Neurocognitive performance in subjects at ultrahigh risk for schizophrenia: a comparison with first-episode schizophrenia

Objective

The aim of the present study was to explore the neurocognitive performance of patients at ultrahigh risk (UHR) compared with patients with first-episode (FE) schizophrenia and healthy control (HC) subjects.

Method

Twenty-seven subjects at UHR for schizophrenia, 25 patients in their FE of schizophrenia, and 33 HCs were included. All participants completed a neurocognitive battery, including tests of general intelligence, attention and working memory, executive function, and verbal and visual memory.

Results

Of the 3 groups, the FE subjects performed poorest at all neurocognitive tests, encompassing the broad range of impairments. The UHR subjects had a similar pattern of neuropsychological dysfunction but less severe than that of FE patients. The UHR subjects were particularly impaired on measures of attention and working memory, executive function, and verbal memory compared with the HCs.

Conclusion

These findings are consistent with the view that the neurocognitive impairments of schizophrenia are neurodevelopmental in nature and, although less severe, those impairments are mostly in place before the onset of the first frank psychotic episode. Neurocognitive impairments may play an important role in the pathogenesis of early psychosis and could help to clarify individuals at UHR for schizophrenia.     

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.     

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.     

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     

Psychosocial outcome in patients at clinical high risk of psychosis: a prospective follow-up

Purpose

In patients at clinical high risk (CHR) of psychosis, transition to psychosis has been the focus of recent studies. Their broader outcome has received less attention. We studied psychosocial state and outcome in CHR patients.

Methods

In the European Prediction of Psychosis Study, 244 young help-seeking CHR patients were assessed with the Strauss and Carpenter Prognostic Scale (SCPS) at baseline, and 149 (61.1 %) of them were assessed for the second time at the 18-month follow-up. The followed patients were classified into poor and good outcome groups.

Results

Female gender, ever-married/cohabitating relationship, and good working/studying situation were associated with good baseline SCPS scores. During follow-up, patients’ SCPS scores improved significantly. Good follow-up SCPS scores were predicted by higher level of education, good working/studying status at baseline, and white ethnicity. One-third of the followed CHR patients had poor global outcome. Poor working/studying situation and lower level of education were associated with poor global outcome. Transition to psychosis was associated with baseline, but not with follow-up SCPS scores or with global outcome.

Conclusion

The majority of CHR patients experience good short-term recovery, but one-third have poor psychosocial outcome. Good working situation is the major indicator of good outcome, while low level of education and non-white ethnicity seem to be associated with poor outcome. Transition to psychosis has little effect on psychosocial outcome in CHR patients. In treating CHR patients, clinicians should focus their attention on a broader outcome, and not only on preventing transition to psychosis.     

A longitudinal study of obsessive-compulsive disorder in individuals at ultra-high risk for psychosis

Background

We evaluated whether (1) a diagnosis of obsessive-compulsive disorder (OCD) at baseline, or (2) the persistence, remission or emergence of de novo OCD at follow-up, were associated with the development of different psychotic disorders in a cohort of individuals at ultra-high risk (UHR) for psychosis.

Methods

Patients were assessed for OCD at baseline and after a mean of 7.4 years follow-up and classified into: (i) Non-OCD group - patients without OCD both at baseline and follow-up (n = 269; 86.2%), (ii) Incident OCD group - patients without OCD at baseline but with OCD at follow-up (n = 17; 5.4%), (iii) Remitting OCD group - patients with OCD at baseline but without OCD at follow-up (n = 20; 6.4%), (iv) Persistent OCD group - patients with OCD both at baseline and at follow-up (n = 6; 1.9%). Rates of different DSM-IV psychotic disorders at follow-up were compared across these groups.

Results

Patients who displayed remitting OCD were not related to the development of any DSM-IV psychotic disorder. A diagnosis of incident OCD was associated with greater rates of psychotic disorders at follow-up, particularly mood disorders with psychotic features and psychotic disorders not otherwise specified (PDNOS), and greater baseline severity of general psychopathology, alogia, and avolition-apathy. Two of the six patients (40%) with persistent OCD developed schizophrenia, while only 12.5%, 5.0%, and 9.7% of incident, remitting, and non-OCD groups, respectively, exhibited the same condition at follow-up. Rates of antipsychotic use in the previous two years were not significantly different between the groups.

