Intelligence trajectories in individuals at ultra-high risk for psychosis: An 8-year longitudinal analysis.

Cognitive impairment is a well-documented predictor of transition to a full-threshold psychotic disorder amongst individuals at ultra-high risk (UHR) for psychosis. However, less is known about whether change in cognitive functioning differs between those who do and do not transition. Studies to date have not examined trajectories in intelligence constructs (e.g., acquired knowledge and fluid intelligence), which have demonstrated marked impairments in individuals with schizophrenia. This study aimed to examine intelligence trajectories using longitudinal data spanning an average of eight years, where some participants completed assessments over three time-points. Participants (N = 139) at UHR for psychosis completed the Wechsler Abbreviated Scale of Intelligence (WASI) at each follow-up. Linear mixed-effects models mapped changes in WASI Full-Scale IQ (FSIQ) and T-scores on Vocabulary, Similarities, Block Design, and Matrix Reasoning subtests. The sample showed stable and improving trajectories for FSIQ and all subtests. There were no significant differences in trajectories between those who did and did not transition to psychosis and between individuals with good and poor functional outcomes. However, although not significant, the trajectories of the acquired knowledge subtests diverged between transitioned and non-transitioned individuals (ß = -0.12, 95 % CI [-0.29, 0.05] for Vocabulary and ß = -0.14, 95 % CI [-0.33, 0.05] for Similarities). Overall, there was no evidence for long-term deterioration in intelligence trajectories in this UHR sample. Future studies with a larger sample of transitioned participants may be needed to explore potential differences in intelligence trajectories between UHR transition groups and other non-psychosis outcomes.

Investigation of structural brain correlates of neurological soft signs in individuals at ultra-high risk for psychosis.

Increased severity of neurological soft signs (NSS) in schizophrenia have been associated with abnormal brain morphology in cerebello-thalamo-cortical structures, but it is unclear whether similar structures underlie NSS prior to the onset of psychosis. The present study investigated the relationship between severity of NSS and grey matter volume (GMV) in individuals at ultra-high risk for psychosis (UHR) stratified for later conversion to psychosis. Structural T1-weighted MRI scans were obtained from 56 antipsychotic-naïve UHR individuals and 35 healthy controls (HC). The UHR individuals had follow-up data (mean follow-up: 5.2 years) to ascertain clinical outcome. Using whole-brain voxel-based morphometry, the relationship between NSS and GMV at baseline was assessed in UHR, HC, as well as individuals who later transitioned (UHR-P, n = 25) and did not transition (UHR-NP, n = 31) to psychosis. NSS total and subscale scores except motor coordination were significantly higher in UHR compared to HC. Higher signs were also found in UHR-P, but not UHR-NP. Total NSS was not associated with GMV in the whole sample or in each group. However, in UHR-P individuals, greater deficits in sensory integration was associated with lower GMV in the left cerebellum, right insula, and right middle frontal gyrus. In conclusion, NSS are present in UHR individuals, particularly those who later transitioned to a psychotic disorder. While these signs show little overall variation with GMV, the association of sensory integration deficits with lower GMV in UHR-P suggests that certain brain areas may be implicated in the development of specific neurological abnormalities in the psychosis prodrome.

Impaired olfactory ability associated with larger left hippocampus and rectus volumes at earliest stages of schizophrenia: A sign of neuroinflammation?

Impaired olfactory identification has been reported as a first sign of schizophrenia during the earliest stages of illness, including before illness onset. The aim of this study was to examine the relationship between volumes of these regions (amygdala, hippocampus, gyrus rectus and orbitofrontal cortex) and olfactory ability in three groups of participants: healthy control participants (Ctls), patients with first-episode schizophrenia (FE-Scz) and chronic schizophrenia patients (Scz). Exploratory analyses were performed in a sample of individuals at ultra-high risk (UHR) for psychosis in a co-submission paper (Masaoka et al., 2020). The relationship to brain structural measures was not apparent prior to psychosis onset, but was only evident following illness onset, with a different pattern of relationships apparent across illness stages (FE-Scz vs Scz). Path analysis found that lower olfactory ability was related to larger volumes of the left hippocampus and gyrus rectus in the FE-Scz group. We speculate that larger hippocampus and rectus in early schizophrenia are indicative of swelling, potentially caused by an active neurochemical or immunological process, such as inflammation or neurotoxicity, which is associated with impaired olfactory ability. The volumetric decreases in the chronic stage of Scz may be due to degeneration resulting from an active immune process and its resolution.

