Psychosis In 22q11 Research Articles

Multivariate patterns of disrupted sleep longitudinally predict affective vulnerability to psychosis in 22q11.2 Deletion Syndrome

22q11.2 deletion syndrome (22q11DS) contributes dramatically to increased genetic risk for psychopathology, and in particular schizophrenia. Sleep disorders, including obstructive sleep apnea (OSA), are also highly prevalent, making 22q11DS a unique model to explore their impact on psychosis vulnerability. Still, the contribution of sleep disturbances to psychosis vulnerability remains unclear. We characterized the sleep phenotype of 69 individuals with 22q11DS and 38 healthy controls with actigraphy and sleep questionnaires. Psychiatric symptoms were measured concomitantly with the baseline sleep assessment and at longitudinal follow-up, 3.58±0.85 years later. We used a novel multivariate partial-least-square-correlation (PLSC) approach to identify sleep patterns combining objective and subjective variables, which correlated with psychiatric symptoms. We dissected longitudinal pathways linking sleep disturbances to psychosis, using multi-layer-network-analysis. 22q11DS was characterized by a non-restorative sleep pattern, combining increased daytime fatigue despite longer sleep duration. Non-restorative sleep combined with OSA symptoms correlated with both emotional and psychotic symptoms. Moreover, a sleep pattern evocative of OSA predicted longitudinal worsening of positive and negative symptoms, by accentuating the effects of emotional dysregulation. These results suggest that sleep disturbances could significantly increase psychosis risk, along an affective pathway. If confirmed, this suggests that systematic screening of sleep quality could mitigate psychosis vulnerability in 22q11DS.

Clinical management of psychosis in 22q11.2 deletion syndrome.

A 17-year-old woman was referred to our centre for treatment of a recent onset psychotic episode in the context of 22q11.2 deletion syndrome. A 3 megabase A–D deletion was identified at birth through microarray-based comparative genomic hybridization, after the discovery of a tetralogy of Fallot.

Altered developmental trajectories of verbal learning skills in 22q11.2DS: associations with hippocampal development and psychosis.

The cognitive profile in 22q11.2 deletion syndrome (22q11.2DS) is often characterized by a discrepancy between nonverbal vs. verbal reasoning skills, in favor of the latter skills. This dissociation has also been observed in memory, with verbal learning skills described as a relative strength. Yet the development of these skills is still to be investigated. We thus aimed to explore verbal learning longitudinally. Furthermore, we explored verbal learning and its respective associations with hippocampal alterations and psychosis, which remain largely unknown despite their high prevalence in 22q11.2DS. In total, 332 individuals (173 with 22q11.2DS) aged 5-30 years completed a verbal-paired associates task. Mixed-models regression analyses were conducted to explore developmental trajectories with threefold objectives. First, verbal learning and retention trajectories were compared between 22q11.2DS vs. HC. Second, we examined hippocampal volume development in 22q11.2DS participants with lower vs. higher verbal learning performance. Third, we explored verbal learning trajectories in 22q11.2DS participants with vs. without positive psychotic symptoms and with vs. without a psychotic spectrum disorder (PSD). Our findings first reveal lower verbal learning performance in 22q11.2DS, with a developmental plateau emerging from adolescence. Second, participants with lower verbal learning scores displayed a reduced left hippocampal tail volume. Third, participants with PSD showed a deterioration of verbal learning performance, independently of verbal reasoning skills. Our study challenges the current view of preserved verbal learning skills in 22q11.2DS and highlights associations with specific hippocampal alterations. We further identify verbal learning as a novel cognitive marker for psychosis in 22q11.2DS.

Blood brain barrier permeability increases with age in individuals with 22q11.2 deletion syndrome

