Doron Gothelf

COMT genotype predicts longitudinal cognitive decline and psychosis in 22q11.2 deletion syndrome

Although schizophrenia is strongly hereditary, there are limited data regarding biological risk factors and pathophysiological processes. In this longitudinal study of adolescents with 22q11.2 deletion syndrome, we identified the catechol-O-methyltransferase low-activity allele (COMTL) as a risk factor for decline in prefrontal cortical volume and cognition, as well as for the consequent development of psychotic symptoms during adolescence. The 22q11.2 deletion syndrome is a promising model for identifying biomarkers related to the development of schizophrenia.

Weight Gain Associated With Olanzapine and Risperidone in Adolescent Patients: A Comparative Prospective Study

OBJECTIVE To evaluate weight gain associated with olanzapine, risperidone, and haloperidol treatment and its clinical risk factors in adolescent patients. METHOD The study was conducted at three adolescent psychiatric departments in two mental health centers in the Tel Aviv area. All patients were Jewish Israelis. Weight and body mass index (BMI) of hospitalized adolescents treated with olanzapine (n = 21), risperidone (n = 21), or haloperidol (n = 8) were prospectively monitored on a weekly basis for the first 12 weeks of treatment. Various clinical risk factors were tested for association with weight gain. RESULTS The olanzapine and risperidone groups experienced significant weight gain between baseline and endpoint (p < .01), whereas the average weight of the haloperidol group did not change. Average weight gain was significantly higher for the olanzapine group (7.2 +/- 6.3 kg, 11.1% +/- 7.8%) than for the risperidone (3.9 +/- 4.8 kg, 6.6% +/- 8.6%) and haloperidol (1.1 +/- 3.3 kg, 1.5% +/- 6.0%) groups. Extreme weight gain (>7%) was recorded in 19 patients (90.5%), 9 patients (42.9%), and 1 (12.5%) patient, respectively Gender (males), low concern about gaining weight (females), low baseline BMI, and paternal BMI were positively correlated with weight gain, whereas previous neuroleptic history, neuroleptic dosage, response to treatment, and illness duration were not. CONCLUSIONS Olanzapine and risperidone are associated with extreme weight gain in adolescents, much higher than that reported in adults. This side effect should be taken into consideration before prescribing these medications, especially in patients at high risk.

Psychiatric Disorders and Intellectual Functioning Throughout Development in Velocardiofacial (22q11.2 Deletion) Syndrome

OBJECTIVE Velocardiofacial syndrome (VCFS) is associated with cognitive deficits and high rates of schizophrenia and other neuropsychiatric disorders. We report the data from two large cohorts of individuals with VCFS from Israel and Western Europe to characterize the neuropsychiatric phenotype from childhood to adulthood in a large sample. METHOD Individuals with VCFS (n = 172) aged 5 to 54 years were evaluated with structured clinical interviews for psychiatric disorders and age-appropriate versions of the Wechsler intelligence tests. RESULTS The frequency of psychiatric disorders was high and remarkably similar between samples. Psychotic disorders and depression were uncommon during childhood but increased in rates during adulthood (depressive disorders: 40.7% in young adults [aged 18-24 years]; psychotic disorders: 32.1% in adults [age >24 years]). Cognitive scores were inversely associated with age in subjects with VCFS, including patients without psychosis. Specifically, Verbal IQ (VIQ) scores negatively correlated with age, and the subjects with VCFS and psychotic disorders had significantly lower VIQ scores than nonpsychotic VCFS subjects. CONCLUSIONS Neuropsychiatric deficits in individuals with VCFS seem to follow a developmental pattern. The VIQ scores are negatively associated with age and rates of mood, and psychotic disorders increase dramatically during young adulthood. The data presented here support careful monitoring of psychiatric symptoms during adolescence and young adulthood in VCFS. Prospective longitudinal studies are needed to examine the nature of age-related cognitive changes and their association with psychiatric morbidity in VCFS.

Correlation of Suicidal and Violent Behavior in Different Diagnostic Categories in Hospitalized Adolescent Patients

OBJECTIVE To determine the relative importance of aggression and depression in adolescent suicide within different diagnostic categories. METHOD One hundred sixty-three consecutive admissions to an adolescent psychiatric inpatient unit were assessed using a semistructure diagnostic instrument, the Schedule for Affective Disorders and Schizophrenia for School-Age Children. Scores for depression, suicidal behaviors, and violent behaviors were calculated from this assessment. RESULTS Anorexia nervosa and conduct disorder patients had the highest suicidal behavior scores. In addition, patients with conduct disorder were significantly more violent than patients with major depressive disorder, and scores on the Violent Behavior Scale correlated with suicidal symptoms but not with depressive symptoms. CONCLUSION Aggression may be as important in some kinds of suicidal behaviors as is depression. Thus it seems that there are hypothetically at least two types of suicidal behaviors during adolescence: a wish to die (depression) and a wish not to be here for a time (impulse control). The first type of suicidal behavior characterizes that seen in disorders with prominent depression such as major depressive disorder and anorexia nervosa, and the second characterizes disorders of impulse control such as conduct disorder.

Neuroanatomy of Fragile X Syndrome Is Associated with Aberrant Behavior and the Fragile X Mental Retardation Protein (FMRP)

To determine how neuroanatomic variation in children and adolescents with fragile X syndrome is linked to reduced levels of the fragile X mental retardation‐1 protein and to aberrant cognition and behavior.

