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Biomedical subjects

J A Lieberman

Publications and source records attributed to J A Lieberman.

At least 55 records · Page 3Linked to original sources
PubMed2000

Comparison of the effects of clozapine, risperidone, and olanzapine on ketamine-induced alterations in regional brain metabolism.

The ability of subanesthetic doses of N-methyl-D-aspartate (NMDA) antagonists to induce positive, negative, and cognitive schizophrenia-like symptoms suggests that reduced NMDA receptor function may contribute to the pathophysiology of schizophrenia. An increasing body of evidence indicates that antipsychotic drugs, especially those with "atypical" properties, can antagonize the effects of NMDA antagonists in a variety of experimental paradigms. We demonstrated previously that clozapine, the prototype of atypical antipsychotics, but not haloperidol, the typical antipsychotic, blocked ketamine-induced alterations in brain metabolism. In this study, effects of clozapine were compared with two of the newer atypical antipsychotic drugs, risperidone and olanzapine, on ketamine-induced alterations in regional [(14)C]2-deoxyglucose (2-DG) uptake. A subanesthetic dose of ketamine (25 mg/kg) induced robust increases in 2-DG uptake in limbic cortical regions, hippocampal formation, nucleus accumbens, and basolateral amygdala. Pretreatment of rats with risperidone (0.3 mg/kg) before ketamine administration did not alter the effects of ketamine. These data suggest that novel pharmacological properties may contribute to the effects of clozapine in this model, in addition to the well characterized actions at D(2) and 5HT(2A) receptors. In contrast to the results with risperidone, olanzapine blocked ketamine-induced increases in 2-DG uptake. However, a higher dose of olanzapine (10 mg/kg) was required to completely block the effects of ketamine than would be expected if D(2) and 5HT(2) receptor blocking properties of the drug were solely responsible for its action. The results suggest that the ketamine challenge 2-DG paradigm may be a useful model to identify antipsychotic drugs with atypical characteristics and to explore mechanisms of atypical antipsychotic action.

Animals↗
PubMed1999

Obstetric complications in schizophrenia, schizoaffective disorder and normal comparison subjects.

Previous studies have indicated that obstetric complications (OCs) may be risk factors for schizophrenia, but findings are inconsistent, and data about other diagnostic groups are relatively scarce. We compared the obstetric histories of subjects with schizophrenia, major affective disorder and normal controls. Our subjects included 61 schizophrenia, 26 schizoaffective, 28 major affective disorder patients and 21 normal controls. OCs were rated on the McNeil-Sjöström Scale using data from mothers reports and for a subsample from hospital and birth certificate records. The frequency of OCs did not differ statistically between diagnostic groups at any stage or for the three stages combined. OCs of at least level 4 were found in 69% of schizophrenia patients, 62% of schizoaffective patients, 68% of major affective disorder patients and 71% of the normal comparison group. OCs of at least level 5 were found in 23% of schizophrenia patients, 23% of schizoaffective patients, 21% of the major affective disorder patients and 14% of the normal comparison group. Our findings indicate that the etiologic significance of OCs may not be specific to schizophrenia.

Adult↗
PubMed1999

Comparison of brain metabolic activity patterns induced by ketamine, MK-801 and amphetamine in rats: support for NMDA receptor involvement in responses to subanesthetic dose of ketamine.

Subanesthetic doses of NMDA receptor antagonists induce positive, negative and cognitive schizophrenia-like symptoms in healthy humans and precipitate psychotic reactions in stabilized schizophrenic patients. These findings suggest that defining neurobiologic effects induced by NMDA antagonists could guide the formulation of experimental models relevant to the pathophysiology of schizophrenia and antipsychotic drug action. Accordingly, the effects of subanesthetic doses of the non-competitive NMDA antagonists ketamine and MK-801 were examined on regional brain [14C]-2-deoxyglucose (2-DG) uptake in rats. The effects of these drugs were compared to those of amphetamine, in order to assess the potential role of generalized behavioral arousal, motor activity and dopamine release in brain metabolic responses to the NMDA antagonists. Subanesthetic doses of MK-801 and ketamine induced identical alterations in patterns of 2-DG uptake. The most pronounced increases in 2-DG for both NMDA antagonists were in the hippocampal formation and limbic cortical regions. By contrast, amphetamine treatment did not increase 2-DG uptake in these regions. In isocortical regions, ketamine and MK-801 reduced uptake in layers 3 and 4, creating a striking shift in the laminar pattern of 2-DG uptake in comparison to control conditions. After amphetamine, the fundamental laminar pattern of isocortical labeling was similar to saline-treated rats. Administration of ketamine and MK-801 decreased 2-DG uptake in the medial geniculate and inferior colliculus, whereas amphetamine tended to increase uptake in these regions. Since ketamine induced similar effects on regional 2-DG uptake as observed for the selective antagonists MK-801, the effects of ketamine are likely related to NMDA antagonistic properties of the drug. The distinct differences in brain 2-DG uptake induced by amphetamine and NMDA antagonists indicate that generalized behavioral arousal, and increased locomotor activity mediated by dopamine release, are not sufficient to account for the alterations in brain metabolic patterns induced by ketamine and MK-801. Thus, the dramatic alteration in regional 2-DG uptake induced by ketamine and MK-801 reflects a state selectively induced by reduced NMDA receptor function.