22q11.2 deletion syndrome (22q11.2DS) is characterised by high rates of psychotic disorders and immune abnormalities. Blood–brain barrier (BBB) permeability is known to be a risk factor for schizophrenia and immune aberrations. Objective To evaluate the relationship between psychosis and BBB permeability in this population. Methods We examined two biomarkers for BBB permeability, s100β and neuron-specific enolase (NSE), in 22q11.2DS individuals with/without psychosis. The first cohort of this Israeli–Belgium study was comprised of 20 22q11.2DS adults (30.58 ± 9.42 years) afflicted with a psychotic disorder, another group of 69 non-psychotic 22q11.2DS adults (23.42 ± 8.36 years), and 58 healthy controls (26.39 ± 7.77 years). A second cohort was comprised of 18 non-psychotic 22q11.2DS Israeli children (5.83 ± 1.55 years) and 14 healthy controls (5.34 ± 1.43 years). NSE and s100β serum levels were detected in all participants. Results Both factors were elevated in adults with 22q11.2DS compared to healthy controls, specifically in the non-psychotic sub-group. In contrast, there were no significant differences in their levels between the two groups of the paediatric cohort. Conclusions Increased BBB permeability seems to be a trait of 22q11.2DS that evolves sometime in early adulthood. Our findings are in line with previous reports on non-syndromic schizophrenia, and suggest potential novel neural pathways to psychosis in 22q11.2DS.

Inter-rater reliability of subthreshold psychotic symptoms in individuals with 22q11.2 deletion syndrome

BackgroundPathways leading to psychosis in 22q11.2 deletion syndrome (22q11.2DS) have been the focus of intensive research during the last two decades. One of the common clinical risk factors for the evolution of psychosis in 22q11.2DS is the presence of positive and negative subthreshold psychotic symptoms. The gold standard for measuring subthreshold symptoms is the Structured Interview for Prodromal Syndromes (SIPS) and its accompanying Scale of Prodromal Symptoms (SOPS) ratings. Although the scale has been used by many centers studying 22q11.2DS, the inter-site reliability of the scale in this population has never been established.MethodsIn the present study, experienced clinical assessors from three large international centers studying 22q11.2DS independently rated video recordings of 18 adolescents and young adults with 22q11.2DS.ResultsThe intraclass correlations coefficients (ICCs) among three raters for the SOPS total scores, as well as for the positive, negative, and disorganization subscale scores, were good-to-excellent (ICCs range 0.73–0.93). The raters were also able to reliably determine the subjects’ subthreshold syndrome status (ICC = 0.71). The reliability of individual items was good-to-excellent for all items, ranging from 0.61 for motor disturbances [G3] to 0.95 for bizarre thinking.ConclusionsOur results show that trained clinicians can reliably screen for subthreshold psychotic symptoms in individuals with 22q11.2DS. To increase assessment reliability, we suggest specific clarifications and simplifications to the standard SIPS interview for future studies.

Striatal dopaminergic alterations in individuals with copy number variants at the 22q11.2 genetic locus and their implications for psychosis risk: a [18F]-DOPA PET study

Dopaminergic dysregulation is one of the leading hypotheses for the pathoetiology underlying psychotic disorders such as schizophrenia. Molecular imaging studies have shown increased striatal dopamine synthesis capacity (DSC) in schizophrenia and people in the prodrome of psychosis. However, it is unclear if genetic risk for psychosis is associated with altered DSC. To investigate this, we recruited healthy controls and two antipsychotic naive groups of individuals with copy number variants, one with a genetic deletion at chromosome 22q11.2, and the other with a duplication at the same locus, who are at increased and decreased risk for psychosis, respectively. Fifty-nine individuals (21 with 22q11.2 deletion, 12 with the reciprocal duplication and 26 healthy controls) received clinical measures and [18F]-DOPA PET imaging to index striatal Kicer. There was an inverse linear effect of copy number variant number on striatal Kicer value (B = −1.2 × 10−3, SE = 2 × 10−4, p < 0.001), with controls showing levels intermediate between the two variant groups. Striatal Kicer was significantly higher in the 22q11.2 deletion group compared to the healthy control (p < 0.001, Cohen’s d = 1.44) and 22q11.2 duplication (p < 0.001, Cohen’s d = 2) groups. Moreover, Kicer was positively correlated with the severity of psychosis-risk symptoms (B = 730.5, SE = 310.2, p < 0.05) and increased over time in the subject who went on to develop psychosis, but was not associated with anxiety or depressive symptoms. Our findings suggest that genetic risk for psychosis is associated with dopaminergic dysfunction and identify dopamine synthesis as a potential target for treatment or prevention of psychosis in 22q11.2 deletion carriers.

