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Perez J, Russo DA, Stochl J, et al. Understanding causes of and developing effective interventions for schizophrenia and other psychoses. Southampton (UK): NIHR Journals Library; 2016 Mar. (Programme Grants for Applied Research, No. 4.2.)

Cover of Understanding causes of and developing effective interventions for schizophrenia and other psychoses

Understanding causes of and developing effective interventions for schizophrenia and other psychoses.

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Work package 5: follow-up of referrals of individuals identified as being at high risk for psychosis

The Prospective Analysis of At-risk mental states and Transitions into psycHosis

Research aims

The first aim of this study was to establish the prevalence of transition from HR mental states into FEP. We then aimed to describe and compare the characteristics of people with HR mental states who transitioned into FEP and the characteristics of those who did not. This would facilitate effective responses with better assessments and more focused interventions. Secondary objectives included various epidemiological and clinical analyses that would (1) contribute to an enhanced delineation of people at HR who are more likely to develop a full psychotic illness and (2) allow comparisons between people at HR and HVs, especially with regard to possible causal factors tied to sociodemographic and comorbid clinical characteristics, substance use and trauma history. Finally, we aimed to describe the morbidity and the effect on social functioning and quality of life of HR states, which are sometimes seen by services as merely predictors of FEP rather than as highly troublesome mental health conditions themselves.

Methods for data collection

All individuals at HR for psychosis living and detected in Cambridgeshire and Peterborough, including those identified by GPs or 16+ educational institutions in the LEGS cRCT, were offered a systematic follow-up in the context of this prospective, naturalistic study. Participants between the ages of 16 and 35 years were referred to our offices through a number of different routes (GPs, schools, relatives, friends). Candidates were initially assessed by both a psychiatrist and an experienced non-medical clinician trained in the CAARMS questionnaire,11 which is used to detect individuals at HR for psychosis. This was already routine practice in the CAMEO EIS. Individuals who met criteria for HR were invited to take part in the study and written consent was obtained.

A total of 60 help-seeking HR participants were followed up for 2 years from the initial referral date. Interestingly, all help-seeking HR individuals referred to us were willing to be followed up in the context of this study. However, as stated below, we encountered difficulties in retaining some of them for the whole follow-up period. During this period they were asked to attend nine interviews (at baseline and then every 3 months until the end of the study) at which they completed structured interviews and questionnaires under the direction of a clinical researcher. These questionnaires targeted different domains such as sociodemographic characteristics, diagnosis, psychiatric morbidity, trauma history, substance use and functioning, among others. The interviews took place in our CAMEO offices in Cambridge and Peterborough, at GP practices or in participants’ homes.

A random sample of 60 HVs matched for age (16–35 years), sex and geographical location was recruited by using the Postcode Address File® (PAF) provided by the Royal Mail. Addresses within the same three-digit postcodes as those of cases were picked at random and sent a letter inviting residents aged 16–35 years to participate. This methodology for finding comparison subjects had been successfully used in the ÆSOP study.6

Healthy volunteers underwent the same battery of questionnaires at baseline, 1 year and the end of the follow-up period unless they were, themselves, diagnosed as HR. In this case they would be offered the same number of interviews, questionnaires and possible clinical interventions as the HR individuals. HVs were offered £50 as a reward for taking part in the study and an incentive of £50 if they completed the interviews. Table 3 provides a sociodemographic comparison between HR and HV participants in the PAATH study.

TABLE 3

TABLE 3

Sociodemographic comparison between HR and HV participants in the PAATH study

Challenges of the Prospective Analysis of At-risk mental states and Transitions into psycHosis study

The process of identifying participants

Young people referred to and assessed by CAMEO but who were not experiencing a FEP were offered a follow-up interview including an assessment using the CAARMS to confirm or refute whether or not they met the criteria for HR for psychosis. Those who met the criteria were invited to another interview at which the outcome of their assessment was explained and they were provided with information about participation in the PAATH study. The study was explained in detail, drawing attention to the fact that there would be no treatment or intervention. It was also explained that participants would be seen over a period of 24 months, once every 3 months, undergoing mental state monitoring in the form of a selection of psychometric tools. It was difficult to describe the required involvement without sounding as though the participants were being asked to give up their time for no obvious advantage or direct therapeutic benefit. No payment was offered to participants but it was explained that by participating in the research they would have their symptoms monitored very carefully. Should the symptoms worsen they could be seen promptly by the psychiatrist leading the research. This provided some incentive because they would be seen much sooner without having to go through the usual route of referral by their GP back into secondary services.

