Kathleen McKenna

Abstract: Background: Childhood-onset schizophrenia is a rare but severe form of the disorder that is often treatmentrefractory. In this study, the efficacy and adverse effects of clozapine and haloperidol were compared for children and adolescents with early-onset schizophrenia. Methods: Twenty-one patients (mean [±SD] age, 14.0 ±2.3 years) with onset of Diagnostic and Statistical Manual of Mental Disorders, Revised Third Edition— defined schizophrenia that began by age 12 years and who had been nonresponsive to typical neuroleptics participated in the study. Patients were randomized to a 6-week double-blind parallel comparison of clozapine (mean [ ±SD] final dose, 176± 149 mg/d), or haloperidol, (16±8 mg/d). Results: Clozapine was superior to haloperidol on all measures of psychosis ( P =.04-.002). Positive and negative symptoms of schizophrenia improved. However, neutropenia and seizures were major concerns. To date, one third of the group has discontinued using clozapine. Conclusions: Clozapine has striking superiority for positive and negative symptoms in treatment-refractory childhood-onset schizophrenia. However, due to possibly increased toxic effects in this pediatric population, close monitoring for adverse events is essential.

Abstract: OBJECTIVE: Sibling recurrence risk in autism has been estimated to be approximately 10%. This study investigated subsyndromal autistic impairments among siblings of probands with pervasive developmental disorders. METHOD: The authors used the Social Responsiveness Scale to obtain quantitative assessments of autistic social impairment in three groups of proband-sibling pairs: 1) autistic children from multiple-incidence families and their closest in age nonautistic brothers (N=49 pairs); 2) children with any pervasive developmental disorder, including autism, and their closest-in-age brothers (N=100 pairs), and 3) children with psychopathology unrelated to autism and their closest-in-age brothers (N=45 pairs). RESULTS: Sibling Social Responsiveness Scale scores were continuously distributed and substantially elevated for both the autistic and pervasive developmental disorder groups. Highest scores (i.e., greatest impairment) were seen among siblings of autistic probands from multiple-incidence families, fo...

Abstract: Objective To review the premorbid histories of 23 children meeting DSM-III-R criteria for schizophrenia with onset before age 12 years and to compare these with childhood data of later-onset schizophrenics. Method Premorbid features up to 1 year before onset of first psychotic symptoms were rated from hospital and clinic records, clinical interviews, rating scales, and tests. Results In keeping with previous studies, specific developmental disabilities and transient early symptoms of autism, particularly motor stereotypies, were common. Comparison with the childhood of later-onset schizophrenics showed greater delay in language development, and more premorbid speech and language disorders, learning disorders, and disruptive behavior disorders. (Sixty percent had received or were estimated to meet criteria for one or more clinical diagnoses.) Conclusions Childhood-onset schizophrenia may represent a more malignant form of the disorder, although selection and ascertainment bias cannot be ruled out. The presence of prepsychotic language difficulties focuses attention on the importance of early temporal and frontal lobe development; early transient motor stereotypies suggest developmental basal ganglia abnormalities and extend previous findings seen in the childhood of later-onset patients.

Abstract: Objective To review psychiatric referrals to a study of childhood-onset schizophrenia. Method Children and adolescents ( N = 71) and their parents selected from a total of 260 patients referred to the National Institute of Mental Health between 1990 and 1993, with onset of psychosis at or before age 12 years, were screened in person, using the Schedule for Affective Disorders and Schizophrenia for School-Age Children-Epidemiologic Version, portions of the Diagnostic Interview for Children and Adolescents-Parent Version, and clinical interview. Best-estimate diagnoses using all sources of information were determined. Thought disorder was rated on a subset of subjects using standardized videotaped speech samples. Results Interrater reliability (k) between two child psychiatrists for best-estimate primary diagnoses ranged from .65 to .81. Schizophrenia was diagnosed for 19 children who by history had had onset at or before age 12, but all were in puberty when interviewed. Affective disorders ( N = 14) and Asperger's syndrome and pervasive developmental disorder not otherwise specified ( N = 6) were also diagnosed. A large group of reliably identifiable children not completely described by any DSM-III-R category and provisionally called "multidimensionally impaired" ( N = 21) with multiple language or learning disorders, mood lability, and transient psychotic symptoms was seen. Conclusions Childhood-onset schizophrenia is often misdiagnosed, perhaps because of the rarity of the disorder and the ambiguity in applying primary criteria. An array of developmental disturbances are seen with less pervasive childhood-onset psychotic symptoms.