Neutrophils to lymphocytes ratio and psychosis in 22q11.2 deletion syndrome – Clinical and scientific implications

BackgroundIndividuals with 22q11.2 deletion syndrome (22q11.2DS) are at risk for having both psychotic and immune disorders, thus, implying a possible link between the two. The aim of the current study was to evaluate the usefulness of the neutrophiles to leukocytes ratio (NLR), an inflammatory marker, as a bio-marker for overt and prodromal psychotic symptoms in 22q11.2DS. MethodsForty-nine individuals with 22q11.2DS (13 with psychotic disorders and 36 without psychotic disorders) and 30 age- and sex-matched healthy controls underwent psychiatric evaluation using a structured psychiatric interview, the Scale of Prodromal Symptoms (SOPS) and the Global Assessment of Functioning (GAF) scale. Blood samples were collected from all participants on the day of assessment. NLR was calculated, compared among the study groups and correlated with SOPS and GAF scores. The non-psychotic 22q11.2DS group was further divided into high- and low-inflammation groups by NLR values and the analyses were done again. ResultsNLR was higher in the psychotic- and the high-inflammation non-psychotic 22q11.2DS groups compared to the low-inflammation non-psychotic 22q11.2DS group and controls. In the high-inflammation non-psychotic 22q11.2DS group NLR increase was associated with an increase of total negative symptoms scores on SOPS and a decrease in GAF scores. ConclusionOur results suggest the potential utility of NLR as a bio-marker for psychotic disorders and subthreshold prodromal symptoms in 22q11.2DS. Furthermore, they imply that a disequilibrium between the innate and adaptive arms of the immune system facilitates the progression of psychosis in at risk populations. Further longitudinal studies are warranted to validate our findings, as this was a cross sectional observation.

Identifying neurodevelopmental anomalies of white matter microstructure associated with high risk for psychosis in 22q11.2DS

Disruptions of white matter microstructure have been widely reported in schizophrenia. However, the emergence of these alterations during preclinical stages remains poorly understood. 22q11.2 Deletion Syndrome (22q11.2DS) represents a unique model to study the interplay of different risk factors that may impact neurodevelopment in premorbid psychosis. To identify the impact of genetic predisposition for psychosis on white matter development, we acquired longitudinal MRI data in 201 individuals (22q11.2DS = 101; controls = 100) aged 5–35 years with 1–3 time points and reconstructed 18 white matter tracts using TRACULA. Mixed model regression was used to characterize developmental trajectories of four diffusion measures—fractional anisotropy (FA), axial (AD), radial (RD), and mean diffusivity (MD) in each tract. To disentangle the impact of additional environmental and developmental risk factors on white matter maturation, we used a multivariate approach (partial least squares (PLS) correlation) in a subset of 39 individuals with 22q11.2DS. Results revealed no divergent white matter developmental trajectories in patients with 22q11.2DS compared to controls. However, 22q11.2DS showed consistently increased FA and reduced AD, RD, and MD in most white matter tracts. PLS correlation further revealed a significant white matter-clinical risk factors relationship. These results indicate that while age-related changes are preserved in 22q11.2DS, white matter microstructure is widely disrupted, suggesting that genetic high risk for psychosis involves early occurring neurodevelopmental insults. In addition, multivariate modeling showed that clinical risk factors further impact white matter development. Together, these findings suggest that genetic, developmental, and environmental risk factors may play a cumulative role in altering normative white matter development during premorbid stages of psychosis.

Favorable effects of omega-3 polyunsaturated fatty acids in attentional control and conversion rate to psychosis in 22q11.2 deletion syndrome

Omega-3-polyunsaturated-fatty-acids were suggested against cognitive dysfunctions and conversion to psychosis. However, a recent multicenter trial found no effect in reducing conversion rates in individuals at risk of developing schizophrenia. Patients’ genetic heterogeneity and the timing of treatment might influence omega-3 efficacy. Here, we addressed the impact of omega-3 early treatment in both mice and human subjects with a 22q11.2 genetic hemi-deletion (22q11DS), characterized by cognitive dysfunctions and high penetrance of schizophrenia. We first tested the behavioural and cognitive consequences of adolescent exposure to normal or omega-3-enriched diets in wild-type and 22q11DS (LgDel/+) mice. We then contrasted mouse data with those gathered from sixty-two patients with 22q11DS exposed to a normal diet or supplemented with omega-3 during pre-adolescence/adolescence. Adolescent omega-3 exposure had no effects in wild-type mice. However, this treatment ameliorated distractibility deficits revealed in LgDel/+ mice by the Five Choice Serial Reaction Time Task (5CSRTT). The omega-3 improvement in LgDel/+ mice was selective, as no other generalized cognitive and non-cognitive effects were evident. Similarly, omega-3-exposed 22q11DS patients showed long-lasting improvements on distractibility as revealed by the continuous performance test (CPT). Moreover, omega-3-exposed 22q11DS patients showed less risk of developing an Ultra High Risk status and lower conversion rate to psychosis. Our convergent mouse-human findings represent a first analysis on the effects of omega-3 early treatment in 22q11DS. The beneficial effects in attentional control and transition to psychosis could support the early use of omega-3 supplementation in the 22q11DS population.