Participant attrition

We implemented a variety of strategies to retain participant involvement in the PAATH study. Despite achieving a good rapport with many of the participants, keeping in touch with them after the baseline session and encouraging them to continue the 3-monthly assessment sessions was a real challenge. This was probably in part because they were generally a mobile, transient young population.

Lack of clinical follow-up by mental health services

Although a high proportion of those meeting the criteria for HR were signposted on to other services for support [e.g. Improving Access to Psychological Therapies (IAPT) service or locality mental health teams], some participants did not engage with the other service at the outset or soon dropped out. Therefore, members of the research team may have been the only mental health professionals seeing the young person. We implemented protocols to take clinical risk issues into account. Clear guidelines were followed, should any clinical crisis occur. However, because the CAMEO team is not funded to work with HR individuals it did create confusion with regard to clinical responsibility. Other mental health teams could mistakenly believe the participant to be under the care of the CAMEO team rather than participating solely in a research study, despite our best efforts to make it very clear in our clinical documentation that this was not the case. Some PAATH participants would inform other mental health professionals that they were ‘under CAMEO’, erroneously giving the impression that they were being treated, without understanding the confusion that this created. To try and solve this potential confusion, we sent a clear explanation of the situation of the participants with regard to clinical responsibility to any mental health professionals involved and to the participants’ GPs. Standard letters were sent out to the referrers or to our clinical colleagues in other secondary care teams as appropriate.

Respondent fatigue

At baseline and thereafter at 6-monthly intervals a batch of 10 assessment tools was administered to each participant. This process took approximately 2 hours for each participant. It was difficult at times to keep the participants engaged with such a lengthy session. Several of the assessment tools contained similar questions despite assessing different aspects of the participants’ mental health and this caused frustration for the participants. Moreover, several of the tools themselves were lengthy, especially some of the self-completing assessments. At times, much encouragement and support was required to ensure that participants completed all of the assessments. We always tried to complete the whole batch in one session to prevent the possibility that participants would drop out, resulting in missing data.

The potential therapeutic effect of monitoring

It was inevitable that working relationships would be formed between the participants and the research clinicians during the months of assessment. Seeing someone every 3 months for 2 years resulted in significant monitoring of their mental health. This resulted in a certain amount of understanding of their current situation and any issues or difficulties that they were having in their lives. Although no overt or deliberate therapeutic intervention was provided, the continuity of contact and necessary interest in the participants’ well-being resulted in a relationship that it could be argued was therapeutic in itself and this may have influenced the course of the participants’ illness to some degree.

For the researchers it became increasingly frustrating that we were seeing many young people for whom there was no appropriate service available. Services are still divided between child and adolescent and adult mental health teams. Therefore, young people have no access to a service that provides specialist, non-stigmatising and youth-friendly approaches to working with mental health problems in young adults.

Referrals to Improving Access to Psychological Therapies in primary care

The majority of young HR individuals that we evaluated and followed up over the course of our programme indicated a strong preference to be treated in primary care rather than in a specialist mental health service. Interestingly, during our programme the NHS implemented in primary care one of the most important innovations in mental health services in recent decades: the IAPT programme [see www.iapt.nhs.uk (accessed 19 January 2016)]. This programme massively increased access to psychological treatments for anxiety and depression in primary care across England, promoting the use of talking therapies based on cognitive–behavioural therapy (CBT) approved by the National Institute for Health and Care Excellence (NICE).