Conclusions

Our findings suggest that, in a cohort of individuals at UHR for psychosis, remission of OCD does not increase the risk of psychosis, while de novo OCD was associated with development of mood disorders with psychotic features and PDNOS.     

Reduced prepulse inhibition in adolescents at risk for psychosis: a 2-year follow-up study

Background

Reduced prepulse inhibition (PPI) of the auditory startle reflex is a hallmark feature of attention-processing deficits in patients with schizophrenia and other psychotic disorders. Recent evidence suggests that these deficits may also be present before the onset of psychosis in individuals at ultra-high risk (UHR) and become progressively worse as psychosis develops. We conducted a longitudinal follow-up study to observe the development of PPI over time in UHR adolescents and healthy controls.

Methods

Two-year follow-up data of PPI measures were compared between UHR adolescents and a matched control group of typically developing individuals.

Results

We included 42 UHR adolescents and 32 matched controls in our study. Compared with controls, UHR individuals showed reduced PPI at both assessments. Clinical improvement in UHR individuals was associated with an increase in PPI parameters.

Limitations

A developmental increase in startle magnitude partially confined the interpretation of the association between clinical status and PPI. Furthermore, post hoc analyses for UHR individuals who became psychotic between assessments had limited power owing to a low transition rate (14%).

Conclusion

Deficits in PPI are present before the onset of psychosis and represent a stable vulnerability marker over time in UHR individuals. The magnitude of this marker may partially depend on the severity of clinical symptoms.     

Temperament and character in individuals at ultra-high risk for psychosis and with first-episode schizophrenia: Associations with psychopathology,psychosocial functioning,and aspects of psychological health

Objective

The psychobiological model of temperament and character indicates that personality traits are heritable and, during development, constantly influence one’s susceptibility to schizophrenia. Our objective was to evaluate temperament and character in subjects at ultra-high risk (UHR) for psychosis and individuals with first-episode schizophrenia.

Methods

UHR for psychosis subjects (n = 50), first-episode schizophrenia patients (n = 33), and normal controls (n = 120) were compared on temperament and character dimensions, and correlation analysis of each personality dimension with psychopathologies, global and social functioning, and self-esteem. General and social self-efficacy reports were conducted. UHR subjects were followed-up for 24 months and the baseline personality dimensions were compared between the converted and non-converted groups.

Results

Both clinical groups showed abnormal personality traits in terms of temperament (higher harm avoidance, lower reward dependence and persistence) and character (lower self-directedness and cooperativeness). Psychosocial functioning and psychological health components were found to be correlated with some personality dimensions. The conversion rate of overt psychotic disorder was 25.0% at the 24-month follow-up. Baseline cooperativeness dimension was a significant predictive dimension for conversion into overt psychosis in the UHR group during the follow-up period.

Conclusion

Patients with first episode schizophrenia have a pervasively altered personality profile from normal controls. More importantly, this altered personality profile already emerged in putative prodromal, UHR individuals. The present findings indicate that certain personality traits can play a protective or vulnerable role in developing schizophrenia.     

Fluvoxamine may prevent onset of psychosis: a case report of a patient at ultra-high risk of psychotic disorder

Background

There is emerging evidence that antidepressants may be effective in preventing patients with non-specific and psychotic-like prodromal symptoms, defined as patients at ultra-high risk (UHR) of psychotic disorder, from transitioning to psychosis. However, the mechanism of such an effect is still unknown.

Methods

We report the case of a 19-year-old Japanese man determined to be at UHR of psychotic disorder in whom fluvoxamine (one of the antidepressants with sigma-1 receptor agonism) showed preventive effects on psychotic-like prodromal symptoms.

Results

Our patient's depressive symptoms were reduced and maintained below remission as a result of treatment with 100 mg/day of fluvoxamine. In addition, it is likely that an additional dose of fluvoxamine (50 mg/day) improved his psychotic-like prodromal symptoms directly, independent of its antidepressive effects.

Conclusion

Fluvoxamine, a sigma-1 receptor agonist, may be effective in preventing patients at UHR of psychotic disorder from onset of psychosis via its neuroprotective/neurotropic actions, independent of its antidepressive effects.     