Longitudinal Cognitive Performance in Individuals at Ultrahigh Risk for Psychosis: A 10-year Follow-up.

It remains unclear whether the onset of psychosis is associated with deterioration in cognitive performance. The aim of this study was to examine the course of cognitive performance in an ultrahigh risk (UHR) cohort, and whether change in cognition is associated with transition to psychosis and change in functioning. Consecutive admissions to Personal Assessment and Crisis Evaluation (PACE) Clinic between May 1994 and July 2000 who had completed a comprehensive cognitive assessment at baseline and follow-up were eligible (N = 80). Follow-up ranged from 7.3 to 13.4 years (M = 10.4 years; SD = 1.5). In the whole sample, significant improvements were observed on the Similarities (P = .03), Information (P < .01), Digit Symbol Coding (P < .01), and Trail Making Test-B (P = .01) tasks, whereas performance on the Rey Auditory Verbal Learning Test (Trials 1-3) declined significantly (P < .01) over the follow-up period. Change in performance on cognitive measures was not significantly associated with transition status. Taking time to transition into account, those who transitioned after 1 year showed significant decline on Digit Symbol Coding, whereas those who did not transition improved on this measure (P = .01; effect size [ES] = 0.85). Small positive correlations were observed between improvements in functioning and improvements in performance on Digit Symbol Coding and Arithmetic (0.24, P = .03 and 0.28, P = .01, respectively). In summary, the onset of psychosis was not associated with deterioration in cognitive ability. However, specific findings suggest that immediate verbal learning and memory, and processing speed may be relevant domains for future risk models and early intervention research in UHR individuals.

Reasons for referral and findings of clinical neuropsychological assessment in youth with mental illness: A clinical file audit.

Study aims were to 1) determine the characteristics and reasons for referral for Clinical Neuropsychological Assessment (CNA) and 2) characterize the findings and recommendations contained in the CNA reports, of clients attending a youth mental health service. File audit of all CNA reports (N = 140) of youth attending a mental health service. Cognitive performances on neuropsychological tests that were administered to >50% of clients were examined. Referral reasons, findings, and recommendations for future treatment were coded and described from neuropsychological files. Age of clients referred for CNA ranged from 13-29, the majority were male (62.5%), referred primarily from the early psychosis clinic (63.2%), and had a mean number of 3.5 presenting problems. Cognitive performances ranged from extremely low to very superior. Mean number of reasons for referral was 2, with treatment recommendation (55%) and diagnostic clarification (50.7%) being the most common. Mean number of findings from CNA was 5.8; most commonly, a diagnosis of clinically meaningful cognitive impairment (85%), followed by a recommendations for additional services/investigations (77.1%). CNA provides diagnostic clarification and treatment recommendations for youth receiving mental health treatment. Future studies should examine the cost-effectiveness, implementation, and objective impact of CNA in clinical practice.

Ventricular volumes across stages of schizophrenia and other psychoses.

OBJECTIVE: Ventricular enlargement is common in established schizophrenia; however, data from ultra high-risk for psychosis and first-episode psychosis studies are inconclusive. This study aims to investigate ventricular volumes at different stages of psychosis. METHODS: Ventricular volumes were measured using a semi-automated and highly reliable method, for 89 established schizophrenia, 162 first-episode psychosis, 135 ultra high-risk for psychosis and 87 healthy controls using 1.5T magnetic resonance images. Clinical outcome diagnoses for ultra high-risk for psychosis were evaluated at long-term follow-up (mean: 7.5 years). RESULTS: Compared to controls, we identified significant ventricular enlargement of 36.2% in established schizophrenia ( p < 0.001). Ventricular enlargement was not significant in first-episode psychosis (6%) or ultra high-risk for psychosis (-3%). Examination across stages of schizophrenia-spectrum diagnoses subgroups revealed a significant linear trend ( p = 0.006; established schizophrenia = 36.2%, first-episode psychosis schizophrenia = 18.5%, first-episode psychosis schizophreniform = -4.2% and ultra high-risk for psychosis-schizophrenia converters = -18.5%). CONCLUSION: Ventricular enlargement is apparent in patients with established schizophrenia but is not a feature at the earliest stages of illness (ultra high-risk for psychosis and first-episode psychosis). Further research is needed to fully characterize the nature and timing of ventricular volume changes early in the course of illness and how these changes impact outcomes.

