Functional Outcome in People at High Risk for Psychosis Predicted by Thalamic Glutamate Levels and Prefronto-Striatal Activation

Little is known about the neurobiological factors that determine functional outcome in people at high risk for psychosis. We use multimodal neuroimaging to investigate whether cortical responses during a cognitive task and thalamic glutamate levels were associated with subsequent functional outcome. Sixty subjects participated: 27 healthy controls (CTRL) and 33 at ultrahigh risk (UHR) for psychosis. At baseline, cortical responses during a verbal fluency task were measured using functional Magnetic Resonance Imaging (fMRI) and proton Magnetic Resonance Spectroscopy (1H-MRS) was used to measure thalamic glutamate levels. The UHR subjects were then followed clinically for a mean duration of 18 months, and subdivided into “good” and “poor” functional outcome subgroups according to their Global Assessment of Function score at follow-up. UHR subjects with a poor functional outcome showed greater cortical and subcortical activation than UHR subjects with a good functional outcome. They also had lower levels of thalamic glutamate and showed a negative relationship between thalamic glutamate levels and prefrontal-striatal activation that was not present in the good functional outcome or control groups. In people at high risk for psychosis, their subsequent level of functioning may depend on the extent to which neurophysiological and neurochemical function is perturbed when they first present to clinical services.Key words: psychosis, ultra-high risk, functional outcomes, functional MRI, spectroscopy, glutamate     

Transition to Psychosis Associated With Prefrontal and Subcortical Dysfunction in Ultra High-Risk Individuals

Background: People at ultra high risk (UHR) of psychosis have an elevated risk of developing a psychotic disorder, but it is difficult to predict which individuals will make a transition to frank illness. We investigated whether functional magnetic resonance imaging (fMRI) in conjunction with a phonological fluency task at presentation could distinguish subjects who subsequently developed psychosis from those who did not. Methods: Sixty-five subjects (41 with an UHR and 24 healthy controls) were assessed at clinical presentation using fMRI, in conjunction with a verbal fluency task. [18F]-DOPA positron emission tomography (PET) data were also available in a subgroup of 21 UHR and 14 healthy controls subjects. UHR subjects were followed clinically for at least 2 years. Results: Compared with UHR subjects who did not become psychotic, UHR subjects who subsequently developed psychosis showed increased activation in bilateral prefrontal cortex (PFC), brainstem (midbrain/basilar pons), the left hippocampus, and greater midbrain-PFC connectivity. Furthermore, exploratory analysis of [18F]-DOPA PET data showed that transition to psychosis was associated with elevated dopaminergic function in the brainstem region. Conclusions: In people at high risk of psychosis, increased activation in a network of cortical and subcortical regions may predict the subsequent onset of illness. Functional neuroimaging, in conjunction with clinical assessment and other investigations, may facilitate the prediction of outcome in subjects who are vulnerable to psychosis.     

Neurological Soft Signs Predict Abnormal Cerebellar-Thalamic Tract Development and Negative Symptoms in Adolescents at High Risk for Psychosis: A Longitudinal Perspective

Introduction: There is an emerging consensus that neurological soft signs (NSS) may not be “soft” at all but rather may reflect neuropathy, particularly in the cerebellum and thalamus. However, our understanding of connective tract abnormalities is limited, and to date, there have been no investigations examining NSS and longitudinal white matter development during the prodrome. Mapping the correlates of NSS in ultrahigh-risk (UHR) youth offers potential for highlighting a viable biomarker as well as for advancing understanding of pathogenic processes during the adolescent risk period. Methods: A total of 68 (33 UHR and 35 healthy control) adolescents were assessed with an NSS inventory, structured interviews, and diffusion tensor imaging. Fractional anisotropy (FA) of theoretically relevant cerebellar-thalamic tracts was calculated (left/right superior cerebellar peduncles [SCPs]). Twelve months later, a subset of 30 (15 UHR and 15 control) participants returned for follow-up diffusion tension imaging/clinical assessments. Results: UHR youth exhibited elevated NSS across domains. While there were no group differences in the integrity of the SCPs at baseline, controls showed a normative increase while the UHR group showed a decrease in FA over 12 months. NSS predicted a longitudinal decrease in cerebellar-thalamic FA and elevations in negative but not positive symptoms 12 months later. Discussion: Findings of abnormal white matter development provide direct empirical evidence to support prominent neurodevelopmental theories. The predictive relationships between NSS and longitudinal cerebellar-thalamic tract integrity and negative symptom course provide insight into the role of cognitive dysmetria in the high-risk period and inform on a unique biomarker tied to core features underlying psychosis.Key words: neurological soft signs, psychosis, prodrome, UHR, DTI, superior cerebellar peduncle, cognitive dysmetria     