Depressive Symptoms and Brain Metabolite Alterations in Subjects at Ultra-high Risk for Psychosis: A Preliminary Study

Objective

Recent neuroimaging studies have suggested that brain changes occur in subjects at ultra-high risk (UHR) for psychosis while experiencing prodromal symptoms, among which depression may increase the risk of developing a psychotic disorder. The goal of this study is to examine brain metabolite levels in the anterior cingulate cortex, the left dorsolateral prefrontal cortex and the left thalamus in subjects at UHR for psychosis and to compare brain metabolite levels between the UHR subjects with comorbid major depressive disorder and healthy controls.

Methods

Proton magnetic resonance spectroscopy was used to examine brain metabolite levels. Twenty UHR subjects and 20 age- and intelligence quotient (IQ)-matched healthy controls were included in this study.

Results

Overall, no significant differences were observed in any metabolite between the UHR and healthy control group. However, UHR subjects with major depressive disorder showed significantly higher myo-inositol (Ins) levels in the left thalamus, compared to the healthy control.

Conclusion

Our results demonstrate that increased thalamic Ins level is associated with prodromal depressive symptoms. Further longitudinal follow-up studies with larger UHR sample sizes are required to investigate the function of Ins concentrations as a biomarker of vulnerability to psychosis.     

Auditory gamma oscillations predict global symptomatic outcome in the early stages of psychosis: A longitudinal investigation

Objectives

The gamma-band auditory steady-state response (ASSR) is thought to reflect the function of parvalbumin-positive γ-aminobutyric acid (GABA)-ergic interneurons and may be a candidate biomarker in early psychosis. Although previous cross-sectional studies have shown that gamma-band ASSR is reduced in early psychosis, whether reduced gamma-band ASSR could be a predictor of the long-term prognosis remains unknown.

The course of neurocognition and social functioning in individuals at ultra high risk for psychosis

OBJECTIVE: This study evaluates longitudinal neuropsychological performance and its association with clinical symptomatology and psychosocial outcome in individuals identified as ultra high risk (UHR) for psychosis. METHODS: Thirty-five UHR individuals completed neurocognitive, clinical, and social/role functioning assessments at baseline and, on average, 8.3 months later. RESULTS: UHR subjects showed significant cognitive deficits at baseline and 2 distinct profiles of cognitive change over time. On average, 50% demonstrated improvement in social and role functioning over the follow-up period, while the other half showed either stability or decline in functioning. Functional improvement was associated with improved processing speed and visual memory, as well as improvement in clinical symptoms over the follow-up period. In contrast, patients who did not improve functionally showed stable clinical symptoms and cognitive performance over time. CONCLUSIONS: Although the degree of neurocognitive deficit at baseline in UHR patients does not predict psychosocial outcome, the course of neurocognitive change over the first 8 months of follow-up does differentiate patients with good and poor functional outcomes.     

A randomized controlled trial of cognitive behavioral therapy for individuals at clinical high risk of psychosis

Background

Symptomatic and functional outcomes in schizophrenia are associated with the duration of untreated psychosis. However, no candidate biomarkers have been adopted in clinical settings. Multichannel near-infrared spectroscopy (NIRS), which can easily and noninvasively measure hemodynamics over the prefrontal cortex, is a candidate instrument for clinical use.

Aims

We intended to explore prefrontal dysfunction among individuals at different clinical stages, including ultra-high-risk (UHR), first-episode psychosis (FEP), and chronic schizophrenia (ChSZ), compared to healthy subjects.

Method

Twenty-two UHR subjects, 27 patients with FEP, 38 patients with ChSZ, and 30 healthy subjects participated. We measured hemodynamic changes during a block-designed letter fluency task using multichannel NIRS instruments.

Results

We found that the activations of the bilateral ventrolateral prefrontal cortex, and the fronto-polar and anterior parts of the temporal cortical regions in the UHR group were lower than those of the controls, but similar to those of the FEP and ChSZ groups. However, the activations in the bilateral dorsolateral prefrontal cortex regions decrease with advancing clinical stage.

Conclusions

To the best of our knowledge, this is the first study directly comparing differences in hemodynamic changes with respect to the 3 clinical stages of psychosis. Furthermore, this study also demonstrates different patterns of impairment according to the progression of clinical stages using NIRS instruments. NIRS measurements for UHR and FEP individuals may be candidate biomarkers for the early detection of the clinical stages of psychosis.     