Improving vocational outcomes in first-episode psychosis by addressing cognitive impairments using Cognitive Adaptation Training.

BACKGROUND: Cognitive Adaptation Training (CAT) uses compensatory strategies and environmental supports to support cognitive impairments and improve functioning. CAT may be useful for addressing vocational recovery in first-episode psychosis (FEP) because cognitive impairments are common and vocational recovery is a key goal of young people with FEP. OBJECTIVE: To describe clinical observations and practice experience when delivering CAT with FEP clients and explore potential benefits via objective outcome measures for improving vocational outcomes. METHODS: In this pilot study, five FEP participants received 9 months of CAT. Participant goals and functional needs and clinical observations were recorded. Formal measures of functioning, quality of life and motivation were independently administered pre- and post-intervention. RESULTS: Vocational recovery (education, employment) was found to be a primary functional goal of FEP participants. Accordingly, CAT had a strong focus on vocational functioning, including functional domains required for successful work or educational outcomes, such as organization and planning, transportation and activities of daily living. Factors of clinical importance when delivering CAT with the FEP participants included cognitive heterogeneity, family involvement, flexibility in compensatory and environmental supports used, and experience of stigma. Improvements from baseline to post-intervention were observed on most measures, with the largest improvements seen in global functioning (including vocation), planning and organization, and quality of life. CONCLUSIONS: CAT is an intervention that appears well suited to addressing vocational functioning in FEP, but larger controlled trials are needed.

Feasibility and acceptability of cognitive adaptation training for first-episode psychosis.

AIM: Cognitive and functioning impairments are present early in the course of psychotic disorder and remain one of the greatest treatment challenges. Cognitive adaptation training (CAT) is a compensatory approach to psychosocial intervention that is underpinned by a model that incorporates the role of cognition in daily functioning. CAT has established effectiveness in chronic schizophrenia but has received limited investigation in first-episode psychosis (FEP). The aim of this study was to examine the feasibility and acceptability of CAT in young people with FEP. METHODS: This was a single-arm feasibility study of CAT conducted at the Early Psychosis Prevention and Intervention Centre, Melbourne, Australia. Five FEP participants received manually guided CAT from a fully trained CAT therapist. A range of feasibility and acceptability measures were recorded throughout the study, including participant and case manager satisfaction ratings. RESULTS: All participants completed the CAT intervention and session attendance rates were very high (95.3%). Participants and their case managers indicated strong satisfaction with CAT as indicated by positive mean ratings on all satisfaction items, although there was a greater range in the participant ratings. Importantly, CAT did not have a negative effect on existing case management, with case managers reporting that CAT enhanced their treatment. CONCLUSIONS: This study provides evidence that CAT is a highly feasible and acceptable intervention in FEP, which may be easily integrated within existing services. The effectiveness of CAT in improving functional outcomes in FEP is worthy of investigation in a larger trial.

Intensive case management for high-risk patients with first-episode psychosis: service model and outcomes.