Learned Irrelevance and Associative Learning Is Attenuated in Individuals at Risk for Psychosis but not in Asymptomatic First-Degree Relatives of Schizophrenia Patients: Translational State Markers of Psychosis?

Learned irrelevance (LIrr) refers to a form of selective learning that develops as a result of prior noncorrelated exposures of the predicted and predictor stimuli. In learning situations that depend on the associative link between the predicted and predictor stimuli, LIrr is expressed as a retardation of learning. It represents a form of modulation of learning by selective attention. Given the relevance of selective attention impairment to both positive and cognitive schizophrenia symptoms, the question remains whether LIrr impairment represents a state (relating to symptom manifestation) or trait (relating to schizophrenia endophenotypes) marker of human psychosis. We examined this by evaluating the expression of LIrr in an associative learning paradigm in (1) asymptomatic first-degree relatives of schizophrenia patients (SZ-relatives) and in (2) individuals exhibiting prodromal signs of psychosis (“ultrahigh risk” [UHR] patients) in each case relative to demographically matched healthy control subjects. There was no evidence for aberrant LIrr in SZ-relatives, but LIrr as well as associative learning were attenuated in UHR patients. It is concluded that LIrr deficiency in conjunction with a learning impairment might be a useful state marker predictive of psychotic state but a relatively weak link to a potential schizophrenia endophenotype.     

Preventing the Second Episode: A Systematic Review and Meta-analysis of Psychosocial and Pharmacological Trials in First-Episode psychosis

Objective: The majority of first-episode psychosis (FEP) patients reach clinical remission; however, rates of relapse are high. This study sought to undertake a systematic review and meta-analysis of randomized controlled trials (RCTs) to determine the effectiveness of pharmacological and non-pharmacological interventions to prevent relapse in FEP patients. Methods: Systematic review and meta-analysis of RCTs. Results: Of 66 studies retrieved, 18 were eligible for inclusion. Nine studies investigated psychosocial interventions and 9 pharmacological treatments. The analysis of 3 RCTs of psychosocial interventions comparing specialist FEP programs vs treatment as usual involving 679 patients demonstrated the former to be more effective in preventing relapse (odds ratio [OR] = 1.80, 95% confidence interval [CI] = 1.31–2.48; P < .001; number needed to treat [NNT] = 10). While the analysis of 3 different cognitive-behavioral studies not specifically intended at preventing relapse showed no further benefits compared with specialist FEP programs (OR = 1.95, 95% CI = 0.76–5.00; P = .17), the combination of specific individual and family intervention targeted at relapse prevention may further improve upon these outcomes (OR = 4.88, 95% CI = 0.97–24.60; P = .06). Only 3 small studies compared first-generation antipsychotics (FGAs) with placebo with no significant differences regarding relapse prevention although all individual estimates favored FGAs (OR = 2.82, 95% CI = 0.54–14.75; P = .22). Exploratory analysis involving 1055 FEP patients revealed that relapse rates were significantly lower with second-generation antipsychotics (SGAs) compared with FGAs (OR = 1.47, 95% CI = 1.07–2.01; P < .02; NNT = 10). Conclusions: Specialist FEP programs are effective in preventing relapse. Cognitive-based individual and family interventions may need to specifically target relapse to obtain relapse prevention benefits that extend beyond those provided by specialist FEP programs. Overall, the available data suggest that FGAs and SGAs have the potential to reduce relapse rates. Future trials should examine the effectiveness of placebo vs antipsychotics in combination with intensive psychosocial interventions in preventing relapse in the early course of psychosis. Further studies should identify those patients who may not need antipsychotic medication to be able to recover from psychosis.     