Alterations in White Matter Evident Before the Onset of Psychosis

Background

Psychotic disorders are associated with widespread reductions in white matter (WM) integrity. However, the stage at which these abnormalities first appear and whether they are correlates of psychotic illness, as opposed to an increased vulnerability to psychosis, is unclear. We addressed these issues by using diffusion tensor imaging (DTI) to study subjects at ultra high risk (UHR) of psychosis before and after the onset of illness.

Methods

Thirty-two individuals at UHR for psychosis, 32 controls, and 15 patients with first-episode schizophrenia were studied using DTI. The UHR subjects and controls were re-scanned after 28 months. During this period, 8 UHR subjects had developed schizophrenia. Between-group differences in fractional anisotropy (FA) and diffusivity were evaluated cross sectionally and longitudinally using a nonparametric voxel-based analysis.

Results

At baseline, WM DTI properties were significantly different between the 3 groups (P < .001). Relative to controls, first-episode patients showed widespread reductions in FA and increases in diffusivity. DTI indices in the UHR group were intermediate relative to those in the other 2 groups. Longitudinal analysis revealed a significant group by time interaction in the left frontal WM (P < .001). In this region, there was a progressive reduction in FA in UHR subjects who developed psychosis that was not evident in UHR subjects who did not make a transition.

Conclusions

People at UHR for psychosis show alterations in WM qualitatively similar to, but less severe than, those in patients with schizophrenia. The onset of schizophrenia may be associated with a progressive reduction in the integrity of the frontal WM.     

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     

Loneliness in psychosis: a systematic review

Purpose

The aim of the review is to understand the relationships between loneliness and related psychological and social factors in individuals with psychosis. Loneliness is poorly understood in people with psychosis. Given the myriad of social challenges facing individuals with psychosis, these findings can inform psychosocial interventions that specifically target loneliness in this vulnerable group.

Methods

We adhered to the PRISMA guidelines and systematically reviewed empirical studies that measured loneliness either as a main outcome or as an associated variable in individuals with psychosis.

Results

A total of ten studies examining loneliness in people diagnosed with a psychotic disorder were examined. Heterogeneity in the assessment of loneliness was found, and there were contradictory findings on the relationship between loneliness and psychotic symptomatology. In individuals with psychosis, loneliness may be influenced by psychological and social factors such as increased depression, psychosis, and anxiety, poor social support, poor quality of life, more severe internalised stigma and perceived discrimination, and low self-esteem.

Conclusions

The relationship between loneliness and psychosis remains poorly understood due to a lack of rigorous studies. Although having strong social relationships is crucial to facilitate recovery from serious mental illness, psychosocial interventions that specifically target loneliness in individuals with psychosis are lacking and sorely needed. Interventions targeting loneliness in those with psychosis will also need to account for additional barriers associated with psychosis (e.g., social skill deficits, impoverished social networks, and negative symptoms).

     

Sexual Trauma Increases the Risk of Developing Psychosis in an Ultra High-Risk “Prodromal” Population

Studies indicate a high prevalence of childhood trauma in patient cohorts with established psychotic disorder and in those at risk of developing psychosis. A causal link between childhood trauma and development of psychosis has been proposed. We aimed to examine the association between experience of childhood trauma and the development of a psychotic disorder in a large “Ultra High Risk” (UHR) for psychosis cohort. The data were collected as part of a longitudinal cohort study of all UHR patients recruited to research studies at the Personal Assessment and Clinical Evaluation clinic between 1993 and 2006. Baseline data were collected at recruitment to these studies. The participants completed a comprehensive follow-up assessment battery (mean time to follow-up 7.5 years, range 2.4–14.9 years), which included the Childhood Trauma Questionnaire (CTQ), a self-report questionnaire that assesses experience of childhood trauma. The outcome of interest was transition to a psychotic disorder during the follow-up period. Data were available on 233 individuals. Total CTQ trauma score was not associated with transition to psychosis. Of the individual trauma types, only sexual abuse was associated with transition to psychosis (P = .02). The association remained when adjusting for potential confounding factors. Those with high sexual abuse scores were estimated to have a transition risk 2–4 times that of those with low scores. The findings suggest that sexual trauma may be an important contributing factor in development of psychosis for some individuals.Key words: trauma, psychosis, ultra high risk     

Apathy,poor verbal memory and male gender predict lower psychosocial functioning one year after the first treatment of psychosis

Background

Apathy is a negative symptom associated with poor psychosocial functioning in schizophrenia but has not been sufficiently studied as predictor of poor functioning in first episode psychosis (FEP).