Amphetamine↗
PubMed1999

Is schizophrenia a neurodegenerative disorder? A clinical and neurobiological perspective.

The history of psychiatric research is filled with widely accepted etiologic and pathophysiologic theories that eventually were proven wrong. The prevailing pathophysiologic theories of schizophrenia have emphasized the role of abnormal neurodevelopment in determining the onset and course of the illness. Relatively little attention has been paid to the role of neurodegenerative processes despite the clinical course of the illness and the fact that most patients experience varying degrees of behavioral and cognitive deterioration. This is partially due to the absence of clear histologic evidence of neurodegeneration, but may also be due to the narrow traditional conception of neurodegeneration that is generally employed. This article suggests that the rejection of a role for neurodegeneration in the pathophysiology of schizophrenia is unproven and may be premature. A wholly neurodevelopmental perspective of the illness imbues the illness with a pessimistic inevitability and therapeutic nihilism that may be unwarranted. This article reviews selectively a diverse body of evidence that is consistent with the hypothesis that schizophrenia involves a limited neurodegenerative process reflected by the psychotic symptoms and that is most active in the early stages of the illness. The evidence for this hypothesis comes from studies of premorbid status, illness course, symptomatology and treatment effects as well as neuroimaging and postmortem findings. Recent results from the latter interpreted in the context of molecular neurobiology suggest new pathophysiologic models.

Brain Diseases↗
PubMed1999

Longitudinal assessment of methylphenidate effects on oral word production and symptoms in first-episode schizophrenia at acute and stabilized phases.

BACKGROUND: Some studies have reported psychotic symptom exacerbation during "pharmacologic challenge" paradigms using dopamine agonists. Few studies, however, have examined the effects of these agonists on neurocognitive functions in patients with schizophrenia. This study assessed the effects of methylphenidate infusion on an oral word production test with demonstrated sensitivity to frontal lobe lesions, and on clinical state. METHODS: Patients were tested at two different phases; at the onset of their first-episode of schizophrenia (acute phase), and then again after they had responded to treatment and were clinically stable (stabilization phase). During each phase, patients were tested prior to and following methylphenidate infusion. Symptom clusters (i.e., positive, negative, and disorganization) were formed from SANS and SADS-C (+PD) ratings at each of these four timepoints. RESULTS: Patients produced significantly more words at preinfusion and while stabilized, suggesting that overall, decreased dopamine activity was associated with better word production. Redundant errors (i.e., perseverations of previously mentioned words and production of multiple words with the same roots) increased significantly following infusion in the stabilized phase. Disorganization symptoms increased significantly following infusion, regardless of study phase. CONCLUSIONS: These findings are consistent with previous theoretical and empirical findings relating dopamine activity to verbal output, a "redundancy bias" in cognitive control, and exacerbation of disorganization symptoms.

Adult↗
PubMed1999

Investigation of frontal lobe subregions in first-episode schizophrenia.

The evidence for frontal lobe structural abnormalities in schizophrenia using magnetic resonance (MR) imaging has been mixed, but most studies used either single slice measures or total volumes of a single frontal region, neither of which is sensitive to potential volume differences in more specific subregions. This study employed reliable methods for parcellation of the frontal lobes from MR images based on the sulcal anatomy. Following a cytoarchitectonic theory that distinguishes dorsomedial (archicortically derived) from ventrolateral (paleocortically derived) frontal subregions, we measured the superior frontal gyrus, anterior cingulate gyrus, and orbital frontal region in 19 first-episode schizophrenia patients and 26 healthy comparison subjects. Results indicated that male patients had significantly larger right orbital frontal volume compared to their left orbital frontal volume and compared to healthy men. Among male patients larger right orbital frontal volume was significantly correlated with smaller right 'archicortical' (i.e. anterior cingulate and superior frontal gyri) volume. Furthermore, the ratio of right orbital frontal to right 'archicortical' volume was significantly and positively correlated with level of delusions among male patients. These findings suggest that there may be reciprocal controls on 'archicortical' and 'paleocortical' neurodevelopment among men with schizophrenia, and that larger paleocortical relative to archicortical volumes may be associated with increased delusions.