Reduced Frontal Glutamate + Glutamine and N-Acetylaspartate Levels in Patients With Chronic Schizophrenia but not in Those at Clinical High Risk for Psychosis or With First-Episode Schizophrenia

Changes in brain pathology as schizophrenia progresses have been repeatedly suggested by previous studies. Meta-analyses of previous proton magnetic resonance spectroscopy (¹H MRS) studies at each clinical stage of schizophrenia indicate that the abnormalities of N-acetylaspartate (NAA) and glutamatergic metabolites change progressively. However, to our knowledge, no single study has addressed the possible differences in ¹H MRS abnormalities in subjects at 3 different stages of disease, including those at ultrahigh risk for psychosis (UHR), with first-episode schizophrenia (FES), and with chronic schizophrenia (ChSz). In the current study, 24 patients with UHR, 19 FES, 25 ChSz, and their demographically matched 3 independent control groups (n = 26/19/28 for the UHR, FES, and ChSz control groups, respectively) underwent ¹H MRS in a 3-Tesla scanner to examine metabolites in medial prefrontal cortex. The analysis revealed significant decreases in the medial prefrontal NAA and glutamate + glutamine (Glx) levels, specifically in the ChSz group as indexed by a significant interaction between stage (UHR/FES/ChSz) and clinical status (patients/controls) (P = .008). Furthermore, the specificity of NAA and Glx reductions compared with the other metabolites in the patients with ChSz was also supported by a significant interaction between the clinical status and types of metabolites that only occurred at the ChSz stage (P = .001 for NAA, P = .004 for Glx). The present study demonstrates significant differences in ¹H MRS abnormalities at different stages of schizophrenia, which potentially correspond to changes in glutamatergic neurotransmission, plasticity, and/or excitotoxicity and regional neuronal integrity with relevance for the progression of schizophrenia.Key words: anterior cingulate cortex, at-risk mental state, biomarkers, frontal lobe, magnetic resonance imaging, neurochemical abnormality     

Personality features in ultra-high risk for psychosis: A comparative study with schizophrenia and control subjects using the Temperament and Character Inventory-Revised (TCI-R)

Several variables have been identified as risk factors for conversion to overt psychosis in ultra-high risk for psychosis (UHR) individuals. Although almost two-thirds of them do not experience a transition to psychosis, they still exhibit functional disabilities. Other subjective developmental features may be useful for a more precise identification of individuals at UHR. Avoidant behaviors are consistently reported in schizophrenia and in UHR individuals and may be the reflection of a pattern of personality. Thus, personality features in UHR individuals deserves further research. The objective of the present study was to compare temperament and character dimensions between UHR individuals, patients with schizophrenia and healthy controls. One hundred participants (25 UHR individuals, 25 schizophrenia patients and 50 control subjects) where evaluated with the Temperament and Character Inventory-Revised (TCI-R). Univariate ANOVAs followed by Bonferroni tests were used. UHR individuals and schizophrenia patients exhibited higher levels of Harm Avoidance (HA) when compared to control subjects. For HA1 Anticipatory worry vs Uninhibited optimism and HA4 Fatigability & asthenia, UHR and schizophrenia groups showed similar scores and both groups were higher compared to control subjects. With respect to Cooperativeness (CO), UHR and schizophrenia reported lower scores than control subjects, in particular CO2 Empathy vs Social disinterest and CO3 Helpfulness vs unhelpfulness. This study replicates and extends the consideration of HA as a psychopathological related endophenotype and gives us further information of the possible role of personality features in the expression of some of the social dysfunctions observed both in prodromal subjects and schizophrenia patients.     

