Elemi J. Breetvelt

Cognitive Decline Preceding the Onset of Psychosis in Patients With 22q11.2 Deletion Syndrome

IMPORTANCE Patients with 22q11.2 deletion syndrome (22q11DS) have an elevated (25%) risk of developing schizophrenia. Recent reports have suggested that a subgroup of children with 22q11DS display a substantial decline in cognitive abilities starting at a young age. OBJECTIVE To determine whether early cognitive decline is associated with risk of psychotic disorder in 22q11DS. DESIGN, SETTING, AND PARTICIPANTS Prospective longitudinal cohort study. As part of an international research consortium initiative, we used the largest data set of intelligence (IQ) measurements in patients with 22q11DS reported to date to investigate longitudinal IQ trajectories and the risk of subsequent psychotic illness. A total of 829 patients with a confirmed hemizygous 22q11.2 deletion, recruited through 12 international clinical research sites, were included. Both psychiatric assessments and longitudinal IQ measurements were available for a subset of 411 patients (388 with ≥1 assessment at age 8-24 years). MAIN OUTCOMES AND MEASURES Diagnosis of a psychotic disorder, initial IQ, longitudinal IQ trajectory, and timing of the last psychiatric assessment with respect to the last IQ test. RESULTS Among 411 patients with 22q11DS, 55 (13.4%) were diagnosed as having a psychotic disorder. The mean (SD) age at the most recent psychiatric assessment was 16.1 (6.2) years. The mean (SD) full-scale IQ at first cognitive assessment was lower in patients who developed a psychotic disorder (65.5 [12.0]) compared with those without a psychotic disorder (74.0 [14.0]). On average, children with 22q11DS showed a mild decline in IQ (full-scale IQ, 7.04 points) with increasing age, particularly in the domain of verbal IQ (9.02 points). In those who developed psychotic illness, this decline was significantly steeper (P < .001). Those with a negative deviation from the average cognitive trajectory observed in 22q11DS were at significantly increased risk for the development of a psychotic disorder (odds ratio = 2.49; 95% CI, 1.24-5.00; P = .01). The divergence of verbal IQ trajectories between those who subsequently developed a psychotic disorder and those who did not was distinguishable from age 11 years onward. CONCLUSIONS AND RELEVANCE In 22q11DS, early cognitive decline is a robust indicator of the risk of developing a psychotic illness. These findings mirror those observed in idiopathic schizophrenia. The results provide further support for investigations of 22q11DS as a genetic model for elucidating neurobiological mechanisms underlying the development of psychosis.

Cannabis use at a young age is associated with psychotic experiences

BACKGROUND Cannabis use is associated with psychosis and a range of subclinical psychiatric symptoms. The strength of this association depends on dosage and age at first use. The current study investigates whether level of cannabis exposure and starting age are associated with specific profiles of subclinical symptoms. METHOD We collected cross-sectional data from a young adult population sample by administering an online version of the Community Assessment of Psychic Experiences (CAPE). Cannabis exposure was quantified as the amount of Euros spent on cannabis per week and the age of initial cannabis use. The primary outcome measure was the odds ratio (OR) to belong to the highest 10% of scores on the total CAPE and the positive-, negative- and depressive symptom dimensions. RESULTS In 17 698 adolescents (mean age 21.6, s.d.=4.2 years), cannabis use at age 12 years or younger was strongly associated with a top 10% score on psychotic experiences [OR 3.1, 95% confidence interval (CI) 2.1-4.3] and to a lesser degree with negative symptoms (OR 1.7, 95% CI 1.1-2.5). The OR of heavy users (>€25/week) for negative symptoms was 3.4 (95% CI 2.9-4.1), for psychotic experiences 3.0 (95% CI 2.4-3.6), and for depressive symptoms 2.8 (95% CI 2.3-3.3). CONCLUSIONS Early start of cannabis use is strongly associated with subclinical psychotic symptoms and to a lesser degree with negative symptoms, while smoking high amounts of cannabis is associated with increased levels of all three symptom dimensions: psychotic, negative and depressive. These results support the hypothesis that the impact of cannabis use is age specific.

Expression of autism spectrum and schizophrenia in patients with a 22q11.2 deletion.