Objective

The main aim of the current study was to evaluate if apathy predicts poor functioning after 1 year in FEP patients in the context of other clinical variables with influence on outcome.

Method

Sixty-four FEP patients completed an extensive clinical and neuro-psychological test battery at baseline and 1-year follow-up. Symptoms were assessed with the Positive and Negative Syndrome scale (PANSS), apathy with the shortened Apathy Evaluation Scale (AES-C-12) and psychosocial functioning with the functioning score from the split version of the Global Assessment of Functioning scale (GAF-F).

Results

High levels of apathy, poor verbal memory and being male were the baseline variables that best predicted poor functioning at 1-year follow-up, explaining 34% of the variance in GAF-F. When PANSS negative factor was included in the analysis, the significance of AES-C-12 diminished.

Conclusion

These findings points to a robust role for apathy among the negative symptoms in the development of persisting psychosocial dysfunction in FEP and supports the current effort in targeting motivation to improve functioning.     

The interplay of psychosis and victimisation across the life course: a prospective study in the general population

Purpose

Psychosis has been associated with adult victimisation. However, it remains unclear whether psychosis predicts incident adult victimisation, or whether adult victimisation predicts incident psychosis. Furthermore, a moderating effect of childhood victimisation on the association between psychosis and adult victimisation has not been investigated.

Methods

The longitudinal association between baseline psychotic experiences and six-year incidence of adult victimisation was assessed in a prospective general population cohort of 6646 adults using logistic regression analysis. The association between baseline adult victimisation and six-year incidence of psychotic experiences was examined as well. Furthermore, the moderating effect of childhood victimisation on these bidirectional associations was analysed.

Results

Psychotic experiences and childhood victimisation were both associated with an increased risk of incident adult victimisation. However, this was through competing pathways, as suggested by a negative interaction between psychotic experiences and childhood victimisation. Baseline adult victimisation and childhood victimisation both independently increased the risk of incident psychotic experiences, but there was no interaction between adult victimisation and childhood victimisation.

Conclusions

Psychosis and victimisation are interconnected throughout the life course. Childhood victimisation is connected to psychosis through two pathways: one direct and one indirect through adult victimisation. In individuals without childhood victimisation, psychosis and adult victimisation bidirectionally impact on each other.

     

Cognitive Behavioral Therapy for Subjects at Ultrahigh Risk for Developing Psychosis: A Randomized Controlled Clinical Trial

Background

: Evidence for the effectiveness of treatments for subjects at ultrahigh risk (UHR) for developing psychosis remains inconclusive. Objective : A new cognitive behavioral intervention specifically targeted at cognitive biases (ie, Cognitive Behavioral Therapy [CBT] for UHR patients plus treatment as usual [TAU] called CBTuhr) is compared with TAU in a group of young help-seeking UHR subjects. Methods : A total of 201 patients were recruited at 4 sites and randomized. In most cases, CBTuhr was an add-on therapy because most people were seeking help for a comorbid disorder. The CBT was provided for 6 months, and the follow-up period was 18 months. Results : In the CBTuhr condition, 10 patients transitioned to psychosis compared with 22 in the TAU condition (χ ² (1) = 5.575, P = .03). The number needed to treat (NNT) was 9 (95% confidence interval [CI]: 4.7–89.9). At 18-month follow-up the CBTuhr group was significantly more often remitted from an at-risk mental state, with a NNT of 7 (95% CI: 3.7–71.2). Intention-to-treat analysis, including 5 violations against exclusion criteria, showed a statistical tendency (χ ² (1) = 3.338, P = .06). Conclusions : Compared with TAU, this new CBT (focusing on normalization and awareness of cognitive biases) showed a favorable effect on the transition to psychosis and reduction of subclinical psychotic symptoms in subjects at UHR to develop psychosis. Key words: cognitive behavioral therapy, ultrahigh risk, cognitive biases, prevention, psychosis, schizophrenia