Impact of smoking Behavior on cognitive functioning in persons at risk for psychosis and healthy controls: A longitudinal study

BackgroundThe high prevalence of smoking in individuals who are at ultra-high risk (UHR) for psychosis is well known and moderate cognitive deficits have also been found in UHR. However, the association between smoking and cognition in UHR is unknown and longitudinal studies are lacking.MethodA cohort study with 330 UHR individuals and 66 controls was conducted, as part of the European network of national schizophrenia networks studying gene–environment interactions (EU-GEI). At baseline and after 6, 12, and 24 months, smoking behavior was assessed with the Composite International Diagnostic Interview and cognitive functioning with a comprehensive test battery. Linear mixed-effects analyses were used to examine the multicross-sectional and prospective associations between (change in) smoking behavior and cognitive functioning, accounting for confounding variables.ResultsAt baseline, 53% of UHR and 27% of controls smoked tobacco. Smoking UHR and controls did not significantly differ from nonsmoking counterparts on the tested cognitive domains (speed of processing, attention/vigilance, working memory, verbal learning, or reasoning/problem solving) across different assessment times. Neither smoking cessation nor initiation was associated with a significant change in cognitive functioning in UHR.ConclusionsNo associations were found between smoking and cognitive impairment in UHR nor in controls. However, the fact that one in every two UHR individuals report daily use of tobacco is alarming. Our data suggest that UHR have fewer cognitive impairments and higher smoking cessation rates compared to patients with first-episode psychosis found in literature. Implications to promote smoking cessation in the UHR stage need further investigation.     

Attribution,cognition and psychopathology in persistent insomnia disorder: outcome and mediation analysis from a randomized placebo-controlled trial of online cognitive behavioural therapy

ObjectivesInsomnia patients complain that mental events keep them awake. This study investigates how cognitive behavioural therapy (CBT) affects such events and considers how attributional, cognitive and psychopathological symptoms may mediate sleep improvement.MethodA pragmatic, parallel-group randomized controlled trial of 164 adults (120 F: (mean 49 years (18–78 years)) meeting Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-5) criteria for insomnia disorder, assigned to CBT (n = 55; 40 F), imagery relief therapy (IRT placebo; n = 55; 42 F), or treatment as usual (TAU; n = 54; 38 F), was conducted. CBT/IRT comprised six online sessions delivered by an animated therapist, with automated web/e-mail support. CBT users had access to a moderated community. TAU comprised ‘usual care’. Participants completed the Sleep Disturbance Questionnaire (SDQ), Glasgow Content of Thoughts Inventory (GCTI), Depression Anxiety and Stress Scales (DASS) and Sleep Condition Indicator (SCI) at baseline, post treatment and 8-week follow-up.ResultsThe sample was characterised by mental arousal, notably ‘trying too hard’ to sleep (SDQ), and by ‘sleep and sleeplessness’ and ‘rehearsal and planning’ thoughts (GCTI). Treatment effects were observed for all SDQ domains (e.g., CBT vs. IRT: d = 0.76 for ‘trying too hard’). CBT was also superior to IRT on the GCTI (e.g., ‘rehearsal and planning’, d = 0.62; ‘sleep and sleeplessness’, d = 0.74). CBT vs. TAU comparisons yielded larger effects, whereas placebo effects (IRT vs. TAU) were small to moderate. Hierarchical regression demonstrated partial mediation of SCI improvement by attributional and cognitive factors (R² = 21–27%) following CBT. Improvement in sleep efficiency appears to be independent of such factors.ConclusionOnline CBT modifies sleep-related attributions, night-time thought content and psychopathology. This process partly mediates improvement in DSM-5-defined insomnia.     

Altered resting-state connectivity in subjects at ultra-high risk for psychosis: an fMRI study

Background  

Individuals at ultra-high risk (UHR) for psychosis have self-disturbances and deficits in social cognition and functioning. Midline default network areas, including the medial prefrontal cortex and posterior cingulate cortex, are implicated in self-referential and social cognitive tasks. Thus, the neural substrates within the default mode network (DMN) have the potential to mediate self-referential and social cognitive information processing in UHR subjects.     