Abstract: Background: Early-onset schizophrenia (first psychotic symptoms by age 12 years) has been the subject of a small number of studies, and its biological continuity with lateronset disorder has not been established. In this study, quantitative anatomic brain magnetic resonance images of children and adolescents with early-onset schizophrenia were compared with those of matched controls. Brain abnormalities in childhood-onset schizophrenia were examined in relation to those reported for later-onset schizophrenics. Methods: Anatomic brain magnetic resonance imaging scans were obtained for 21 patients (mean±SD age, 14.6±2.1 years; range, 10 to 18 years) with childhood-onset schizophrenia (13 males, eight females) and 33 age-, sex-, height-, and weight-matched normal controls. Quantitative measurements were obtained for the cerebrum, anterior frontal region, lateral ventricles, thalamus, caudate, putamen, and globus pallidus. Results: Total cerebral volume and midsagittal thalamic area were smaller in the patients (analysis of variance, P =.002, and analysis of covariance, P =.03, respectively); the caudate, putamen, and globus pallidus were larger in the patients (analysis of covariance, P =.05, P =.007, and P P =.06). Globus pallidus enlargement correlated with neuroleptic exposure and with age of onset of psychosis. The magnitude of abnormalities compared with controls was similar to that reported in adult studies, although there was a trend toward relatively smaller cerebral volumes for the childhood-onset group compared with controls. Conclusion: Brain anatomic abnormalities in childhoodonset schizophrenia are similar to those reported for adult populations, indicating overall continuity between these rare childhood cases and the adult schizophrenia populations.

Abstract: OBJECTIVE: The purpose of this study was to estimate and compare the effects of anti­psychotics—both the newer ones and the conventional ones—on body weight. METHOD: A comprehensive literature search identified 81 English- and non-English-language articles that included data on weight change in antipsychotic-treated patients. For each agent, a meta-analysis and random effects metaregression estimated the weight change after 10 weeks of treatment at a standard dose. A comprehensive narrative review was also conducted on all articles that did not yield quantitative information but did yield important qualitative information. RESULTS: Placebo was associated with a mean weight reduction of 0.74 kg. Among conventional agents, mean weight change ranged from a reduction of 0.39 kg with molindone to an increase of 3.19 kg with thioridazine. Among newer antipsychotic agents, mean increases were as follows: clozapine, 4.45 kg; olanzapine, 4.15 kg; sertindole, 2.92 kg; risperidone, 2.10 kg; and ziprasidone, 0.04 kg....

Abstract: After more than 100 years of research, the neuropathology of schizophrenia remains unknown and this is despite the fact that both Kraepelin (1919/1971 : Kraepelin, E, 1919/1971 Dementia praecox Churchill Livingston Inc, New York) and Bleuler (1911/1950 : Bleuler, E, 1911/1950 Dementia praecox or the group of schizophrenias International Universities Press, New York), who first described ‘dementia praecox’ and the ‘schizophrenias’, were convinced that schizophrenia would ultimately be linked to an organic brain disorder Alzheimer (1897 : Alzheimer, A, 1897 Beitrage zur pathologischen anatomie der hirnrinde und zur anatomischen grundlage einiger psychosen Monatsschrift fur Psychiarie und Neurologie 2, 82–120) was the first to investigate the neuropathology of schizophrenia, though he went on to study more tractable brain diseases The results of subsequent neuropathological studies were disappointing because of conflicting findings Research interest thus waned and did not flourish again until 1976, following the pivotal computer assisted tomography (CT) finding of lateral ventricular enlargement in schizophrenia by Johnstone and colleagues Since that time significant progress has been made in brain imaging, particularly with the advent of magnetic resonance imaging (MRI), beginning with the first MRI study of schizophrenia by Smith and coworkers in 1984 (Smith, RC, Calderon, M, Ravichandran, GK, et al (1984) Nuclear magnetic resonance in schizophrenia: A preliminary study Psychiatry Res 12, 137–147) MR in vivo imaging of the brain now confirms brain abnormalities in schizophrenia The 193 peer reviewed MRI studies reported in the current review span the period from 1988 to August, 2000 This 12 year period has witnessed a burgeoning of MRI studies and has led to more definitive findings of brain abnormalities in schizophrenia than any other time period in the history of schizophrenia research Such progress in defining the neuropathology of schizophrenia is largely due to advances in in vivo MRI techniques These advances have now led to the identification of a number of brain abnormalities in schizophrenia Some of these abnormalities confirm earlier post-mortem findings, and most are small and subtle, rather than large, thus necessitating more advanced and accurate measurement tools These findings include ventricular enlargement (80% of studies reviewed) and third ventricle enlargement (73% of studies reviewed) There is also preferential involvement of medial temporal lobe structures (74% of studies reviewed), which include the amygdala, hippocampus, and parahippocampal gyrus, and neocortical temporal lobe regions (superior temporal gyrus) (100% of studies reviewed) When gray and white matter of superior temporal gyrus was combined, 67% of studies reported abnormalities There was also moderate evidence for frontal lobe abnormalities (59% of studies reviewed), particularly prefrontal gray matter and orbitofrontal regions Similarly, there was moderate evidence for parietal lobe abnormalities (60% of studies reviewed), particularly of the inferior parietal lobule which includes both supramarginal and angular gyri Additionally, there was strong to moderate evidence for subcortical abnormalities (ie cavum septi pellucidi—92% of studies reviewed, basal ganglia—68% of studies reviewed, corpus callosum—63% of studies reviewed, and thalamus—42% of studies reviewed), but more equivocal evidence for cerebellar abnormalities (31% of studies reviewed) The timing of such abnormalities has not yet been determined, although many are evident when a patient first becomes symptomatic There is, however, also evidence that a subset of brain abnormalities may change over the course of the illness The most parsimonious explanation is that some brain abnormalities are neurodevelopmental in origin but unfold later in development, thus setting the stage for the development of the symptoms of schizophrenia Or there may be additional factors, such as stress or neurotoxicity, that occur during adolescence or early adulthood and are necessary for the development of schizophrenia, and may be associated with neurodegenerative changes Importantly, as several different brain regions are involved in the neuropathology of schizophrenia, new models need to be developed and tested that explain neural circuitry abnormalities effecting brain regions not necessarily structurally proximal to each other but nonetheless functionally interrelated Future studies will likely benefit from: (1) studying more homogeneous patient groups so that the relationship between MRI findings and clinical symptoms become more meaningful; (2) studying at risk populations such as family members of patients diagnosed with schizophrenia and subjects diagnosed with schizotypal personality disorder in order to define which abnormalities are specific to schizophrenia spectrum disorders, which are the result of epiphenomena such as medication effects and chronic institutionalization, and which are needed for the development of frank psychosis; (3) examining shape differences not detectable from measuring volume alone; (4) applying newer methods such as diffusion tensor imaging to investigate abnormalities in brain connectivity and white matter fiber tracts; and, (5) using methods that analyze brain function (fMRI) and structure simultaneously

