[Suicidality in adolescents with therapy refractory internalising behaviour]. / Suïcidaliteit bij adolescenten met therapieresistente internaliserende problematiek.

BACKGROUND: Suicidality in adolescence is increasingly becoming a societal problem, especially because there remains a small group of patients in which treatment effectiveness is small. Existing formal guidelines often are of limited value in this group that often shows complex comorbidity.
AIM: To contribute to the diagnostic and aetiological perspective in order to better understand therapy refractory internalising behaviour.
METHOD: Integration of several scientific theoretical concepts into a holistic model.
RESULTS: Evidence shows that suicidality should be considered within a broader scope of therapy refractory internalising behaviour. Important underpinnings comprise a partially overprotective parenting style, disturbed attachment processes and social anxiety. Internalising and externalising behaviour problems are viewed as expressions of avoidance behaviour. Furthermore, we discuss important implications for treatment.
CONCLUSION: Applying an aetiological model for therapy refractory internalising behaviour may help to increase efficacy of treatment. Thus, transdiagnostic treatment can be offered, being less dependent on specific dsm-classifications. Focus of treatment is on restoration of basic trust between the youngster and his parents, and on ending avoidance behaviour that is based on social anxiety.

Motor Disturbance in ASD: A Pilot Study Showing Hypokinetic Behavior?

Data supporting theoretical models linking autism spectrum disorders (ASD) to motor disturbance are inconclusive. In the present study, children and adolescents with ASD (n = 44) were compared with a matched group of typically developing individuals (n = 49) on both instrumental and observational assessments of motor abnormalities. No group differences were found in the instrumental data. However, more bradykinetic motor behavior was found using an observational scale in the ASD groups. More rigid motor behavior was found in the adolescents with ASD but not in the children. Individuals with ASD show significantly more hypokinetic behavior, which may not be strictly dopaminergic in origin, but may reflect a weak central coherency in neuronal networks related to the motor system in which developmental changes are present.

More than 25 years of genetic studies of clozapine-induced agranulocytosis.

Clozapine is one of the most effective atypical antipsychotic drugs prescribed to patients with treatment-resistant schizophrenia. Approximately 1% of patients experience potential life-threatening adverse effects in the form of agranulocytosis, greatly hindering its applicability in clinical practice. The etiology of clozapine-induced agranulocytosis (CIA) remains unclear, but is thought to be a heritable trait. We reviewed the genetic studies of CIA published thus far. One recurrent finding from early candidate gene study to more recent genome-wide analysis is that of the involvement of human leukocyte antigen locus. We conclude that CIA is most likely a complex, polygenic trait, which may hamper efforts to the development of a genetic predictor test with clinical relevance. To decipher the genetic architecture of CIA, it is necessary to apply more rigorous standards of phenotyping and study much larger sample sizes.

[Somatic screening in child and adolescent psychiatry: a descriptive pilot study]. / Somatische screening in kinder- en jeugdpsychiatrie: een descriptieve pilotstudie.

BACKGROUND: Somatic disorders occur more often in psychiatric patients than in the general population. Somatic symptoms can cause or increase psychiatric symptoms. Psychiatric symptoms and their treatment can have an effect on the physical state of the patient. A pilot study involving an adult outpatient population has demonstrated that 62% of the patients studied had new clinically relevant symptoms. So far, no other data are available relating to somatic screening in child and adolescent psychiatry. AIM: To assess whether somatic screening of children and adolescents newly referred to a department of child and adolescent psychiatry in the Netherlands gives added value to the diagnosis and treatment policy. METHOD: In a pilot study 43 newly referred patients aged between 6 and 18 were screened by means of somatic history, a physical examination and blood parameters. On this basis we could calculate the percentage of somatic symptoms and , where necessary, follow-up treatment could be applied. RESULTS: One or more clinically relevant disorders were found in almost 56% of the children and adolescents investigated. The disorders included dysmorphic anomalies, weight and height deviations, raised thyroid hormone levels, dyslipidaemia, anaemia and vitamin D and B12 deficiency. Advice about a healthy lifestyle was given to 44% of the patients. An antipsychotic medication in 25% of the patients was changed, in the case of 16% of the patients a family doctor was contacted about subsequent treatment and 19% of the patients were referred to a medical specialist. CONCLUSION: Although the results of the pilot study indicate that somatic screening does provide added value, more research is needed in order to optimise the screening procedure.