Three‐year course of clinical symptomatology in young people at ultra high risk for transition to psychosis

Velthorst E, Nieman DH, Klaassen RMC, Becker HE, Dingemans PM, Linszen DH, de Haan L. Three year course of clinical symptomatology in young people at ultra high risk for transition to psychosis. Objective: The investigation into the course of ultra high risk (UHR) symptomatology of those patients who eventually do not meet the psychosis‐threshold criteria within the 3‐year timeframe of the study. Method: The course of UHR symptoms, GAF score and employment status was investigated in 57 patients who did not make a transition to psychosis and who were examined within the Dutch Prediction of Psychosis Study in Amsterdam, the Netherlands. Results: At the 3‐ year follow‐up, 75% of the patients who did not make a transition to psychosis had remitted from UHR status. With a Generalized Estimation Equation Model it was shown that this group recovered from positive (F = 52.7, P < 0.0001), negative (F = 24.3, P < 0.0001), disorganization (F = 14.4, P < 0.0001) and general symptoms (F = 25.0, P < 0.0001) within the timeframe of the study. In addition, the level of global functioning and likelihood of having a job and/or education significantly improved. The largest improvements occurred within the first year. UHR symptoms did not re‐occur after improvement. Conclusion: With the current UHR criteria, a large percentage of the included subjects appear to have transitory complaints and dysfunctioning. A refinement of the UHR criteria may diminish the chance of including ‘false positives’ in future UHR studies.     

Do Psychological Interventions Work for Psychosis in Adolescents?

BackgroundThere is emerging evidence to show that psychological interventions such as cognitive remediation therapy (CRT), psychoeducation, family therapy, and group psychotherapies may be useful for adolescents with psychosis. The current review is on the effects of various psychological interventions for adolescents with psychosis compared with treatment as usual (TAU) or other psychological interventions.MethodsWe undertook a comprehensive search for all randomized controlled trials on the topic as per predefined criteria. For binary data, a standard estimation of risk ratio, and, for continuous data, the mean difference between groups were estimated. GRADE approach was used to assess studies. “Risk of Bias” was calculated, and finally random-effects model was used for analyses. ResultsThe review included 7 studies (n = 317). Two studies compared CRT and TAU with TAU alone. CRT showed improvement in short-term memory compared with those in the TAU group (relative risk 0.58, 95% CI 0.37 to 0.89, participants = 31, very low-certainty evidence). When comparing group psychosocial therapy with TAU, global state scores measured using Children’s Global Assessment Scale (CGAS) were clearly higher in the intervention arm (mean difference 5.10, 95% CI 1.35 to 8.85, participants = 56, very low-certainty evidence) as compared with the TAU group. None of the other interventions were found to be significantly effective for the treatment of psychosis in adolescents.ConclusionsEvidence suggests that psychological interventions may have beneficial effects in the treatment of adolescents with psychosis, but the evidence is of low or very low certainty.     

Clinical efficacy of individual cognitive therapy in reducing psychiatric symptoms in people at ultra-high risk for psychosis

Aim: Recently, cognitive therapy in people at ultra‐high risk (UHR) for psychosis has been reported to show modest treatment benefits. The aim of this study was to assess the feasibility and efficacy of cognitive therapy in reducing psychiatric symptoms in UHR people in Korea. Methods: We developed cognitive therapy for people at UHR for psychosis inspired by Morrison in 2004. Twenty‐two UHR subjects were assigned to cognitive therapy, and 18 subjects completed the 10‐session therapy. Psychopathology scores were assessed at baseline and post‐treatment. Results: Cognitive therapy significantly reduced the severity of psychopathology including positive, negative and depressive symptoms. The within‐group effect sizes indicated large treatment benefits for these psychopathologies. Conclusion: These findings suggest that cognitive therapy can be administered to people at UHR for psychosis in non‐western culture.     