Recent developments in understanding the relationship between 22q11.2 deletion syndrome and psychosis.

Individuals with 22q11.2 deletion syndrome have high rates of comorbid mental illness, particularly psychosis and schizophrenia. The purpose of this review is to summarize recent research in the area of 22q11.2 deletion syndrome and psychosis. Research over the past year has identified negative symptoms, functional impairment, dysphoric mood and a childhood diagnosis of attention deficit hyperactivity disorder as important clinical predictors of psychosis risk in 22q11.2 deletion syndrome. As previously reported in nondeleted schizophrenia, recent studies have implicated neuroinflammation as a possible neurobiological mechanism for psychosis in 22q11.2 deletion syndrome. Recent neuroimaging findings suggest that the cortex is significantly thinner in those with 22q11.2 deletion syndrome and psychosis compared to those without psychosis, replicating similar findings in nondeleted schizophrenia. Further data from the International 22q11.2 Deletion Syndrome Brain and Behavior Consortium have suggested that chromosomal microdeletions are significantly more likely to involve protein-coding genes and several rare copy number variants are associated with the presence of psychosis in deleted individuals. There have been several significant recent advances to further characterize the high rates of psychosis in 22q11.2 deletion syndrome, to identify additional clinical predictors of psychosis and to increase our understanding of the neural substrate and genetic aetiology of psychosis in 22q11.2 deletion syndrome.

M104 - EXAMINING ATTENTION DEFICIT HYPERACTIVITY DISORDER (ADHD) INATTENTION SYMPTOMS AS ANTECEDENTS OF PSYCHOSIS RISK IN 22Q11.2 DELETION SYNDROME (22Q11.2DS)

Background 22q11.2 Deletion Syndrome (22q11.2DS) is associated with high risk for developing schizophrenia in adulthood while Attention Deficit Hyperactivity Disorder (ADHD) constitutes the most frequent diagnosis in childhood. Individuals with 22q11.2DS show marked inattention symptoms. Interestingly, schizophrenia is also characterized by attentional deficits. This raises the question of whether childhood inattention is an antecedent of psychosis in 22q11.2DS. This is the first longitudinal study to examine whether childhood inattention is associated with the later emergence of Psychotic Experiences (PEs) and psychosis spectrum disorders in 22q11.2DS. Methods 294 individuals (mean age (SD):15.9(5.8)) completed assessments on psychotic symptoms and ADHD at two time points and did not report PEs at time 1(T1). Results Inattention symptoms and ADHD diagnosis at T1 were associated with PEs at T2 when adjusting for age, sex, IQ and assessment differences (Odds Ratio: 1.18, p=0.02). ADHD diagnosis at T1 was also associated with psychosis spectrum disorder at T2 (Odds Ratio: 4.8, p Discussion This is the first study to examine the longitudinal associations between ADHD and psychosis in 22q11.2DS. Our findings support an important role of ADHD inattention symptoms in the development of psychosis in 22q11.2DS.