Given the high prevalence of depression and anxiety in the HR individuals assessed in our services, we made a number of referrals (n = 66) to IAPT services. Many of them (n = 22; 33%) were not accepted because IAPT therapists were not appropriately trained to provide psychological therapies to people experiencing psychotic-like experiences, even if these were in the context of depression and anxiety. Of those who were accepted (n = 44; 67%) for treatment by IAPT services, a significant proportion (n = 25; 57%) disengaged after one or two therapy sessions. This uncovered the need to tailor IAPT CBT to engage and treat individuals with these clinical presentations, enhancing engagement, assessment of complex problems and management of psychotic-like experiences by de-catastrophising and normalising, as also recommended in NICE guidelines for schizophrenia.33

Prevalence of transition from high risk to first-episode psychosis over 2 years

Key findings

Only three out of 60 (5%) of our HR sample made a full transition to a psychotic disorder based on structured clinical diagnosis (10% when CAARMS11 criteria were employed) over the 2-year follow-up period. This was an unexpectedly low figure given our prior beliefs at the beginning of the programme in 2008, but is in line with the results of other studies published over recent years, including the Early Detection and Intervention Evaluation for people at risk of psychosis (EDIE-Two) study,7 a RCT of CBT for young people with HR mental states in which we were a study site. Overall, the transition in the intervention and control groups was < 10%. This is a really important finding for young people with HR mental states – they are not at very HR of transition to a FEP over 2 years and the term ‘high risk’ is almost a misnomer. Rather, services can focus on the mental health problems that they have in addition to their psychotic experiences, largely depression and anxiety (see Psychiatric morbidity in the high-risk sample).

Thus, it is important not only to pay attention to the evolution of HR individuals but also to thoroughly understand the type and severity of the psychopathology and the psychological and demographic characteristics of these presentations as an independent morbid population cluster. The development of specific care pathways or beneficial interventions for this population is urgently required.

Strengths

The epidemiologically principled design, the standardised assessment with the CAARMS11 and the 2-year follow-up are particular strengths of this study.

Limitations

The study is relatively small with low precision in the prevalence of transitions to FEP. Recruiting a sample large enough to lead to a step change in power and precision (e.g. 10 times as many) would be a huge challenge requiring multicentre working. Participation in the PAATH study could indirectly involve the provision of non-specific clinical care. One-to-one sessions with a supportive research clinician every 3 months could reduce stress and subsequently the likelihood of conversion into frank psychotic disorders. This may have reduced the number of transitions.

Recommendations for future research

The inclusion of a follow-up component in future research in this area with a more sophisticated approach to outcome than merely HR, FEP or normal is recommended. These states all have a wide range of expression, with a kaleidoscopic variability over the medium term in some people. Studies equipped to capture this would allow the relationships between psychotic experiences and other psychopathology to be more clearly understood and more effective management to be devised.

Psychiatric morbidity in the high-risk sample

See Appendix 9 for the published report of this work.34

Research aims

To ensure that appropriate care pathways and interventions are put in place that benefit people at HR for psychosis, the type and severity of psychopathology in this group must be understood. The aims of this study were to describe the clinical and functional characteristics of young people at HR for psychosis. We compared their level of global functioning, occupational status and quality of life with those of a sample of HVs recruited from the same geographical area.

Methods for data collection

We collected sociodemographic information, clinical morbidity measures including the Positive and Negative Syndrome Scale (PANSS),35 the Beck Depression Inventory version II (BDI-II),36 the Beck Anxiety Inventory (BAI),37 the Young Mania Rating Scale (YMRS)38 and the Yale–Brown Obsessive Compulsive Scale (YBOCS),39 functioning measures including the Global Assessment of Functioning (GAF)40 and occupational status, as well as subjective quality of life measured by the Manchester Short Assessment of Quality of Life (MANSA)41 for 60 HR individuals and 45 HVs. Although the final sample total for the HV group in the PAATH study was 60, this paper was published before recruitment was complete; therefore, the HV sample includes only 45 participants.

Analysis

All comparisons were made using the chi-squared test or Fisher’s exact test for categorical variables and the t-test or Mann–Whitney U-test for continuous variables.

Key findings

Individuals at HR are a heterogeneous group with members commonly having more than one psychiatric disorder, mainly depression and/or anxiety or anxiety-related states such as obsessive–compulsive disorder. In contrast with previous cohorts, individuals at clinical HR in our sample were affected by mild psychotic symptoms. In addition to psychotic symptoms, a wide range of serious psychiatric disorders, suicidal ideation/intention, depressive and anxiety symptoms, low levels of quality of life and employment status impede the global functioning of those at HR.