Cognitive Biases Questionnaire for Psychosis

Objective:

The Cognitive Biases Questionnaire for psychosis (CBQp) was developed to capture 5 cognitive distortions (jumping to conclusions, intentionalising, catastrophising, emotional reasoning, and dichotomous thinking), which are considered important for the pathogenesis of psychosis. Vignettes were adapted from the Cognitive Style Test (CST),¹ relating to “Anomalous Perceptions” and “Threatening Events” themes.

Method:

Scale structure, reliability, and validity were investigated in a psychosis group, and CBQp scores were compared with those of depressed and healthy control samples.

Results:

The CBQp showed good internal consistency and test-retest reliability. The 5 biases were not independent, with a 2-related factor scale providing the best fit. This structure suggests that the CBQp assesses a general thinking bias rather than distinct cognitive errors, while Anomalous Perception and Threatening Events theme scores can be used separately. Total CBQp scores showed good convergent validity with the CST, but individual biases were not related to existing tasks purporting to assess similar reasoning biases. Psychotic and depressed populations scored higher than healthy controls, and symptomatic psychosis patients scored higher than their nonsymptomatic counterparts, with modest relationships between CBQp scores and symptom severity once emotional disorders were partialled out. Anomalous Perception theme and Intentionalising bias scores showed some specificity to psychosis.

Conclusions:

Overall, the CBQp has good psychometric properties, although it is likely that it measures a different construct to existing tasks, tentatively suggested to represent a bias of interpretation rather than reasoning, judgment or decision-making processes. It is a potentially useful tool in both research and clinical arenas.Key words: schizophrenia, thinking errors, delusions, hallucinations, cognitive behavior therapy for psychosis     

Reduced Binding Potential of GABA-A/Benzodiazepine Receptors in Individuals at Ultra-high Risk for Psychosis: An [18F]-Fluoroflumazenil Positron Emission Tomography Study

Background:

Altered transmission of gamma-aminobutyric acid (GABA), a major inhibitory neurotransmitter, may contribute to the development of schizophrenia. The purpose of the present study was to investigate the presence of GABA-A/benzodiazepine (BZ) receptor binding abnormalities in individuals at ultra-high risk (UHR) for psychosis in comparison with normal controls using [¹⁸F]-fluoroflumazenil (FFMZ) positron emission tomography (PET). In particular, we set regions of interest in the striatum (caudate, putamen, and nucleus accumbens) and medial temporal area (hippocampus and parahippocampal gyrus).

Methods:

Eleven BZ-naive people at UHR and 15 normal controls underwent PET scanning using [¹⁸F]-FFMZ to measure GABA-A/BZ receptor binding potential. The regional group differences between UHR individuals and normal controls were analyzed using Statistical Parametric Mapping 8 software. Participants were evaluated using the structured interview for prodromal syndromes and neurocognitive function tasks.

Results:

People at UHR demonstrated significantly reduced binding potential of GABA-A/BZ receptors in the right caudate.

Conclusions:

Altered GABAergic transmission and/or the imbalance of inhibitory and excitatory systems in the striatum may be present at the putative prodromal stage and play a pivotal role in the pathophysiology of psychosis.Key words: GABA, schizophrenia, ultra-high, risk for psychosis, caudate, PET, fluoroflumazenil     

Development and Validation of a Computerized Adaptive Assessment Tool for Discrimination and Measurement of Psychotic Symptoms