BACKGROUND Copy number variants (CNVs) associated with neuropsychiatric disorders are increasingly being identified. While the initial reports were relatively specific, i.e. implicating vulnerability for a particular neuropsychiatric disorder, subsequent studies suggested that most of these CNVs can increase the risk for more than one neuropsychiatric disorder. Possibly, the different neuropsychiatric phenotypes associated with a single genetic variant are really distinct phenomena, indicating pleiotropy. Alternatively, seemingly different disorders could represent the same phenotype observed at different developmental stages or the same underlying pathogenesis with different phenotypic expressions. AIMS To examine the relation between autism and schizophrenia in patients sharing the same CNV. METHOD We interviewed parents of 78 adult patients with the 22q11.2 deletion (22q11.2DS) to examine if autistic symptoms during childhood were associated with psychosis in adulthood. We used Chi-square, T-tests and logistic regression while entering cognitive level, gender and age as covariates. RESULTS The subgroup of 22q11.2DS patients with probable ASD during childhood did not show an increased risk for psychosis in adulthood. The average SRS scores were highly similar between those with and those without schizophrenia. CONCLUSIONS ASD and schizophrenia associated with 22q11.2DS should be regarded as two unrelated, distinct phenotypic manifestations, consistent with true neuropsychiatric pleiotropy. 22q11.2DS can serve as a model to examine the mechanisms associated with neuropsychiatric pleiotropy associated with other CNVs.

Schizophrenia risk factors constitute general risk factors for psychiatric symptoms in the population

BACKGROUND The presence of a psychosis continuum is suggested by studies showing that schizophrenia and non-clinical psychotic symptoms in the general population share the same risk factors. However, to our knowledge no large-scale studies have been conducted which examine the specificity of these risk factors in the general population. AIM To investigate whether socio-demographic characteristics associated with non-clinical psychotic symptoms are also associated with other psychiatric symptoms. And secondly, to examine to what extent concomitant psychiatric symptoms explain the relationship between socio-demographic characteristics and non-clinical psychotic symptoms. METHODS In a general population sample of 4894 subjects (mean age 39 years, 45% men) from the Utrecht Health Project we investigated the associations of socio-demographical characteristics with non-clinical psychotic symptoms and other psychiatric symptoms by using the SCL-90. We examined these associations using multivariable logistic regression analyses with and without controlling for the presence of other psychiatric symptoms. RESULTS Participants with non-clinical psychotic symptoms had an 89% probability of concomitant depressive, anxiety or phobic anxiety symptoms, compared to 11% in participants without psychotic symptoms. The risk profiles for non-clinical psychotic symptoms and other psychiatric symptoms were largely similar. Non-Dutch ethnicity was most strongly associated with non-clinical psychotic symptoms. Adjusting for other psychiatric symptoms did not increase the specificity of the risk factors. CONCLUSION Socio-demographic risk factors for non-clinical psychotic symptoms in the general population are also risk factors for other psychiatric symptoms. The relationship between these risk factors and psychotic symptoms are for a substantial part explained by an increase in other psychiatric symptoms.

Early interventions in risk groups for schizophrenia: what are we waiting for?

Intervention strategies in adolescents at ultra high-risk (UHR) for psychosis are promising for reducing conversion to overt illness, but have only limited impact on functional outcome. Recent studies suggest that cognition does not further decline during the UHR stage. As social and cognitive impairments typically develop before the first psychotic episode and even years before the UHR stage, prevention should also start much earlier in the groups at risk for schizophrenia and other psychiatric disorders. Early intervention strategies could aim to improve stress resilience, optimize brain maturation, and prevent or alleviate adverse environmental circumstances. These strategies should urgently be tested for efficacy: the prevalence of ~1% implies that yearly ~22 in every 100,000 people develop overt symptoms of this illness, despite the fact that for many of them—e.g., children with an affected first-degree family member or carriers of specific genetic variants—increased risk was already identifiable early in life. Our current ability to recognize several risk groups at an early age not only provides an opportunity, but also implies a clinical imperative to act. Time is pressing to investigate preventive interventions in high-risk children to mitigate or prevent the development of schizophrenia and related psychiatric disorders.

The association of the alpha-5 subunit of the nicotinic acetylcholine receptor gene and the brain-derived neurotrophic factor gene with different aspects of smoking behavior.