Genome-wide association study of lymphoblast cell viability after clozapine exposure.

Clozapine is an antipsychotic drug with proven efficacy in treatment-resistant schizophrenia but also known to induce potentially lethal agranulocytosis (CIA) in 1% of patients. Genetic factors are likely to play a role in the molecular basis of CIA. We explored an in vitro system to study the genetic susceptibility of CIA. Cell viability was measured in 90 lymphoblast cell lines exposed to a series of increasing concentrations of clozapine for 48 hr. Quantitative trait measures of cell viability as well as area under the survival curve were used in a linear mixed model for genome-wide association analyses. The estimated heritability of clozapine-induced cell viability reduction in these cell lines is h2=0.76. No genome-wide significant association was observed after correction for multiple testing. Two independent loci with nominal evidence of association were observed at 30× clinical clozapine concentration: rs2709505 (P=1.41×10(-8)) in an intron of MDFIC and rs10457252 (P=1.79×10(-8)) located in a gene desert at chromosome 6q21. We identified one locus (rs1293970) near PRG4 that was consistently associated for all separate concentration analyses at P<5×10(-5). PRG4 encodes hemangiopoietin, a growth stimulator for hematopoietic stem cells. No evidence was observed for involvement of the MHC region. Our results demonstrate that clozapine-induced viability reduction in lymphoblast cell lines is a heritable, polygenic trait. Thus, in vitro models of CIA might be a useful tool for future discovery of genetic risk factors, although larger sample sizes will be required to unambiguously identify these loci.

[The challenge of staging developmental disorders]. / Stagering: een ontwikkelingspuzzel.

BACKGROUND: On the basis of our current knowledge, developmental disorders can be divided into the following stages: stage 0: normal variation, stage 1: simple disorder of moderate severity, stage 2: complicating co-morbidity and/or harmful background circumstances, and stage 3: serious disorder with harmful background circumstances. AIM: To describe the current views on prognostic aspects of staging from a developmental perspective. METHOD: The study is based on a critical review of the relevant literature. RESULTS: The current division into stages is still insufficiently predictive, partly because development is a flexible process with risks, chances and second chances. All psychiatric disorders are in essence developmental disorders that arise in the course of development as a result of the interaction between predisposition and background circumstances. As from the very first meiosis the hereditary predisposition is subject to influences in the womb environment. The forming of networks in the brain, the distribution of neurotransmitters and the neurological profile are influenced by the genetic potential for chances and risks and are all a result of interactions. This complicated developmental history raises questions about the specificity of current clinical syndromes. CONCLUSION: In time there is likely to be a much more accurate staging system. This will come about if, as a result of the analysis of large pooled databases, it becomes possible to make a better assessment of the relative risks of genetic configurations, brain connections, stress regulation in the brain, neuropsychological profiles and behavioural and emotional forms of expression in the light of the interactions that occur with the aforementioned background circumstances.

A double hit implicates DIAPH3 as an autism risk gene.

Recent studies have shown that more than 10% of autism cases are caused by de novo structural genomic rearrangements. Given that some heritable copy number variants (CNVs) have been observed in patients as well as in healthy controls, to date little attention has been paid to the potential function of these non-de novo CNVs in causing autism. A normally intelligent patient with autism, with non-affected parents, was identified with a maternally inherited 10 Mb deletion at 13q21.2. Sequencing of the genes within the deletion identified a paternally inherited nonsynonymous amino-acid substitution at position 614 of diaphanous homolog 3 (DIAPH3) (proline to threonine; Pro614Thr). This variant, present in a highly conserved domain, was not found in 328 healthy subjects. Experiments showed a transient expression of Diaph3 in the developing murine cerebral cortex, indicating it has a function in brain development. Transfection of Pro614Thr in murine fibroblasts showed a significant reduction in the number of induced filopodia in comparison to the wild-type gene. DIAPH3 is involved in cell migration, axon guidance and neuritogenesis, and is suggested to function downstream of SHANK3. Our findings strongly suggest DIAPH3 as a novel autism susceptibility gene. Moreover, this report of a 'double-hit' compound heterozygote for a large, maternally inherited, genomic deletion and a paternally inherited rare missense mutation shows that not only de novo genomic variants in patients should be taken seriously in further study but that inherited CNVs may also provide valuable information.