A Mini Review on the Contribution of the Anterior Cingulate Cortex in the Risk of Psychosis in 22q11.2 Deletion Syndrome

22q11.2 deletion syndrome (22q11DS) is a neurogenetic disorder that causes a high risk of developing schizophrenia, thus representing a unique model for the investigation of biomarkers of psychosis. Cognitive and clinical risk factors have been identified as reliable predictors of schizophrenia in patients with 22q11DS and are currently used in the clinical practice. However, biomarkers based on neuroimaging are still lacking, mainly because of the analytic approaches adopted so far, which are almost uniquely based on the comparison of 22q11DS patients with healthy controls. Such comparisons do not take into account the heterogeneity within patients with 22q11DS, who indeed show various clinical manifestations. More recently, a number of studies compared measures of brain morphology and connectivity between patients with 22q11DS with different symptomatic profiles. The aim of this short review is to highlight the brain alterations found in patients with 22q11DS fulfilling ultra-high risk (UHR) criteria. Findings point to alterations in brain morphology and connectivity in frontal brain regions, and in particular in the anterior cingulate cortex, in patients with 22q11DS presenting UHR symptoms. These alterations may represent valuable biomarkers of psychosis in 22q11DS.

Olfactory deficits and psychosis-spectrum symptoms in 22q11.2 deletion syndrome

Olfactory functioning is a promising biomarker for psychosis in 22q11.2 deletion syndrome (22q11DS) but has not been well studied to date. This is a pilot effort to evaluate the potential for tests of olfactory functioning to contribute to risk and resilience prediction in 22q11DS, and is the first study to evaluate relationships among olfactory deficits, cognition and psychosis-spectrum symptoms. Odor identification and discrimination were evaluated in 32 individuals with 22q11DS and 110 healthy comparison subjects (HC). Individuals with 22q11DS also underwent cognitive testing with the Penn Computerized Neurocognitive Battery, which evaluates executive functioning, episodic memory, complex cognition, and social cognition. Positive, negative, disorganized and general psychosis-spectrum symptoms were rated according to the Scale of Prodromal Symptoms. Age-normalized scores were calculated for odor identification and discrimination based on normative data. Both odor identification (p < 0.001, Cohen's d = −2.15, 95% CI [−2.62, −1.68]) and discrimination (p < 0.001, Cohen's d = −1.81, 95% CI [−2.26, −1.35]) were significantly impaired in 22q11DS relative to HC. There were no sex differences in either group. Neither odor identification nor discrimination was correlated with overall cognition or any specific cognitive domain in 22q11DS. Impairment in odor discrimination was correlated with higher negative and overall psychosis-spectrum symptoms. There was no significant effect of catechol-O-methyltransferase Val(158)Met genotype or presence of velopharyngeal insufficiency on olfactory functioning. Olfactory deficits, particularly olfactory discrimination, are robust in 22q11DS and appear to be independent of cognitive deficits. They are also clinically relevant and related to psychosis-spectrum symptoms. Olfactory functioning appears to be a promising biomarker for psychosis in 22q11DS.

Attention Deficit Hyperactivity Disorder Symptoms and Psychosis in 22q11.2 Deletion Syndrome.

22q11.2 Deletion Syndrome (22q11.2DS) is associated with increased risk for schizophrenia in adulthood while Attention Deficit Hyperactivity Disorder (ADHD) is the most prevalent diagnosis in childhood. Inattention symptoms are pronounced in 22q11.2DS and given that attentional impairment is a core feature of schizophrenia, inattention symptoms may reflect underlying ADHD, psychosis, or both. We investigate whether inattention is associated with psychosis in 22q11.2DS and in other groups at risk for psychosis but without the deletion (ND) (idiopathic clinical risk and first degree family members of individuals with schizophrenia). One hundred thirty-seven individuals with 22q11.2DS (mean age: 14.0), 84 ND individuals with subthreshold psychosis (mean age: 16.9) and 31 ND individuals with family history of psychosis (mean age: 17.0) were included in the study. Psychopathology was assessed using research diagnostic assessments. ADHD total symptoms were associated with overall levels of subthreshold psychosis symptoms in 22q11.2DS (β = .8, P = .04). Inattention symptoms were specifically associated with positive (β = .5, P = .004), negative (β = .5, P = .03), and disorganized (β = .5, P < .001) symptoms, while hyperactivity-impulsivity symptoms were associated with disorganized symptoms (β = .5, P = .01). The prevalence of ADHD inattention symptoms was higher in 22q11.2DS with subthreshold psychosis compared to ND individuals with subthreshold psychosis (P < .001), even when adjusting for cognitive impairment and overall psychopathology. The pattern was similar when comparing individuals with 22q11.2DS and ND individuals with family history of psychosis. This is the first study to examine the associations between ADHD symptoms and psychosis in 22q11.2DS. Our findings support a potentially important role of ADHD inattention symptoms in psychosis in 22q11.2DS.

