Mirjam Sprong

Transition and remission in adolescents at ultra-high risk for psychosis

BACKGROUND Future success of early intervention initiatives to prevent the onset of psychosis will rely on the validity of methods to predict clinical outcome. Proper identification is particularly essential for young adolescents, as psychotic-like symptoms are often transitory during this period and mislabeling can lead to early stigmatization and unnecessary treatment. This article presents results from a prospective, naturalistic 2-year follow-up study of a cohort of young adolescents putatively at ultra-high risk (UHR) for psychosis. METHODS Seventy-two adolescents between 12 and 18years were recruited, fulfilling either UHR criteria or the basic symptom-based criterion cognitive disturbances (COGDIS). Incidence of transition as well as the remission rate from UHR status was calculated. Individuals who made a transition (UHR-P) were compared to those who did not (UHR-NP) and to those who remitted (UHR-R) on socio-demographic and clinical characteristics. RESULTS Fifty-seven UHR individuals completed the 2-year follow-up assessment. The confirmed transition rate was 15.6% and 35.3% still met UHR criteria. The remaining 49.1% had remitted from an initial UHR status. The UHR subgroups did not differ on socio-demographic or clinical variables at baseline. CONCLUSIONS Half of young adolescents meeting UHR criteria continue to experience prodromal or psychotic symptoms after 2 years. However, they are at least three times more likely to have remitted from their UHR status than to have made a transition to psychosis. In addition, baseline characteristics are not indicative of clinical outcome at follow-up. Our results emphasize the need for further improvement and stratification of relative risk factors for psychosis.

Proline Affects Brain Function in 22q11DS Children with the Low Activity COMT158 Allele

The association between the 22q11.2 deletion syndrome (22q11DS) and psychiatric disorders, particularly psychosis, suggests a causal relationship between 22q11DS genes and abnormal brain function. The genes catechol-O-methyl-transferase (COMT) and proline dehydrogenase both reside within the commonly deleted region of 22q11.2. COMT activity and proline levels may therefore be altered in 22q11DS individuals. Associations of both COMT158 genotype and elevated serum proline levels with abnormal brain function have been reported. Fifty-six 22q11DS children and 75 healthy controls were assessed on physiological measures of brain function, including prepulse inhibition (PPI) of startle, P50 auditory sensory gating and smooth pursuit eye movements (SPEM). COMT158 genotype and plasma proline levels were determined in the 22q11DS children. We hypothesized an interaction between the COMT158 genotype and proline, predicting the strongest negative effect of high proline on brain function to occur in 22q11DS children who are carriers of the COMTmet allele. Of the three physiological measures, only SPEM and PPI were abnormal in the patient sample. With regard to the SPEM performance, there was a significant interaction between the COMT158 genotype and proline level with significantly decreased SPEM performance in children with high plasma proline levels and the low activity COMTmet allele. A similar interaction effect was not observed with regard to PPI. These findings are consistent with a model in which elevated proline negatively affects brain function by an increase in dopamine in the prefrontal cortex. 22q11DS patients with low dopamine catabolic capacity are therefore especially vulnerable to this functional disruption.

Pathways to psychosis: a comparison of the pervasive developmental disorder subtype Multiple Complex Developmental Disorder and the "At Risk Mental State".

BACKGROUND The comparison of high-risk populations with different developmental pathways to psychosis may lend more insight into the heterogeneity of the manifestation of the psychotic syndrome, and possible differing etiological pathways. AIM To compare high-risk traits and symptoms in two populations at risk for psychosis, i.e. (1) help-seeking adolescents presenting with prodromal symptoms meeting the criteria for At Risk Mental State (ARMS), and (2) adolescents with Multiple Complex Developmental Disorder (MCDD), a PDD-NOS subtype characterized by severe, early childhood-onset deficits in affect regulation, anxieties, disturbed social relationships, and thought disorder. METHOD 80 ARMS- and 32 MCDD-adolescents (12-18 years) were compared on prodromal symptoms (Structured Interview of Prodromal Symptoms, and Bonn Scale for the Assessment of Basic Symptoms-Prediction list), and autism traits (Social Communication Questionnaire). In addition, both high-risk groups were compared with 82 healthy controls on schizotypal traits (Schizotypal Personality Questionnaire-Revised). RESULTS Although the high-risk groups clearly differed in early developmental and treatment histories as well as autism traits, they did not differ with regard to schizotypal traits and basic symptoms, as well as disorganized and general prodromal symptoms. There were, however, group differences in positive and negative prodromal symptoms. Interestingly, 78% of the adolescents with MCDD met criteria for ARMS. CONCLUSION These findings suggest that children diagnosed with MCDD are at high risk for developing psychosis later in life, and support the notion that there are different developmental pathways to psychosis. Follow-up research is needed to compare the rates of transition to psychosis in both high-risk groups.

Misattribution of facial expressions of emotion in adolescents at increased risk of psychosis: the role of inhibitory control.