High-risk individuals had poorer functioning with significantly lower GAF scores for symptoms and disability than HVs (both p < 0.001). There was a statistically significant higher prevalence of moderate/severe depression (p < 0.001 and p = 0.025, respectively), anxiety (p < 0.001), obsessive–compulsive behaviours (p < 0.001) and suicidality (p < 0.001) in HR individuals than in HVs. Therefore, a HR mental state may be associated not only with an increased risk for psychosis but also other psychiatric disorders (Table 4). Indeed, linked psychometric analyses by the authors (JS, JP, TJC and PBJ) in other population samples indicated that psychotic experiences measure the severe end of a common mental distress factor, which is consistent with these results.42

TABLE 4

TABLE 4

Clinical comparison between HR individuals and HVs in the PAATH study

This prominently poor global functioning and quality of life (Table 5) combined with a significant risk of suicidality justifies special attention from mental health services to develop appropriate care pathways.

TABLE 5

TABLE 5

Functioning and quality of life comparison between HR individuals and HVs in the PAATH study

Limitations

A chronicity criterion should have been used to determine any differences in psychopathological profiles between individuals with longer and shorter durations of HR symptoms.

The study was cross-sectional and therefore it was not possible to identify causal relationships between the HR state, psychiatric morbidity and impaired functioning.

Recommendations for future research

Rather than exclusively focusing on the treatment and/or prevention of psychosis, clinical interventions with individuals at HR identified in EISs should aim at targeting a broader range of psychopathology, especially mood and anxiety symptoms.

Substance use

See Appendix 10 for the published report of this work.43

Research aims

The role of substance use in the development of HR for psychosis or its impact on the transition to full psychotic presentations is overlooked in the literature. The aim of this study was to describe in detail past and current substance use in HR individuals and compare this profile with that of a random sample of HVs recruited from the same geographical area.

Methods for data collection

We recorded information on alcohol and substance use profiles for both groups, including identification of abuse/dependence and influence on psychotic-like experiences. Additionally, differences between HR individuals and HVs were assessed for sex, ethnicity, occupational status, age of lifetime first substance use and prevalence and frequency of substance use.

Analysis

To compare the two groups a two-sample t-test was used for age and Fisher’s exact test was used for sex, ethnicity and occupational status. Fisher’s exact test was also used for assessing the differences between substance use distributions and patterns. The Wilcoxon signed-rank test was employed for non-normally distributed continuous variables (age of lifetime first substance use, frequency of substance use). Box plots were used for graphical representation of the differences in frequency of substance use.

Key findings

High-risk individuals were significantly younger than HVs when they started using alcohol and drugs (p = 0.014). This may be important as harmful effects of drugs may differ according to brain development, with younger brains and minds being more vulnerable to deleterious effects. The prevalence of HR substance use was generally similar to that of HV substance use except for past polydrug use, which was higher for HR individuals. HR polydrug users experimented with a wider range of substances than HV polydrug users. Choice of substance was similar when comparing HR individuals’ and HVs’ current and past use. Alcohol was the most frequently reported substance used in both groups. This was different from previous findings in which cannabis was the most commonly used substance.44 Cannabis was the most widely used drug in both groups, the use of other illicit substances being considerably lower; the least used substances for both groups were sedatives and opiates.

None of the HR individuals or HVs met the criteria for a Diagnostic and Statistical Manual of Mental Disorders, 4th edition, text revision (DSM-IV TR)45 substance use disorder or dependence. Thus, the HR substance use profile in our sample was significantly different from that of FEP patients in our region at the time of their referral to CAMEO. The pattern of comparatively low use in people with HR mental states could have some influence on psychotic-like experiences but not on transition to a frank psychotic disorder.

The main difference between HR individuals and HVs was the frequency of substance use. Current frequency of use was significantly higher in HR individuals than in HVs for alcohol (p = 0.001) and cannabinoids (p = 0.03) (Figure 7). None of our HR group used cannabis daily. This was contrary to many reports in the literature regarding HR individuals, in which around 60% of participants used these substances.44 Frequency of substance use for HR individuals was similar for current and past use whereas HVs were more likely to have had a period in the past when they used these substances more frequently (see Figure 7). This sustained substance use over a protracted period could be more deleterious than a shorter period of increased use. The higher frequency of substance use in HR individuals combined with a significantly younger age of first use could contribute to the development of psychotic-like experiences.

FIGURE 7. Frequency of substance use in HR individuals and HVs in the PAATH study.

FIGURE 7

Frequency of substance use in HR individuals and HVs in the PAATH study. (a) Current frequency of substance use; and (b) past frequency of substance use.