Update on the 22q11.2 deletion syndrome and its relevance to schizophrenia

Schizophrenia occurs in ∼25% of individuals with 22q11.2 deletion syndrome (22q11.2DS), the strongest known molecular genetic risk factor for schizophrenia. This review highlights recent literature in 22q11.2DS as it pertains to psychosis and schizophrenia. Advances in noninvasive prenatal testing allow for early detection of 22q11.2DS in utero, whereas premature birth has been shown to be a significant risk factor for development of psychotic illness in 22q11.2DS. Impairments in various domains of cognitive and social functioning, as well as neuroanatomical alterations, are comparable with those in other high-risk groups and may serve as early signs of psychosis in 22q11.2DS. Novel research on the pathogenesis of schizophrenia in 22q11.2DS using cellular and mouse models indicates changes in expression of genes within the 22q11.2 deletion region and elsewhere in the genome, implicating molecular pathways involved in schizophrenia and associated neurocognitive deficits. Increased risks of obesity and of Parkinson's disease in 22q11.2DS warrant consideration in antipsychotic management. Progress in characterizing and predicting psychotic illness in 22q11.2DS supports this identifiable subpopulation as a molecular model with important implications for understanding the pathogenesis of schizophrenia in the general population and for development of potential novel therapies.

Ultra high risk status and transition to psychosis in 22q11.2 deletion syndrome

The 22q11.2 deletion syndrome (22q11DS) is characterized by high rates of psychotic symptoms and schizophrenia, making this condition a promising human model for studying risk factors for psychosis. We explored the predictive value of ultra high-risk (UHR) criteria in a sample of patients with 22q11DS. We also examined the additional contribution of sociodemographic, clinical and cognitive variables to predict transition to psychosis within a mean interval of 32.56176 months after initial assessment. Eighty-nine participants with 22q11DS (age range: 8–30 years; mean: 16.1647) were assessed using the structured interview for psychosis-risk syndromes. Information on axis I diagnoses, internalizing and externalizing symptoms, level of functioning and IQ was also collected. At baseline, 22 (24.7%) participants met UHR criteria. Compared to those without a UHR condition, they had a significantly lower functioning, more frequent anxiety disorders and more severe psychopathology. Transition rate to psychosis was 27.3% in UHR and 4.5% in non-UHR participants. Cox regression analyses revealed that UHR status significantly predicted conversion to psychosis. Baseline level of functioning was the only other additional predictor. This is the first study investigating the predictive value of UHR criteria in 22q11DS. It indicates that the clinical path leading to psychosis is broadly comparable to that observed in other clinical high-risk samples. Nevertheless, the relatively high transition rate in non-UHR individuals suggests that other risk markers should be explored in this population. The role of low functioning as a predictor of transition to psychosis should also be investigated more in depth.Disclosure of interestThe authors have not supplied their declaration of competing interest.

Subthreshold Psychosis in 22q11.2 Deletion Syndrome: Multisite Naturalistic Study.

Nearly one-third of individuals with 22q11.2 deletion syndrome (22q11.2DS) develop a psychotic disorder during life, most of them by early adulthood. Importantly, a full-blown psychotic episode is usually preceded by subthreshold symptoms. In the current study, 760 participants (aged 6-55 years) with a confirmed hemizygous 22q11.2 microdeletion have been recruited through 10 medical sites worldwide, as part of an international research consortium. Of them, 692 were nonpsychotic and with complete measurement data. Subthreshold psychotic symptoms were assessed using the Structured Interview for Prodromal Syndromes (SIPS). Nearly one-third of participants met criteria for positive subthreshold psychotic symptoms (32.8%), less than 1% qualified for acute positive subthreshold symptoms, and almost a quarter met criteria for negative/disorganized subthreshold symptoms (21.7%). Adolescents and young adults (13-25 years) showed the highest rates of subthreshold psychotic symptoms. Additionally, higher rates of anxiety disorders and attention deficit/hyperactivity disorder (ADHD) were found among the study participants with subthreshold psychotic symptoms compared to those without. Full-scale IQ, verbal IQ, and global functioning (GAF) scores were negatively associated with participants' subthreshold psychotic symptoms. This study represents the most comprehensive analysis reported to date on subthreshold psychosis in 22q11.2DS. Novel findings include age-related changes in subthreshold psychotic symptoms and evidence that cognitive deficits are associated with subthreshold psychosis in this population. Future studies should longitudinally follow these symptoms to detect whether and how early identification and treatment of these manifestations can improve long-term outcomes in those that eventually develop a psychotic disorder.

