic resonance imaging facility. Nineteen patients with first-episode psychosis, 25 of their unaffected first-degree relatives, and 26 healthy control subjects were included in this study. MAIN OUTCOMES AND MEASURES: Voxelwise statistical parametric maps testing differences in the strength of functional connectivity between 6 striatal seed regions of interest (3 caudate and 3 putamen) per hemisphere and all other brain regions. RESULTS: Disease-related changes, reflecting differences between patients and control subjects, involved widespread dysregulation of corticostriatal systems characterized most prominently by a dorsal-to-ventral gradient of hypoconnectivity to hyperconnectivity between striatal and prefrontal regions. A similar gradient was evident in comparisons between relatives and control subjects, identifying it as a genetically inherited risk phenotype. In patients, functional connectivity in risk-affected and disease-affected dorsal frontostriatal circuitry correlated with the severity of both positive and negative symptoms. CONCLUSIONS AND RELEVANCE: First-episode psychosis is associated with pronounced dysregulation of corticostriatal systems, characterized most prominently by hypoconnectivity of dorsal and hyperconnectivity of ventral frontostriatal circuits. These changes correlate with symptom severity and are also apparent in unaffected first-degree relatives, suggesting that they represent a putative risk phenotype for psychotic illness

Behavioural and molecular endophenotypes in psychotic disorders reveal heritable abnormalities in glutamatergic neurotransmission

This is the final published version. It first appeared at http://www.nature.com/tp/journal/v5/n3/full/tp201526a.html.Psychotic disorders such as schizophrenia are biologically complex and carry huge population morbidity due to their prevalence,\ud persistence and associated disability. Defined by features such as delusions and hallucinations, they involve cognitive dysfunction\ud and neurotransmitter dysregulations that appear mostly to involve the dopaminergic and glutamatergic systems. A number of\ud genetic and environmental factors are associated with these disorders but it has been difficult to identify the biological pathways\ud underlying the principal symptoms. The endophenotype concept of stable, heritable traits that form a mechanistic link between\ud genes and an overt expression of the disorder has potential to reduce the complexity of psychiatric phenotypes. In this study, we\ud used a genetically sensitive design with individuals with a first episode of psychosis, their non-affected first-degree relatives and\ud non-related healthy controls. Metabolomic analysis was combined with neurocognitive assessment to identify multilevel\ud endophenotypic patterns: one concerned reaction times during the performance of cognitive and emotional tests that have\ud previously been associated with the glutamate neurotransmission system, the other involved metabolites involved directly and\ud indirectly in the co-activation of the N-methyl-D-aspartate receptor, a major receptor of the glutamate system. These cognitive and\ud metabolic endophenotypes may comprise a single construct, such that genetically mediated dysfunction in the glutamate system\ud may be responsible for delays in response to cognitive and emotional functions in psychotic disorders. This focus on glutamatergic\ud neurotransmission should guide drug discovery and experimental medicine programmes in schizophrenia and related disorders.This study was funded by the\ud Mason Medical Research Trust, the Stanley Medical Research Institute, the\ud GlaxoSmithKlein and the Pinsent Darwin funding