Obsessive-compulsive disorder in patients with velocardiofacial (22q11 deletion) syndrome

The study of neurogenetic microdeletion syndromes provides an insight into the developmental psychopathology of psychiatric disorders. The aim of the study was to evaluate the prevalence of psychiatric disorders, especially obsessive‐compulsive disorder (OCD), in patients with velocardiofacial syndrome (VCFS), a 22q11 microdeletion syndrome. Forty‐three subjects with VCFS of mean age 18.3 ± 10.6 years were comprehensively assessed using semi‐structured psychiatric interview and the Yale–Brown obsessive compulsive scale (Y‐BOCS). Best estimate diagnoses were made on the basis of information gathered from subjects, parents, teachers, and social workers. Fourteen VCFS subjects (32.6%) met the DSM‐IV criteria for OCD. OCD had an early age of onset and generally responded to fluoxetine treatment. It was not related to mental retardation. The most common obsessive‐compulsive symptoms were contamination, aggression, somatic worries, hoarding, repetitive questions, and cleaning. Sixteen of the 43 patients (37.2%) had attention‐deficit/hyperactivity disorder (ADHD), and 7 (16.2%) had psychotic disorder. The results of our study suggest that there is a strong association between VCFS and early‐onset OCD. This finding may be significant in the understanding of the underlying genetic basis of OCD.

Developmental trajectories of brain structure in adolescents with 22q11.2 deletion syndrome: A longitudinal study

The 22q11.2 deletion syndrome (22q11.2DS) is associated with very high rates of schizophrenia-like psychosis and cognitive deficits. Here we report the results of the first longitudinal study assessing brain development in individuals with 22q11.2DS. Twenty-nine children with 22q11.2DS and 29 age and gender matched controls were first assessed during childhood or early adolescence; Nineteen subjects with 22q11.2DS and 18 controls underwent follow-up during late adolescence-early adulthood. The 22q11.2DS subjects showed greater longitudinal increase in cranial and cerebellar white matter, superior temporal gyrus, and caudate nucleus volumes. They also had a more robust decrease in amygdala volume. Verbal IQ (VIQ) scores of the 22q11.2DS group that developed psychotic disorders declined significantly between assessments. Decline in VIQ in 22q11.2DS was associated with more robust reduction of left cortical grey matter volume. No volumetric differences were detected between psychotic and nonpsychotic subjects with 22q11.2DS. Brain maturation associated with verbal cognitive development in 22q11.2DS varies from that observed in healthy controls. Further longitudinal studies are likely to elucidate brain developmental trajectories in 22q11.2DS and their association to psychotic disorders and cognitive deficits in this population.

Impulsivity as a correlate of suicidal behavior in adolescent psychiatric inpatients

One hundred and eighteen inpatient adolescents in a psychiatric hospital were evaluated to determine the relationship of aggression, self injury, and suicidal behavior to impulsivity. It was hypothesized that all these variables would be significantly and positively correlated with one another. This hypothesis was in part based on the results of psychobiological research that found serotonin dysfunction to be the common denominator of these psychopathological dimensions. As predicted, a significant correlation was found between the measures of suicidal behavior, aggressive behavior, and impulsivity. This correlation between suicidal behavior and impulsivity remained after partialing out the factor of aggression. Furthermore, the correlations between impulsivity and suicidality appeared greater in males than in females. Since male suicide attempters are more likely to eventually commit suicide than female suicide attempters, these findings may have a bearing on suicide prediction.

Velocardiofacial manifestations and microdeletions in schizophrenic inpatients

Velocardiofacial syndrome (VCFS) is associated with an increased frequency of schizophrenia and other types of psychiatric morbidity. In this study, we tried to identify a subgroup of schizophrenic patients with deletions in the VCFS region of the long arm of chromosome 22. For that purpose, we screened the records of two major general hospitals for patients with abnormalities characteristic of VCFS, such as cardiac anomalies and cleft palate, and cross-checked the data with the register of psychiatric hospitalizations in four psychiatric hospitals. Of the 24 patients that qualified, only seven patients could be studied. An additional eight schizophrenic inpatients were ascertained clinically, based on a working VCFS Clinical Scale. FISH studies and molecular analyses, using polymorphic markers from the VCFS region, documented hemizygosity of 22q11 in three out of 15 patients (20.0%). Increased awareness of psychiatrists to signs of VCFS among patients with psychiatric illnesses is encouraged, in order to direct molecular studies effectively. In order to cut down the cost of testing, we suggest screening suspected patients with a single marker, such as D22S941, and to study further only those who have a single electrophoretic band.

Hyperacusis in Williams syndrome Characteristics and associated neuroaudiologic abnormalities

Background: Hyperacusis and phonophobia are common, debilitating symptoms in Williams syndrome (WS), yet little is known about their underlying audiologic and neurologic processes. Methods: The mothers of 49 subjects with WS were asked to complete the Hyperacusis Screening Questionnaire. Subjects with reported hyperacusis and sufficient developmental capacity underwent comprehensive audiological and brain auditory evoked response (BAER) testing. Findings were compared with those from pair-matched typically developing control subjects. Results: Forty-one of the 49 children with WS (84%) had hyperacusis of moderate to severe degree, which began in infancy. Of these, 21 (mean age 15.8 ± 5.5 years) were quantitatively tested. Subjects with WS reported discomfort at sound intensities on average 20 dB lower than control subjects. Pure-tone audiometry and distortion products otoacoustic emission test revealed a high-frequency cochlear hearing loss. An absence of ipsilateral acoustic reflex responses to maximum stimulation was significantly more common in the subjects with WS than controls. On BAER testing, the WS group had a significant prolongation in wave I latency. Conclusions: Hyperacusis in Williams syndrome (WS) is associated with a high-frequency hearing loss resembling the configuration of noise-induced hearing loss. The hyperacusis and hearing loss in WS may stem from a deficiency in the acoustic reflex resulting from auditory nerve dysfunction. Additional mechanisms that may mediate hyperacusis in WS and should be evaluated in future studies include recruitment, malformation of the facial canal, and haploinsufficiency of the elastin gene.