Associations between neurodevelopmental genes, neuroanatomy, and ultra high risk symptoms of psychosis in 22q11.2 deletion syndrome.

22q11.2 deletion syndrome is a neurogenetic disorder resulting in the deletion of over 40 genes. Up to 40% of individuals with 22q11.2DS develop schizophrenia, though little is known about the underlying mechanisms. We hypothesized that allelic variation in functional polymorphisms in seven genes unique to the deleted region would affect lobar brain volumes, which would predict risk for psychosis in youth with 22q11.2DS. Participants included 56 individuals (30 males) with 22q11.2DS. Anatomic MR images were collected and processed using Freesurfer. Participants were genotyped for 10 SNPs in the COMT, DGCR8, GNB1L, PIK4CA, PRODH, RTN4R, and ZDHHC8 genes. All subjects were assessed for ultra high risk symptoms of psychosis. Allelic variation of the rs701428 SNP of RTN4R was significantly associated with volumetric differences in gray matter of the lingual gyrus and cuneus of the occipital lobe. Moreover, occipital gray matter volumes were robustly associated with ultra high risk symptoms of psychosis in the presence of the G allele of rs701428. Our results suggest that RTN4R, a relatively under-studied gene at the 22q11 locus, constitutes a susceptibility gene for psychosis in individuals with this syndrome through its alteration of the architecture of the brain. © 2017 Wiley Periodicals, Inc.

Ultra high risk status and transition to psychosis in 22q11.2 deletion syndrome

The 22q11.2 deletion syndrome (22q11DS) is characterized by high rates of psychotic symptoms and schizophrenia, making this condition a promising human model for studying risk factors for psychosis. We explored the predictive value of ultra high risk (UHR) criteria in a sample of patients with 22q11DS. We also examined the additional contribution of socio-demographic, clinical and cognitive variables to predict transition to psychosis within a mean interval of 32.5 ± 17.6 months after initial assessment. Eighty-nine participants with 22q11DS (age range: 8-30 years; mean 16.1 ± 4.7) were assessed using the Structured Interview for Psychosis-Risk Syndromes. Information on Axis I diagnoses, internalizing and externalizing symptoms, level of functioning and IQ was also collected. At baseline, 22 (24.7%) participants met UHR criteria. Compared to those without a UHR condition, they had a significantly lower functioning, more frequent anxiety disorders, and more severe psychopathology. Transition rate to psychosis was 27.3% in UHR and 4.5% in non-UHR participants. Cox regression analyses revealed that UHR status significantly predicted conversion to psychosis. Baseline level of functioning was the only other additional predictor. This is the first study investigating the predictive value of UHR criteria in 22q11DS. It indicates that the clinical path leading to psychosis is broadly comparable to that observed in other clinical high-risk samples. Nevertheless, the relatively high transition rate in non-UHR individuals suggests that other risk markers should be explored in this population. The role of low functioning as a predictor of transition to psychosis should also be investigated more in depth.

Association between prematurity and the evolution of psychotic disorders in 22q11.2 deletion syndrome.

In this study, we report the developmental, physical and psychiatric manifestations of 22q11.2 deletion syndrome (22q11.2DS) in a large Israeli cohort, and search for a possible association between preterm birth and the risk for psychotic disorders. The study population consisted of 128 individuals with 22q11.2DS (77 male, 51 female), aged 1-55years (mean±SD 12.9±11.0). All subjects underwent a comprehensive medical evaluation. All subjects older than 5years (n=104) were also evaluated psychiatrically. Overall, we found rates of physical manifestations similar to those previously reported in the literature. Psychiatric disorders were very common among our study population, with psychotic disorders occurring in 16.3% of the psychiatrically evaluated population. We found an association between the presence of psychotic disorders and preterm birth. Our results replicate and extend the findings of a previous work and suggest that the evolution of psychosis in 22q11.2DS is a neurodevelopmental process with early obstetric and medical precursors.