ObjectiveTime constraints limit the use of measurement-based approaches in research and routine clinical management of psychosis. Computerized adaptive testing (CAT) can reduce administration time, thus increasing measurement efficiency. This study aimed to develop and test the capacity of the CAT-Psychosis battery, both self-administered and rater-administered, to measure the severity of psychotic symptoms and discriminate psychosis from healthy controls.MethodsAn item bank was developed and calibrated. Two raters administered CAT-Psychosis for inter-rater reliability (IRR). Subjects rated themselves and were retested within 7 days for test-retest reliability. The Brief Psychiatric Rating Scale (BPRS) was administered for convergent validity and chart diagnosis, and the Structured Clinical Interview (SCID) was used to test psychosis discriminant validity.ResultsDevelopment and calibration study included 649 psychotic patients. Simulations revealed a correlation of r = .92 with the total 73-item bank score, using an average of 12 items. Validation study included 160 additional patients and 40 healthy controls. CAT-Psychosis showed convergent validity (clinician: r = 0.690; 95% confidence interval [95% CI]: 0.610–0.757; self-report: r = .690; 95% CI: 0.609–0.756), IRR (intraclass correlation coefficient [ICC] = 0.733; 95% CI: 0.611–0.828), and test-retest reliability (clinician ICC = 0.862; 95% CI: 0.767–0.922; self-report ICC = 0.815; 95%CI: 0.741–0.871). CAT-Psychosis could discriminate psychosis from healthy controls (clinician: area under the receiver operating characteristic curve [AUC] = 0.965, 95% CI: 0.945–0.984; self-report AUC = 0.850, 95% CI: 0.807–0.894). The median length of the clinician-administered assessment was 5 minutes (interquartile range [IQR]: 3:23–8:29 min) and 1 minute, 20 seconds (IQR: 0:57–2:09 min) for the self-report.ConclusionCAT-Psychosis can quickly and reliably assess the severity of psychosis and discriminate psychotic patients from healthy controls, creating an opportunity for frequent remote assessment and patient/population-level follow-up.     

Impact of Comorbid Affective Disorders on Longitudinal Clinical Outcomes in Individuals at Ultra-high Risk for Psychosis

IntroductionDiagnoses of anxiety and/or depression are common in subjects at Ultra-High Risk for Psychosis (UHR) and associated with extensive functional impairment. Less is known about the impact of affective comorbidities on the prospective course of attenuated psychotic symptoms (APS).MethodLatent class mixed modelling identified APS trajectories in 331 UHR subjects assessed at baseline, 6, 12, and 24 months follow-up. The prognostic value of past, baseline, and one-year DSM-IV depressive or anxiety disorders on trajectories was investigated using logistic regression, controlling for confounders. Cox proportional hazard analyses investigated associations with transition risk.Results46.8% of participants fulfilled the criteria for a past depressive disorder, 33.2% at baseline, and 15.1% at one-year follow-up. Any past, baseline, or one-year anxiety disorder was diagnosed in 42.9%, 37.2%, and 27.0%, respectively. Participants were classified into one of three latent APS trajectory groups: (1) persistently low, (2) increasing, and (3) decreasing. Past depression was associated with a higher risk of belonging to the increasing trajectory group, compared to the persistently low (OR = 3.149, [95%CI: 1.298–7.642]) or decreasing group (OR = 3.137, [1.165–8.450]). In contrast, past (OR = .443, [.179–1.094]) or current (OR = .414, [.156–1.094]) anxiety disorders showed a trend-level association with a lower risk of belonging to the increasing group compared to the persistently low group. Past depression was significantly associated with a higher risk of transitioning to psychosis (HR = 2.123, [1.178–3.828]).ConclusionA past depressive episode might be a particularly relevant risk factor for an unfavorable course of APS in UHR individuals. Early affective disturbances may be used to advance detection, prognostic, and clinical strategies.     