BACKGROUND: The first episode of psychosis is a crucial period when early intervention can alter the trajectory of the young person's ongoing mental health and general functioning. After an investigation into completed suicides in the Early Psychosis Prevention and Intervention Centre (EPPIC) programme, the intensive case management subprogramme was developed in 2003 to provide assertive outreach to young people having a first episode of psychosis who are at high risk owing to risk to self or others, disengagement, or suboptimal recovery. We report intensive case management model development, characterise the target cohort, and report on outcomes compared with EPPIC treatment as usual. METHODS: Inclusion criteria, staff support, referral pathways, clinical review processes, models of engagement and care, and risk management protocols are described. We compared 120 consecutive referrals with 50 EPPIC treatment as usual patients (age 15-24 years) in a naturalistic stratified quasi-experimental real-world design. Key performance indicators of service use plus engagement and suicide attempts were compared between EPPIC treatment as usual and intensive case management, and psychosocial and clinical measures were compared between intensive case management referral and discharge. FINDINGS: Referrals were predominately unemployed males with low levels of functioning and educational attainment. They were characterised by a family history of mental illness, migration and early separation, with substantial trauma, history of violence, and forensic attention. Intensive case management improved psychopathology and psychosocial outcomes in high-risk patients and reduced risk ratings, admissions, bed days, and crisis contacts. INTERPRETATION: Characterisation of intensive case management patients validated the clinical research focus and identified a first episode of psychosis high-risk subgroup. In a real-world study, implementation of an intensive case management stream within a well-established first episode of psychosis service showed significant improvement in key service outcomes. Further analysis is needed to determine cost savings and effects on psychosocial outcomes. Targeting intensive case management services to high-risk patients with unmet needs should reduce the distress associated with pathways to care for patients, their families, and the community. FUNDING: National Health & Medical Research Council and the Colonial Foundation.

Investigation of orbitofrontal sulcogyral pattern in chronic schizophrenia.

Abnormalities of orbitofrontal cortex (OFC) pattern type distribution have been associated with schizophrenia-spectrum disorders. We investigated OFC pattern type in a large sample of chronic schizophrenia patients and healthy controls. We found an increased frequency of Type II but no difference in Type I or III folding pattern in the schizophrenia group in comparison to controls. Further large studies are required to investigate the diagnostic specificity of altered OFC pattern type and to confirm the distribution of pattern type in the normal population.

Altered depth of the olfactory sulcus in ultra high-risk individuals and patients with psychotic disorders.

A shallow olfactory sulcus has been reported in schizophrenia, possibly reflecting abnormal forebrain development during early gestation. However, it remains unclear whether this anomaly exists prior to the onset of psychosis and/or differs according to illness stage. In the current study, magnetic resonance imaging was used to investigate the length and depth of the olfactory sulcus in 135 ultra high-risk (UHR) individuals [of whom 52 later developed psychosis (UHR-P) and 83 did not (UHR-NP)], 162 patients with first-episode psychosis (FEP), 89 patients with chronic schizophrenia, and 87 healthy controls. While there was no group difference in the length of the sulcus, UHR-P subjects had significantly shallower olfactory sulcus at baseline as compared with UHR-NP and control subjects. The depth of this sulcus became increasingly more superficial as one moved from UHR-P subjects to FEP patients to chronic schizophrenia patients. Finally, the depth of the olfactory sulcus in the UHR-P subjects was negatively correlated with the severity of negative symptoms. These findings suggest that the altered depth of the olfactory sulcus, which exists before psychosis onset, could be predictive of transition to psychosis, but also suggest ongoing changes of the sulcus morphology during the course of the illness.

Long-term follow-up of a group at ultra high risk ("prodromal") for psychosis: the PACE 400 study.

IMPORTANCE: The ultra high-risk (UHR) criteria were introduced to prospectively identify patients at high risk of psychotic disorder. Although the short-term outcome of UHR patients has been well researched, the long-term outcome is not known. OBJECTIVE: To assess the rate and baseline predictors of transition to psychotic disorder in UHR patients up to 15 years after study entry. DESIGN: Follow-up study of a cohort of UHR patients recruited to participate in research studies between 1993 and 2006. SETTING: The Personal Assessment and Crisis Evaluation (PACE) clinic, a specialized service for UHR patients in Melbourne, Australia. PARTICIPANTS: Four hundred sixteen UHR patients previously seen at the PACE clinic. MAIN OUTCOMES AND MEASURES: Transition to psychotic disorder, as measured using the Comprehensive Assessment of At-Risk Mental States, Brief Psychiatric Rating Scale/Comprehensive Assessment of Symptoms and History, or state public mental health records. RESULTS: During the time to follow-up (2.4-14.9 years after presentation), 114 of the 416 participants were known to have developed a psychotic disorder. The highest risk for transition was within the first 2 years of entry into the service, but individuals continued to be at risk up to 10 years after initial referral. The overall rate of transition was estimated to be 34.9% over a 10-year period (95% CI, 28.7%-40.6%). Factors associated with transition included year of entry into the clinic, duration of symptoms before clinic entry, baseline functioning, negative symptoms, and disorders of thought content. CONCLUSIONS AND RELEVANCE: The UHR patients are at long-term risk for psychotic disorder, with the highest risk in the first 2 years. Services should aim to follow up patients for at least this period, with the possibility to return for care after this time. Individuals with a long duration of symptoms and poor functioning at the time of referral may need closer monitoring. Interventions to improve functioning and detect help-seeking UHR patients earlier also may be indicated.