Recent studies show that different aspects of smoking behavior are associated with the α-5 subunit of the nicotinic acetylcholine receptor (CHRNA5) gene and the gene coding for brain-derived neurotrophic factor (BDNF). This raises the question whether the amount of cigarettes smoked per day has a different genetic background than smoking initiation and what other smoking phenotypes may be relevant. The aim of this study was to replicate these associations in a large population-based sample. We investigated the association with smoking initiation and the number of cigarettes used per day and additional smoking phenotypes in a population-based sample of 2166 participants of Dutch origin. Rs6265 in BDNF was not associated with smoking initiation. This single nucleotide polymorphism was associated with smoking cessation. Rs16969968 in CHRNA5 was associated with the amount of nicotine used and in particular smoking 25 cigarettes or more per day. Overall, the results confirm the involvement of the CHRNA5 gene in the amount of nicotine use and further suggest involvement of the BDNF gene in smoking behavior.

Association between cannabis and psychiatric hospitalization

Schubart CD, Boks MPM, Breetvelt EJ, van Gastel WA, Groenwold RHH, Ophoff RA, Sommer IEC, Kahn RS. Association between cannabis and psychiatric hospitalization.

An incidence study of diagnosed autism-spectrum disorders among immigrants to the Netherlands

To estimate the risk of developing autism‐spectrum disorder (ASD) in children born to immigrants as compared with children of Dutch‐born parents.

Autism Spectrum and psychosis risk in the 22q11.2 deletion syndrome. Findings from a prospective longitudinal study

BACKGROUND Individuals with 22q11.2 deletion syndrome (22q11DS) have a 25% risk for schizophrenia and related psychotic disorders. Some have hypothesized that Autism Spectrum Disorders (ASDs) diagnosed in children with 22q11DS may actually represent the social-communicative defects often observed during the early developmental stages of schizophrenia. METHODS We prospectively studied 89 children with 22q11DS to test this hypothesis. At baseline, the Autism Diagnostic Interview was used to assess ASD, evaluating both current and early childhood behaviors. At follow-up, the Schedule for Affective Disorders and Schizophrenia for School-Age Children (K-SADS) was used to determine development of a psychotic disorder or psychotic symptoms. RESULTS The average age (±SD) at first and last assessments was 14.3±1.9 and 19.0±3.0years, respectively. Nineteen (21.3%) children developed a psychotic disorder. Contrary to our hypothesis, there was no significant difference in the proportion that developed a psychotic disorder, comparing those with (n=9, 17.3%) and those without ASD at baseline (n=10, 27%; OR=0.500, 95% CI=0.160-1.569, p=0.235). Similar results were obtained using autistic symptom severity as quantitative predicting variable, psychotic symptoms as the outcome, and when correcting for age, gender and full scale IQ. CONCLUSION Results indicate that in children with 22q11DS, early childhood autistic features are not associated with an increased risk for subsequent development of psychotic disorders or symptoms, replicating previous retrospective findings in adults with 22q11DS. These results indicate that ASD and psychotic disorders can emerge independently, as pleiotropic phenotypes in the context of 22q11DS.

BDNF Val66Met homozygosity does not influence plasma BDNF levels in healthy human subjects

A putative pathway by which the BDNF Val66Met polymorphism (rs6265) leads to aberrant phenotypes is its influence on plasma BDNF. Research into the impact of rs6265 on plasma BDNF has given rise to conflicting results. Moreover, most such studies have compared Met-carriers with Val-homozygous subjects. We therefore genotyped subjects from a population-based cohort (the Utrecht Health Project, N=2743) and assessed whether plasma BDNF differs between rs6265 homozygous groups. We maximized the number of Met-homozygous subjects in whom we measured plasma BDNF, resulting in plasma BDNF being available for 19 Met-homozygous and 42 matched Val-homozygous subjects. Mean concentrations (S.D.) were 1963.1 (750.1) and 2133.2 pg/ml (1164.3) for the Val/Val and Met/Met groups, respectively. Using ANOVA, no differences in plasma BDNF between the two groups were detected. In conclusion, these results add to a growing body of evidence indicating that allelic variation at rs6265 does not have medium to large effects on plasma BDNF concentrations.