Thickness profile generation for the corpus callosum using Laplace's equation

The corpus callosum facilitates communication between the cerebral hemispheres. Morphological abnormalities of the corpus callosum have been identified in numerous psychiatric and neurological disorders. To quantitatively analyze the thickness profile of the corpus callosum, we adapted an automatic thickness measurement method, which was originally used on magnetic resonance (MR) images of the cerebral cortex (Hutton et al. [ 2008 ]: NeuroImage 40:1701–10; Jones et al. [ 2002 ]: Hum Brain Mapp 11:12–32; Schmitt and Böhme [ 2002 ]: NeuroImage 16:1103–9; Yezzi and Prince [ 2003 ]: IEEE Trans Med Imaging 22:1332–9), to MR images of the corpus callosum. The thickness model was derived by computing a solution to Laplace's equation evaluated on callosal voxels. The streamlines from this solution form non‐overlapping, cross‐sectional contours the lengths of which are modeled as the callosal thickness. Apart from the semi‐automated segmentation and endpoint selection procedures, the method is fully automated, robust, and reproducible. We compared the Laplace method with the orthogonal projection technique previously published (Walterfang et al. [ 2009a ]: Psych Res Neuroimaging 173:77–82; Walterfang et al. [ 2008a ]: Br J Psychiatry 192:429–34; Walterfang et al. [ 2008b ]: Schizophr Res 103:1–10) on a cohort of 296 subjects, composed of 86 patients with chronic schizophrenia (CSZ), 110 individuals with first‐episode psychosis, 100 individuals at ultra‐high risk for psychosis (UHR; 27 of whom later developed psychosis, UHR‐P, and 73 who did not, UHR‐NP), and 55 control subjects (CTL). We report similar patterns of statistically significant differences in regional callosal thickness with respect to the comparisons CSZ vs. CTL, UHR vs. CTL, UHR‐P vs. UHR‐NP, and UHR vs. CTL. Hum Brain Mapp, 2011. © 2011 Wiley Periodicals, Inc.     

Progressive structural brain changes during development of psychosis

Background:

Ultra-high risk (UHR) for psychosis has been associated with widespread structural brain changes in young adults. The onset of these changes and their subsequent progression over time are not well understood.

Methods:

Rate of brain change over time was investigated in 43 adolescents at UHR for psychosis compared with 30 healthy controls. Brain volumes (total brain, gray matter, white matter [WM], cerebellum, and ventricles), cortical thickness, and voxel-based morphometry were measured at baseline and at follow-up (2 y after baseline) and compared between UHR individuals and controls. Post hoc analyses were done for UHR individuals who became psychotic (N = 8) and those who did not (N = 35).

Results:

UHR individuals showed a smaller increase in cerebral WM over time than controls and more cortical thinning in the left middle temporal gyrus. Post hoc, a more pronounced decrease over time in total brain and WM volume was found for UHR individuals who became psychotic relative to controls and a greater decrease in total brain volume than individuals who were not psychotic. Furthermore, UHR individuals with subsequent psychosis displayed more thinning than controls in widespread areas in the left anterior cingulate, precuneus, and temporo-parieto-occipital area. Volume loss in the individuals who developed psychosis could not be attributed to medication use.

Conclusion:

The development of psychosis during adolescence is associated with progressive structural brain changes around the time of onset. These changes cannot be attributed to (antipsychotic) medication use and are therefore likely to reflect a pathophysiological process related to clinical manifestation of psychosis.     

Ultra high-risk state for psychosis and non-transition: a systematic review

Background

Most effort in ultra high-risk (UHR) research has been directed at defining the clinical and neurobiological characteristics of those UHR subjects who go on to develop psychosis. The characteristics and outcome of the remaining UHR subjects have remained relatively unexplored.

Method

We performed a systematic review of clinical UHR studies to investigate whether information was available on the characteristics and outcome of UHR subjects who did not convert to psychosis.

Results

Of 2462 potentially relevant papers, 31 met inclusion criteria, i.e. 20 naturalistic and 11 intervention studies. On average 76% (range 46–92.6%) of the UHR patients made no transition to psychosis during follow-up (range 6 to 40 months). Nearly half of the studies provided no characteristics of those UHR subjects who did not develop psychosis. Six studies reported remission rates from initial UHR status (range 15.4% to 54.3%). Linear regression showed that more recent studies reported significantly lower transition rates as compared to earlier publications. An older mean age at baseline was associated with significant lower transition rates in publications with follow-ups exceeding 1 year.

Conclusions

Our review illustrates that the long-term outcome of UHR subjects that do not develop psychosis is to date under-investigated. The studies reporting remission rates suggest that UHR criteria capture a non-negligible proportion of subjects that do not convert to psychosis.