Limitations

The short follow-up period in this study could explain the low transition rate. In addition, the 3 monthly follow-ups may have been therapeutic and consequently reduced the likelihood of transition. The sociodemographic differences between our groups could also have influenced the findings. HVs were significantly older than HR individuals. In addition, as male sex is associated with substance use in patients and psychotic disorders in the general population, the slightly higher proportion of males in the HR group may have influenced the substance use profiles.

Recommendations for future research

The pattern of substance use by each individual following their referral to CAMEO was not closely monitored. Future research should include a prospective follow-up to show any changes in patterns of substance use and identify any associations with incidence of psychotic experiences over time.

Substance use in HR individuals requires a greater emphasis and a more detailed consideration in future studies. All of our studies are from secondary analyses in a relatively small sample; the younger age of onset of use in the HR group may be important and, chiming with findings from other studies44 including birth cohorts, merits further enquiry at clinical and biological levels.

History of psychological, physical and sexual trauma

See Appendix 11 for the published report of this work.46

Research aims

Differences in the experience of trauma such as severity, frequency and age at trauma exposure could result in different responses among individuals and explain the likelihood of developing particular psychiatric symptoms. The aim of this study was to compare the characteristics of the trauma history between young people at HR for psychosis and a sample of HVs recruited from the same geographical area to determine which are more likely to be associated with HR mental states.

Methods for data collection

The Trauma History Screen (THS)47 was used to enable an assessment of the number and perceived intensity of adverse life events and age at trauma exposure. The BDI-II36 and BAI37 were also used to assess the relationship between these factors and depression and anxiety.

Analysis

Fisher’s exact test was used to compare demographic information and negative binomial regression was used for the comparison of the total number of traumas and the age at which trauma occurred.

Poisson regression and the t-test were used to compare individual traumas and the intensity of trauma respectively. Relationships between age at which trauma occurred, number and intensity of traumas, BDI-II score and BAI score were explored with Pearson correlations. Logistic regression was used to assess the influence of age at trauma exposure and the intensity and number of traumas with regard to the presence of HR mental states. We also presented graphical comparisons of both groups using box plots.

Key findings

High-risk participants had a higher incidence of trauma and reported repeated exposure to trauma compared with HVs. Traumatic events involving physical abuse with intention to harm accounted for the largest proportion of reported trauma for both groups and showed the largest difference between HVs and HR participants. Traumatic events involving sexual abuse were uncommon in both groups.

High-risk participants experienced significantly more traumatic events than HVs (p ≤ 0.001) but equivalent distress in relation to these events. Although up to 70% of individuals endorsed experiencing distress, in both groups 30–40% of traumatic experiences were not considered to be emotionally distressing. There was only a single case of post-traumatic stress disorder in the whole sample. The perceived intensity of trauma could be a future predictor of psychopathology other than psychosis.

First incidents of trauma and the total number of traumas (p < 0.001) occurred at an earlier age for HR participants, who also experienced significantly more traumas during the developmental period between the ages of 0 and 8 years (p ≤ 0.001) (Figure 8). HVs experienced more traumas between the ages of 25 and 35 years and higher instances of trauma occurred between the ages of 9 and 24 years than between the ages of 0 and 8 years. Both incidences of trauma and age at which trauma occurred were the most likely predictors of becoming HR, not the degree of distress reported as a result of the trauma. Higher age for trauma exposure and lack of sexual abuse could be ameliorating factors for the HR individuals in this study.

FIGURE 8. Box plots showing (a) the distribution of traumatic events; (b) the intensity of trauma; and (c) the age at trauma exposure for HR and HV participants in the PAATH study.

FIGURE 8

Box plots showing (a) the distribution of traumatic events; (b) the intensity of trauma; and (c) the age at trauma exposure for HR and HV participants in the PAATH study.

Higher levels of anxiety (p ≤ 0.001) and depression (p ≤ 0.001) were found in our HR group. Combined with the very low transition rates to date, this could be interpreted as a lack of diagnostic specificity and predictive value in the HR model. A HR mental state is not necessarily a specific marker for psychosis. The prevalent co-presence of anxiety and depression in this group indicates that trauma may play a role in this manifestation of symptoms.