Brain↗
PubMed1999

Predictors of relapse following response from a first episode of schizophrenia or schizoaffective disorder.

BACKGROUND: We examined relapse after response to a first episode of schizophrenia or schizoaffective disorder. METHODS: Patients with first-episode schizophrenia were assessed on measures of psychopathologic variables, cognition, social functioning, and biological variables and treated according to a standardized algorithm. The sample for the relapse analyses consisted of 104 patients who responded to treatment of their index episode and were at risk for relapse. RESULTS: Five years after initial recovery, the cumulative first relapse rate was 81.9% (95% confidence interval [CI], 70.6%-93.2%); the second relapse rate was 78.0% (95% CI, 46.5%-100.0%). By 4 years after recovery from a second relapse, the cumulative third relapse rate was 86.2% (95% CI, 61.5%-100.0%). Discontinuing antipsychotic drug therapy increased the risk of relapse by almost 5 times (hazard ratio for an initial relapse, 4.89 [99% CI, 2.49-9.60]; hazard ratio for a second relapse, 4.57 [99% CI, 1.49-14.02]). Subsequent analyses controlling for antipsychotic drug use showed that patients with poor premorbid adaptation to school and premorbid social withdrawal relapsed earlier. Sex, diagnosis, obstetric complications, duration of psychotic illness before treatment, baseline symptoms, neuroendocrine measures, methylphenidate hydrochloride challenge response, neuropsychologic and magnetic resonance imaging measures, time to response of the initial episode, adverse effects during treatment, and presence of residual symptoms after the initial episode were not significantly related to time to relapse. CONCLUSIONS: There is a high rate of relapse within 5 years of recovery from a first episode of schizophrenia and schizoaffective disorder. This risk is diminished by maintenance antipsychotic drug treatment.

Adolescent↗
PubMed1999

Effects of chronic treatment with typical and atypical antipsychotic drugs on the rat striatum.

Human MRI studies have demonstrated that treatment with typical antipsychotics may increase the volume of the caudate nucleus while clozapine treatment is associated with either no change or a reversal of the previous volume increase. In this study four groups of seven rats were treated for 8 months with either the typical antipsychotic haloperidol, the atypical antipsychotic clozapine, the D2/D3 receptor antagonist raclopride, or vehicle (plain drinking water). Striatal sections were prepared using D1-like and D2-like receptor ligand autoradiography. Images (4-6 sections per rat, per ligand) were digitized and the area of the striatum was measured on each section. Rats treated with haloperidol did not have a larger mean striatum area than the control group on either D1- or D2-like ligand autoradiograms. Using the D2-like ligand autoradiograms, the clozapine treated animals had a smaller mean striatum area than the control group. Mean left striatum area was larger than mean right striatum area in each treatment group and in the control group. In contrast to the MRI findings reported in schizophrenia, the area of the striatum was not increased in rats treated with typical antipsychotic agents, but the clozapine-associated area reduction may parallel the clinical studies.

Animals↗
PubMed1999

An integrated view of pathophysiological models of schizophrenia.

Pathophysiological processes that underlie the profound neuropsychiatric disturbances in schizophrenia are poorly understood. However, the clinical course of the disease, and a number of clinical and basic science observations, provide direction for formulating pathophysiological models that could be empirically tested. For example, repeated psychostimulant administration to healthy subjects can induce psychotic symptoms, and acute stimulant challenge in schizophrenia patients can precipitate psychosis. Also, NMDA antagonists induce positive, negative, and cognitive schizophrenic-like symptoms in healthy volunteers and precipitate thought disorder and delusions in schizophrenia patients. These human studies provide support for the dopamine and NMDA receptor hypofunction hypotheses of schizophrenia. Well-documented effects of NMDA antagonists on dopamine systems provide a basis to integrate the dopamine and NMDA receptor hypofunction hypotheses. Furthermore, it has become apparent that prominent actions of antipsychotic drugs, especially those with 'atypical' properties, involve antagonism of behavioral, electrophysiological and brain metabolic effects produced by administration of NMDA receptor antagonists. A confluence of clinical and basic science data suggests that an early developmental insult, potentially involving reduced NMDA receptor function, could facilitate sensitization of dopamine systems, leading to the formal onset of schizophrenia in late adolescence and early adulthood. Although clearly speculative, this conceptual model is consistent with existing evidence and suggests lines of future experimental investigation.

Animals↗
PubMed1999

Cerebral volume asymmetries in schizophrenia and mood disorders: a quantitative magnetic resonance imaging study.