Identification of novel autism candidate regions through analysis of reported cytogenetic abnormalities associated with autism.

The identification of the candidate genes for autism through linkage and association studies has proven to be a difficult enterprise. An alternative approach is the analysis of cytogenetic abnormalities associated with autism. We present a review of all studies to date that relate patients with cytogenetic abnormalities to the autism phenotype. A literature survey of the Medline and Pubmed databases was performed, using multiple keyword searches. Additional searches through cited references and abstracts from the major genetic conferences from 2000 onwards completed the search. The quality of the phenotype (i.e. of the autism spectrum diagnosis) was rated for each included case. Available specific probe and marker information was used to define optimally the boundaries of the cytogenetic abnormalities. In case of recurrent deletions or duplications on chromosome 15 and 22, the positions of the low copy repeats that are thought to mediate these rearrangements were used to define the most likely boundaries of the implicated 'Cytogenetic Regions Of Interest' (CROIs). If no molecular data were available, the sequence position of the relevant chromosome bands was used to obtain the approximate molecular boundaries of the CROI. The findings of the current review indicate: (1) several regions of overlap between CROIs and known loci of significant linkage and/or association findings, and (2) additional regions of overlap among multiple CROIs at the same locus. Whereas the first finding confirms previous linkage/association findings, the latter may represent novel, not previously identified regions containing genes that contribute to autism. This analysis not only has confirmed the presence of several known autism risk regions but has also revealed additional previously unidentified loci, including 2q37, 5p15, 11q25, 16q22.3, 17p11.2, 18q21.1, 18q23, 22q11.2, 22q13.3 and Xp22.2-p22.3.

Structural brain abnormalities in chronic schizophrenia at the extremes of the outcome spectrum.

OBJECTIVE: This study investigated the relationship between outcome and structural brain abnormalities in schizophrenia. METHOD: Intracranial volume and volumes of the cerebrum, gray and white matter, lateral and third ventricles, frontal lobes, thalamus, and cerebellum were measured in 20 patients with a poor outcome, 25 with a favorable outcome, and 23 healthy comparison subjects with magnetic resonance imaging. RESULTS: Thalamic volume was significantly smaller both in poor-outcome patients and good-outcome patients. In contrast, only poor-outcome patients displayed significantly smaller cerebral gray matter, particularly prefrontal, and enlargement of the lateral and third ventricles. No significant differences were found for intracranial, cerebellar, or cortical CSF volumes. CONCLUSIONS: Smaller thalamic volumes in schizophrenia may reflect a greater susceptibility for the disorder and seem unrelated to outcome. In contrast, gray matter volume loss of the cerebrum, particularly in the frontal lobes, and lateral and third ventricular enlargement appear related to outcome in schizophrenia.

Automated separation of gray and white matter from MR images of the human brain.

A simple automatic procedure for segmentation of gray and white matter in high resolution 1.5T T1-weighted MR human brain images was developed and validated. The algorithm is based on histogram shape analysis of MR images that were corrected for scanner nonuniformity. Calibration and validation was done on a set of 80 MR images of human brains. The automatic method's values for the gray and white matter volumes were compared with the values from thresholds set twice by the best three of six raters. The automatic procedure was shown to perform as good as the best rater, where the average result of the best three raters was taken as reference. The method was also compared with two other histogram-based threshold methods, which yielded comparable results. The conclusion of the study thus is that automated threshold based methods can separate gray and white matter from MR brain images as reliably as human raters using a thresholding procedure.

Neuropsychological dysfunctions in siblings discordant for schizophrenia.