Limitations

Trauma was measured only using the respondents’ subjective information and not corroborated by independent information. Using a combination of methods would yield the most accurate record of trauma. A valid measure of distress should have been used to elucidate any relationships between distress, trauma, anxiety and psychotic experiences/symptoms.

Although the THS47 does examine trauma involving physical abuse as a child and events that induce feelings of fear, helplessness and horror, there is no specific question concerning bullying. It is possible that a large proportion of traumatic experiences were missed because of this omission.

Recommendations for future research

We need to understand the emotional impact of trauma on the subjective perceptions of the individual. This can extend our understanding of why particular events cause traumatic stress in particular individuals.

To enable differentiation between psychotic-like experiences that may reflect dissociative responses to trauma and genuine prodromal psychotic presentations, trauma characteristics in individuals at clinical HR should be thoroughly assessed routinely.

First-rank symptoms

See Appendix 12 for the published report of this work.48

Research aims

Kurt Schneider49 considered certain types of psychotic experience of first-rank importance in deciding whether or not a psychotic syndrome was schizophrenia. These ‘first-rank symptoms’ (FRSs) remain influential in operational diagnostic criteria today, but there is little work evaluating their significance in HR mental states or even whether or not they occur there at all. Would they predict transition from HR to FEP?

The aims of this study were to describe (1) the prevalence of FRSs among individuals at HR; (2) the association between FRSs and transition to full-blown psychosis; and (3) the level of adjustment of individuals at HR and with FRSs during their childhood (aged 6–11 years) in terms of social and academic functioning. Comparisons were made between a sample of individuals at HR who were referred to an EIS and HVs recruited from the same geographical area.

Methods for data collection

All subjects were assessed by senior research clinicians using the MINI12 and the PANSS.35 FRSs were defined according to Kurt Schneider’s49 original classification and information was collected from the PANSS,35 CAARMS11 and clinical reports. Early premorbid functioning was measured using the Premorbid Adjustment Scale (PAS).50 We grouped individuals by number and type of FRSs and analysed transitions to full-blown psychosis over a 2-year follow-up period. We also correlated the general social and functional adjustment of these individuals during their childhood (aged 6–11 years) with the future development of HR mental states and FRSs.

Analysis

Fisher’s exact test was used for comparing the categorical sociodemographic variables; for age the t-test was used. The Wilcoxon signed-rank test was used to compare PAS domains between HR individuals and HVs. Fisher’s exact test was also used to investigate associations between the FRSs in HR individuals and transitions to psychosis.

Key findings

At least one FRS was present in 43.3% of HR individuals and 21.6% of HR individuals had more than one FRS. Auditory hallucinations and passivity experiences were the most commonly reported (Figure 9).

FIGURE 9. Distribution and frequency of FRSs in HR individuals in the PAATH study.

FIGURE 9

Distribution and frequency of FRSs in HR individuals in the PAATH study.

Except for passivity experiences, the presence of one or more FRS was not significantly associated with transition to FEP. Compared with HVs, HR individuals, especially those with FRSs, had poorer premorbid functioning and adjustment as children across educational, social and peer relationship domains; however, this was not associated with FEP 2 years later (Figure 10).

FIGURE 10. Comparison of PAS domains (aged 6–11 years) between HR individuals, HVs and a subgroup of HR individuals with FRSs in the PAATH study.

FIGURE 10

Comparison of PAS domains (aged 6–11 years) between HR individuals, HVs and a subgroup of HR individuals with FRSs in the PAATH study. Q1: sociability and withdrawal; Q2: peer relationships; Q3: scholastic performance; Q4: adaptation to school. (more...)

Strengths

The study was controlled, including both HVs and help-seeking HR individuals. The longitudinal design and high retention rates over 2 years made it possible to address the limitations associated with cross-sectional studies.

Limitations

The sample size did not allow further adjustment for comorbid mental disorders, which may have shed light on specific associations between level of impairment and increased risk for non-psychotic mental disorders.

It was possible that early premorbid adjustment was subject to recall bias because of the retrospective measure employed. In addition, conversion rates to psychosis could have been higher if follow-up had been longer than 2 years.

Studies with larger samples will be required to replicate findings regarding associations between specific FRSs and future conversions to psychosis, especially the relevance of those FRSs that were absent in our sample (somatic hallucinations and delusional perceptions).