Clinical neuropsychology within adolescent and young-adult psychiatry: conceptualizing theory and practice.

Historically, clinical neuropsychology has made significant contributions to the understanding of brain-behavior relationships, particularly in neurological conditions. During the past several decades, neuropsychology has also become established as an important discipline in psychiatric settings. Cognition is increasingly recognized as being core to psychiatric illnesses and predictive of functional outcomes, augmenting theories regarding symptomatology and illness progression. Adult-type psychiatric disorders (including schizophrenia and other psychotic, mood, anxiety, eating, substance-related, and personality disorders) typically emerge during adolescence or young adulthood, a critical neurodevelopmental period. Clinical neuropsychological assessment in adolescent psychiatric patients is particularly valuable in informing clinical formulation and intervention and can be therapeutic across a number of levels. This article articulates the theoretical considerations and practical challenges and applications of clinical neuropsychology within adolescent and young-adult psychiatry. The importance of considering the neurodevelopmental context and its relationship to current theoretical models underpinning clinical practice are discussed.

Phenylthiocarbamide (PTC) perception in ultra-high risk for psychosis participants who develop schizophrenia: testing the evidence for an endophenotypic marker.

Reports suggesting that schizophrenia participants are more likely to be phenylthiocarbamide (PTC) non-tasters when compared to controls have recently been controversial. If supported, a genetic-based phenotypic variation in PTC taster status is implicated, suggesting a greater illness risk for those participants with recessive alleles for the TAS2R38 receptor. Should PTC insensitivity be a schizophrenia endophenotype, then it would be expected in follow-up of ultra high-risk for psychosis participants who later develop schizophrenia (UHR-S). UHR-S was hypothesised to show reduced PTC sensitivity compared to those who were previously at risk, but did not transition (UHR-NP). PTC perception was assessed in 219 UHR participants at long-term follow-up, of whom 53 had transitioned to psychosis (UHR-P) during the follow-up period. Fifteen of the 219 participants were diagnosed with schizophrenia. Seventy-eight had a family history of psychotic disorder. No differences in PTC taster status were found in UHR participants based upon transition to psychosis status, schizophrenia diagnosis, or family history of schizophrenia. This report indicates that schizophrenia development among UHR participants is not associated with PTC tasting deficits and fails to support previous findings that inability to detect the bitter taste of PTC is a schizophrenia endophenotype.

The impact of cannabis use on cognitive functioning in patients with schizophrenia: a meta-analysis of existing findings and new data in a first-episode sample.

Cannabis use is highly prevalent among people with schizophrenia, and coupled with impaired cognition, is thought to heighten the risk of illness onset. However, while heavy cannabis use has been associated with cognitive deficits in long-term users, studies among patients with schizophrenia have been contradictory. This article consists of 2 studies. In Study I, a meta-analysis of 10 studies comprising 572 patients with established schizophrenia (with and without comorbid cannabis use) was conducted. Patients with a history of cannabis use were found to have superior neuropsychological functioning. This finding was largely driven by studies that included patients with a lifetime history of cannabis use rather than current or recent use. In Study II, we examined the neuropsychological performance of 85 patients with first-episode psychosis (FEP) and 43 healthy nonusing controls. Relative to controls, FEP patients with a history of cannabis use (FEP + CANN; n = 59) displayed only selective neuropsychological impairments while those without a history (FEP - CANN; n = 26) displayed generalized deficits. When directly compared, FEP + CANN patients performed better on tests of visual memory, working memory, and executive functioning. Patients with early onset cannabis use had less neuropsychological impairment than patients with later onset use. Together, these findings suggest that patients with schizophrenia or FEP with a history of cannabis use have superior neuropsychological functioning compared with nonusing patients. This association between better cognitive performance and cannabis use in schizophrenia may be driven by a subgroup of "neurocognitively less impaired" patients, who only developed psychosis after a relatively early initiation into cannabis use.