BACKGROUND By studying behavior, cognitive abilities and brain functioning in adolescents at high risk for psychosis, we can gain an insight into the vulnerability markers or protective factors in the development of psychotic symptoms. Although many high-risk studies have focused on impairments in neurocognitive functions, such as memory and attention, very few studies have investigated problems in processing social cues such as facial expressions as a possible vulnerability marker for psychosis. METHOD Thirty-six adolescents at ultra-high risk (UHR) for psychosis and 21 non-clinical controls completed a face recognition test, a facial affect labeling test and an inhibitory control test. Schizotypal traits and schizophrenia symptoms were assessed using a schizotypy questionnaire and the Positive and Negative Syndrome Scale (PANSS). RESULTS The UHR group showed impairments in labeling facial expressions of others, in addition to a spared ability to recognize facial identity. More specifically, the UHR group made more errors in labeling neutral expressions compared to the controls, and an analysis of error types indicated that neutral faces were misattributed as being angry. The degree of misattribution of neutral-as-angry faces correlated significantly with reduced inhibitory control. CONCLUSIONS Our findings suggest that misattributing social cues might contribute to vulnerability for psychosis. This social cognitive deficit may be related to problems in inhibitory control, which potentially plays an important role in the selection of appropriate social meaning. These findings may have relevance for understanding the mechanisms underlying prodromal social dysfunction, which should be targeted in future remediation interventions.

Neurocognitive and clinical predictors of long-term outcome in adolescents at ultra-high risk for psychosis: a 6-year follow-up.

Background Most studies aiming to predict transition to psychosis for individuals at ultra-high risk (UHR) have focused on either neurocognitive or clinical variables and have made little effort to combine the two. Furthermore, most have focused on a dichotomous measure of transition to psychosis rather than a continuous measure of functional outcome. We aimed to investigate the relative value of neurocognitive and clinical variables for predicting both transition to psychosis and functional outcome. Methods Forty-three UHR individuals and 47 controls completed an extensive clinical and neurocognitive assessment at baseline and participated in long-term follow-up approximately six years later. UHR adolescents who had converted to psychosis (UHR-P; n = 10) were compared to individuals who had not (UHR-NP; n = 33) and controls on clinical and neurocognitive variables. Regression analyses were performed to determine which baseline measures best predicted transition to psychosis and long-term functional outcome for UHR individuals. Results Low IQ was the single neurocognitive parameter that discriminated UHR-P individuals from UHR-NP individuals and controls. The severity of attenuated positive symptoms was the only significant predictor of a transition to psychosis and disorganized symptoms were highly predictive of functional outcome. Conclusions Clinical measures are currently the most important vulnerability markers for long-term outcome in adolescents at imminent risk of psychosis.

No evidence for structural brain changes in young adolescents at ultra high risk for psychosis

OBJECTIVE The onset of psychosis is thought to be preceded by neurodevelopmental changes in the brain. However, the timing of these changes has not been established. We investigated structural brain changes in a sample of young adolescents (12-18 years) at ultra high-risk for psychosis (UHR). METHODS Structural MRI data from young UHR subjects (n=54) and typically developing, matched controls (n=54) were acquired with a 1.5 Tesla scanner and compared. RESULTS None of the measures differed between UHR subjects and controls. CONCLUSIONS Our results do not support the presence of gross neuroanatomical changes in young UHR subjects. This suggests that early changes are too subtle to detect with conventional imaging techniques. Therefore, changes observed in older cohorts may only onset later developmentally or occur secondary to prodromal symptoms.

717 – Clinical measures trump neurocognition in predicting long-term outcome for adolescents at ultra-high risk for psychosis

Background Most studies aiming to predict transition to psychosis for individuals at ultra-high risk (UHR) have focused on either neurocognitive or clinical variables and have made little effort to combine the two. We aimed to investigate the relative value of neurocognitive and clinical variables for predicting transition to psychosis as well as long-term functional outcome. Methods Sixty-seven adolescents at UHR and 72 controls completed an extensive clinical and neurocognitive assessment. Forty-three UHR individuals and 47 controls participated in long-term follow-up approximately six years later. UHR adolescents who had converted to psychosis (UHR-P) were compared to individuals who had not (UHR-NP) and controls on clinical and neurocognitive variables. Regression analyses were performed to determine which baseline measures best predicted transition to psychosis and long-term functional outcome for UHR individuals. Results Low IQ was the single neurocognitive parameter that discriminated UHR-P individuals from UHR-NP individuals and controls. The severity of attenuated positive symptoms was the only significant predictor of a transition to psychosis and disorganized symptoms were highly predictive of functional outcome. Conclusions IQ was lowest for those individuals at ultra high risk for psychosis who later went on to have a psychotic episode. However, IQ was not a good predictor of either transition or functional outcome. Rather, clinical measures proved to be the most important vulnerability markers for long-term outcome.