Multiple abnormalities of brain structure have been identified in schizophrenia using in vivo neuroimaging methods, but little is known about the diagnostic specificity of these abnormalities. In a prior study of first-episode schizophrenia we found that this group lacked the normal pattern of cerebral volume asymmetries. Data from that study were combined with data from groups of patients with more chronic schizophrenia, and with bipolar and unipolar mood disorders, to determine the specificity of this abnormality to diagnostic subgroups defined by syndromal status or chronicity. The total sample comprised 235 patients (67 healthy volunteers, 81 patients with mood disorders or schizoaffective disorders, and 87 with schizophrenia or schizophreniform disorders). Asymmetries of regional cerebral volumes were measured on coronal magnetic resonance images with 3.1-mm contiguous slices and nominal in-plane resolution of 1 mm x 1 mm. Asymmetries differed significantly across groups in the occipitoparietal, prefrontal, and temporal regions. These asymmetries, and a composite index of asymmetry across regions ('torque'), all showed the same diagnostic group effect, with the schizophrenia group showing the least normal asymmetry, the mood disorder group intermediate asymmetry, and the control group the most marked asymmetry. No other diagnostic subgroup or chronicity effects were apparent. The findings support a 'continuum' rather than a 'diagnostic specificity' hypothesis, and suggest that the reduction of normal hemispheric asymmetries may mark a neurodevelopmental risk factor for major mental illnesses, and that some syndromal characteristics may be correlated with the degree of deviation from the normal anatomic pattern.

Adolescent↗
PubMed1999

Association of the MscI polymorphism of the dopamine D3 receptor gene with tardive dyskinesia in schizophrenia.

In 112 schizophrenic patients previously treated with typical neuroleptics, we investigated the putative role of the dopamine D3 receptor gene (DRD3) in tardive dyskinesia (TD). Patients were assessed for TD severity using the Abnormal Involuntary Movement Scale (AIMS) and were subsequently genotyped for the MscI polymorphism that identifies a serine to glycine substitution in DRD3. A modified analysis of covariance model, which incorporated several clinical risk factors for TD, was utilized to detect differences in TD severity among the various genotypic groups. The glycine allele of DRD3 was found to be associated with typical neuroleptic-induced TD (F[2,95] = 8.25, p < .0005). Higher mean AIMS scores were found in patients homozygous for the glycine variant of the DRD3 gene, as compared to both heterozygous and serine homozygous patients. Although replication is necessary, this finding supports a role for the dopamine D3 receptor in the pathogenesis of TD.

Adolescent↗
PubMed1999

Obstetric complications predict treatment response in first-episode schizophrenia.

BACKGROUND: Understanding the role of obstetric complications (OCs) in schizophrenia could potentially shed light on the heterogeneity in the aetiology and course of schizophrenia. Many investigators have reported an association between OCs and schizophrenia, but few have examined the association between OCs and treatment outcome. We investigated this question in a sample of patients studied during their first episode of schizophrenia, schizoaffective or schizophreniform disorder. METHOD: OC histories were obtained for 59 patients participating in the Hillside First Episode Study. Cox proportional hazards regression analysis was used to estimate the effect of OCs on treatment response during the first episode of schizophrenia. RESULTS: Twelve of the 59 patients (20%) had positive histories of OCs. This group exhibited lower rates of treatment response than those with negative OC histories (hazard ratio controlling for sex = 0.28; 95% CI = 0.13, 0.62). The positive OC group also had significantly greater lateral ventricle volume, baseline disorganization and number of live births. The effect of OC history on treatment response held when these three variables were controlled for. CONCLUSION: A history of obstetric complications predicted poor response to treatment in the first episode of schizophrenia. This large effect was based on a small sample of 59 patients. Thus, replication is called for.

Adolescent↗
PubMed1999

Neurobiological basis of relapse prediction in stimulant-induced psychosis and schizophrenia: the role of sensitization.

A number of consistent clinical observations provide direction for the hypothesis that pathological sensitization of neuronal systems may be an important factor for relapse or the onset of stimulant-induced psychosis (eg, methamphetamine or amphetamine psychosis, cocaine psychosis and phencyclidine psychosis) and schizophrenia. First, psychotic symptoms can be produced in normal subjects by stimulants. Secondly, a large portion of schizophrenic patients exhibit exacerbation of psychotic symptoms in response to stimulants at doses which would not be psychotogenic in normal subjects. Lastly, the ability of stress to precipitate the onset and relapse of schizophrenia is well documented. In this regard, acute responses to stimulants provide useful information for relapse prediction of schizophrenia and substance abuse. This paper addresses the nature and role of pathological sensitization in relapse of stimulant- and phencyclidine-induced psychosis and schizophrenia, and its relation to pathophysiology of schizophrenia.

Animals↗