Differential olfactory identification in children with autism and Asperger's disorder: a comparative and longitudinal study.

Key theories of autism implicate orbitofrontal cortex (OFC) compromise, while olfactory identification (OI) deficits are associated with OFC dysfunction. This study aimed to complete a 5-year follow-up of children with high-functioning autism (HFA) who previously lacked the normal age-OI association; and compare unirhinal-OI in children with HFA, Asperger's disorder (ASP), and controls. While both HFA and controls had improved birhinal-OI at follow-up, reduced OI in some HFA participants suggested OFC deterioration and heterogeneous OFC development. Unirhinal-OI was impaired in HFA but not ASP relative to controls, suggesting orbitofrontal compromise in HFA but integrity in ASP. Differing IQ-OI relationships existed between HFA and ASP. Findings support the hypothesis of separate neurobiological underpinnings in ASP and HFA, specifically differential orbitofrontal functioning.

Olfactory sensitivity: functioning in schizophrenia and implications for understanding the nature and progression of psychosis.

Prefrontal neural processes maturing during neurodevelopment parallel normal improvement in higher order olfactory processing (identification) from childhood. Hence, disorders of adolescence such as schizophrenia that implicate prefrontal regions are associated with olfactory identification deficits in the presence of relatively intact lower order olfactory processing capacity (sensation) and mediating neural processes (limbic system). Understanding the linear neural trajectory of olfactory processing can assist in detecting the location, nature, and extent of early compromise of circuitry implicated in neurodevelopmental disorders such as psychosis. More recently, relatively discreet odorant sensitivity problems in schizophrenia have been described and these appear related to secretion of malodorous compounds. These findings have significant implications for future genetic prediction of this disorder.

Grey and white matter abnormalities are associated with impaired spatial working memory ability in first-episode schizophrenia.

Spatial working memory (SWM) dysfunction has been suggested as a trait marker of schizophrenia and implicates a diffuse network involving prefrontal, temporal and parietal cortices. However, structural abnormalities in both grey and white matter in relation to SWM deficits are largely unexplored. The current magnetic resonance imaging (MRI) study examined this relationship in a sample of young first-episode schizophrenia (FES) patients using a whole-brain voxel-based method. SWM ability of 21 FES patients and 41 comparable controls was assessed by the CANTAB SWM task. Using an automated morphometric analysis of brain MRI scans, we assessed the relationship between SWM abilities and both grey matter volume and white matter density in both groups. Our findings demonstrated the different directionality of the association between SWM errors and grey matter volume in left frontal regions and white matter tracts connecting these regions with temporal and occipital areas between FES patients and controls. This suggests that the substrate underpinning the normal variability in SWM function in healthy individuals may be abnormal in FES, and that the normal neurodevelopmental processes that drive the development of SWM networks are disrupted in schizophrenia.

Neurobiological markers of illness onset in psychosis and schizophrenia: The search for a moving target.

In this review, we describe neuropsychological and brain imaging findings in the early stages of psychosis and schizophrenia. We focus on recent clinical high-risk studies and consider whether the evidence supports these as 'endophenotypes' of a vulnerability to the illness or as 'biomarkers' of illness onset and transition. The findings suggest that there are a number of processes at psychosis onset that may represent biomarkers of incipient illness. These neurobiological indices particularly implicate the integrity of frontal and temporal cortices, which may or may not be related to the genetics of psychosis (i.e. potential 'endophenotypes'). However, these brain regions are dynamically changing during normal maturation, meaning that any putative neurobiological markers identified at the earliest stages of illness may be relatively unstable.We suggest that, while such measures maybe readily identified as potential neurobiological markers of established illness, they are inconsistent at (or around) the time of illness onset when assessed cross-sectionally. Instead,identification of more valid risk markers may require longitudinal assessment to ascertain normal or abnormal trajectories of neurodevelopment. Accordingly, we assert that the current conceptualisations of potential biomarkers and/or 'endophenotypes' for schizophrenia may need to be reconsidered in the context of normal and abnormal brain maturational processes at the time of onset of psychotic disorders.