Abstract: Despite a hundred years' research, the neuropathology of schizophrenia remains obscure. However, neither can the null hypothesis be sustained--that it is a 'functional' psychosis, a disorder with no structural basis. A number of abnormalities have been identified and confirmed by meta-analysis, including ventricular enlargement and decreased cerebral (cortical and hippocampal) volume. These are characteristic of schizophrenia as a whole, rather than being restricted to a subtype, and are present in first-episode, unmedicated patients. There is considerable evidence for preferential involvement of the temporal lobe and moderate evidence for an alteration in normal cerebral asymmetries. There are several candidates for the histological and molecular correlates of the macroscopic features. The probable proximal explanation for decreased cortical volume is reduced neuropil and neuronal size, rather than a loss of neurons. These morphometric changes are in turn suggestive of alterations in synaptic, dendritic and axonal organization, a view supported by immunocytochemical and ultrastructural findings. Pathology in subcortical structures is not well established, apart from dorsal thalamic nuclei, which are smaller and contain fewer neurons. Other cytoarchitectural features of schizophrenia which are often discussed, notably entorhinal cortex heterotopias and hippocampal neuronal disarray, remain to be confirmed. The phenotype of the affected neuronal and synaptic populations is uncertain. A case can be made for impairment of hippocampal and corticocortical excitatory pathways, but in general the relationship between neurochemical findings (which centre upon dopamine, 5-hydroxytryptamine, glutamate and GABA systems) and the neuropathology of schizophrenia is unclear. Gliosis is not an intrinsic feature; its absence supports, but does not prove, the prevailing hypothesis that schizophrenia is a disorder of prenatal neurodevelopment. The cognitive impairment which frequently accompanies schizophrenia is not due to Alzheimer's disease or any other recognized neurodegenerative disorder. Its basis is unknown. Functional imaging data indicate that the pathophysiology of schizophrenia reflects aberrant activity in, and integration of, the components of distributed circuits involving the prefrontal cortex, hippocampus and certain subcortical structures. It is hypothesized that the neuropathological features represent the anatomical substrate of these functional abnormalities in neural connectivity. Investigation of this proposal is a goal of current neuropathological studies, which must also seek (i) to establish which of the recent histological findings are robust and cardinal, and (ii) to define the relationship of the pathological phenotype with the clinical syndrome, its neurochemistry and its pathogenesis.

Abstract: Objective: The authors’ goal was to determine whether patients with schizophrenia differ from comparison subjects in regional brain volumes and whether these differences are similar in male and female subjects. Method: They conducted a systematic search for structural magnetic resonance imaging (MRI) studies of patients with schizophrenia that reported volume measurements of selected cortical, subcortical, and ventricular regions in relation to comparison groups. They carried out a meta-analysis of the volumes of these regions in the patients with schizophrenia and the comparison subjects using a random effects model; they also used random effects regression analysis to examine the influence of gender on effect sizes. Results: Fifty-eight studies were identified as suitable for analysis; these studies included 1,588 independent patients with schizophrenia. Assuming a volume of 100% in the comparison group, they found that the mean cerebral volume of the subjects with schizophrenia was smaller (98%), but the mean total ventricular volume of the subjects with schizophrenia was greater (126%). Relative to the cerebral volume differences, the regional volumes of the subjects with schizophrenia were 94% in the left and right amygdala, 94% in the left and 95% in the right hippocampus/amygdala, and 93% in the left and 95% in the right parahippocampus. Relative to the global ventricular system differences, the largest differences in ventricular subdivisions were in the right and left body of the lateral ventricle, where the volumes of schizophrenic subjects were 116% and 116%, respectively. For most regions, effect size was not significantly related to gender. Conclusions: Regional structural differences in patients with schizophrenia include bilaterally reduced volume of medial temporal lobe structures. There is a need for greater integration of results from structural MRI studies to avoid redundant research activity. (Am J Psychiatry 2000; 157:16‐25)