Insights from the clinical team

In Appendix 13 we include a subjective view from the researchers and clinicians who were on the ground delivering the programme and collecting the data. We share this perspective, which could be acquired only through the process of operationalising this programme, reflecting on the merit, worth and significance of our work and providing insights that we hope will guide future research.

Inter-relation between aspects of the programme

It is noteworthy that the elements of our research plan mostly run in parallel, reinforcing each other to successfully achieve most of our aims by the time that this programme ended.

We also significantly enhanced some aspects of the programme through an efficient use of available resources. For example, we systematically followed all individuals at HR for psychosis in the context of a separate, naturalistic, observational design, which is described in Work package 5. Furthermore, this study was linked with several epidemiological and neurobiological research projects, representing an example of efficiencies in science.

The Prospective Analysis of At-risk mental states and Transitions into psycHosis study as an example of efficiency in health research

As previously mentioned, the PAATH study enhanced the original grant application through an efficient use of available resources. This study was not only aligned with other epidemiological projects (see Work package 3) but also nurtured neurobiological projects, creating a remarkably efficient research network around it that included backwards translation to investigate biological mechanisms underlying the HR state. HR individuals have not often been studied and so this group of 60 research volunteers represented a remarkable resource for other studies. This development was particularly important as the programme grant application did not consider cognitive or neurobiological examinations in the HR sample, which would add valuable information and provide a more comprehensive evaluation of this population cluster. Thus, the NIHR funding had an impact beyond our programme.

Some of these more biological projects that rely on our programme are briefly described in the following sections, including the title, chief investigator and aims. All of these projects were adopted onto the NIHR portfolio.

Neurobiological factors underlying the onset of psychosis

Chief investigators

Professor Philip McGuire and Dr Paul Allen, Institute of Psychiatry, London, UK.

Funder

Wellcome Trust, UK.

Aims

The key objective of this study is to examine the relationship between the medial temporal lobe and glutamatergic, gamma-aminobutyric acid (GABA)ergic and dopaminergic dysfunction in people at HR of psychosis. A further aim is to determine whether or not neuroimaging measures of these factors can be used in a clinical setting to predict the risk of later transition to psychosis in individuals at HR for psychosis.

The influence of cortisol levels on cognitive function and psychotic symptoms in patients with at-risk mental states for psychosis

Chief investigators

Professors Paul Fletcher and Ian Goodyer with Dr Veronika Dobler, University of Cambridge, Cambridge, UK.

Funder

Wellcome Trust, UK.

Aims

The proposed research focuses on particular aspects of the stress–diathesis model by further defining cognitive deficits and exploring the differential impact of variation in circulating cortisol levels (as a biological marker of stress) on current cognitive function in HR. This will be examined in three inter-related studies:

  • study 1 – the influence of physiologically induced stress on cognitive function in patients with at-risk mental states for psychosis and age- and sex-matched controls
  • study 2 – cognitive and perceptual processing deficits in HR
  • study 3 – functional magnetic resonance imaging (fMRI) analysis of brain responses during reward learning processes before and after the induction of stress in HR individuals and age- and sex-matched control subjects.

The learning study

Chief investigator

Dr Graham Murray, University of Cambridge, Cambridge, UK.

Funder

Medical Research Council, UK.

Aims

This study aims to identify brain regions involved in simple learning tasks in patients and HVs using fMRI. Any group differences may inform on both the neurophysiological and the neuropsychological features of mild psychosis. Better insights into these features will be of benefit to patients and their families in making sense of otherwise strange and potentially frightening symptoms and will lead to more informed and appropriate use of currently available treatments and may ultimately lead to novel pharmacological and/or psychological treatments for psychosis.

Copyright © Queen’s Printer and Controller of HMSO 2016. This work was produced by Perez et al. under the terms of a commissioning contract issued by the Secretary of State for Health. This issue may be freely reproduced for the purposes of private research and study and extracts (or indeed, the full report) may be included in professional journals provided that suitable acknowledgement is made and the reproduction is not associated with any form of advertising. Applications for commercial reproduction should be addressed to: NIHR Journals Library, National Institute for Health Research, Evaluation, Trials and Studies Coordinating Centre, Alpha House, University of Southampton Science Park, Southampton SO16 7NS, UK.

Included under terms of UK Non-commercial Government License.

Bookshelf ID: NBK350244

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