Although cognitive impairments are well recognized in patients with schizophrenia, it is unclear which impairments are due to a genetic predisposition and which are caused by secondary disease effects or phenotype. The aim of this study is to investigate the possible relationship between genetic vulnerability to schizophrenia and cognitive functioning. Three groups of subjects were compared: 14 patients with schizophrenia, 15 healthy siblings and 32 healthy control subjects. All subjects were tested neuropsychologically. The raw test data were rescaled to standard equivalents (z-scores). Subjects' z scores on tests assessing the same cognitive domain were clustered and analyzed. Differences in cognitive functioning were found in the domains of abstraction, attention, executive functioning, spatial memory, and sensory-motor functioning. The schizophrenic probands were impaired on all these five domains whereas the healthy probands showed impairments on executive functioning and partially on sensory-motor functioning. Furthermore, for spatial memory the significant finding could mainly be attributed to impaired functioning in the patients, but not healthy siblings or control subjects, whereas for executive functioning patients and healthy siblings seemed equally impaired as compared to control subjects. The planning time of the Tower of London (TOL) and the initiation time of the Motor Planning Task (MPT) were used for measures of executive functioning, while the 'time to move of the Motor Planning Task' was used as measures of sensory motor functioning. These results suggest that the cognitive abnormalities in schizophrenia that may be related to genotype are represented in the domain of executive functioning and to some extent in the domain of sensory-motor functioning.

Structural brain abnormalities in patients with schizophrenia and their healthy siblings.

OBJECTIVE: The authors sought to investigate the contribution of genotype on structural brain abnormalities in schizophrenia. METHOD: Intracranial volumes and volumes of the cerebrum, white and gray matter, lateral and third ventricles, frontal lobes, caudate nucleus, amygdala, hippocampus, parahippocampal gyrus, and the cerebellum were measured in 32 same-sex siblings discordant for schizophrenia and 32 matched comparison subjects by means of magnetic resonance imaging. RESULTS: Third ventricle volumes did not differ between the schizophrenic patients and their healthy siblings. However, both had higher third ventricle volumes than did the comparison subjects. The schizophrenic patients had lower cerebrum volumes than did the comparison subjects, whereas the cerebrum volume of the healthy siblings did not significantly differ from the patients or comparison subjects. Additionally, patients with schizophrenia displayed a volume reduction of the frontal lobe gray matter and a volume increase of the caudate nuclei and lateral ventricles compared to both their healthy siblings and comparison subjects. Intracranial volume, CSF volume, or volumes of the cerebellum, amygdala, hippocampus, or the parahippocampal gyrus did not significantly differ among the patients, siblings, and comparison subjects. CONCLUSIONS: Healthy siblings share third ventricle enlargement with their affected relatives and may partially display a reduction in cerebral volume. These findings suggest that third ventricular enlargement, and to some extent cerebral volume decrease, may be related to genetic defects that produce a susceptibility to schizophrenia.

Outcome of schizophrenia in relation to brain abnormalities.

This article reviews the 21 studies that investigated possible relationships between structural brain abnormalities and outcome in schizophrenia. Fifteen studies used computer tomography to visualize brain morphology. In these studies, images were obtained of the ventricles but not of specific brain regions. The remaining six studies used magnetic resonance imaging, examining possible relationships between outcome, ventricular size, and specific brain regions. One out of two studies found relationships between brain structure and outcome. The data suggest that the extent of ventricular enlargement in patients with schizophrenia may be related to outcome. No clear relationship between outcome and changes in specific brain regions was found. Apart from considerations about the methodology of measuring different brain regions, the procedure used to measure outcome is important. Outcome, as it is assessed at various points during the course of illness, may be variable and seems to fluctuate during the first 10 to 15 years of disease. Significantly, to date no studies relating outcome to brain structure have used patient samples with a duration of illness longer than 15 years.

Partial volume decrease of the thalamus in relatives of patients with schizophrenia.

OBJECTIVE: The authors' goal was to compare the thalamic, total brain, and intracranial volumes of patients with schizophrenia, their healthy siblings, and normal comparison subjects. METHOD: Magnetic resonance imaging (MRI) brain scans were obtained for 32 same-sex siblings who were discordant for schizophrenia and 32 matched normal comparison subjects. RESULTS: Mean total thalamic volume, corrected for total brain volume, was significantly different among affected siblings, unaffected siblings, and comparison subjects. Thalamic volume was smallest in the patients; thalamic volume in their siblings was smaller than that of comparison subjects but larger than that of the patients with schizophrenia. CONCLUSIONS: These results suggest that healthy siblings of patients with schizophrenia partially share the thalamic abnormalities of their affected relatives.