PubMed Health⌕ Search

Biomedical subjects

Jeffrey A Lieberman

Publications and source records attributed to Jeffrey A Lieberman.

At least 19 recordsLinked to original sources
PubMed2021

High-impact rare genetic variants in severe schizophrenia.

Extreme phenotype sequencing has led to the identification of high-impact rare genetic variants for many complex disorders but has not been applied to studies of severe schizophrenia. We sequenced 112 individuals with severe, extremely treatment-resistant schizophrenia, 218 individuals with typical schizophrenia, and 4,929 controls. We compared the burden of rare, damaging missense and loss-of-function variants between severe, extremely treatment-resistant schizophrenia, typical schizophrenia, and controls across mutation intolerant genes. Individuals with severe, extremely treatment-resistant schizophrenia had a high burden of rare loss-of-function (odds ratio, 1.91; 95% CI, 1.39 to 2.63; P = 7.8 × 10-5) and damaging missense variants in intolerant genes (odds ratio, 2.90; 95% CI, 2.02 to 4.15; P = 3.2 × 10-9). A total of 48.2% of individuals with severe, extremely treatment-resistant schizophrenia carried at least one rare, damaging missense or loss-of-function variant in intolerant genes compared to 29.8% of typical schizophrenia individuals (odds ratio, 2.18; 95% CI, 1.33 to 3.60; P = 1.6 × 10-3) and 25.4% of controls (odds ratio, 2.74; 95% CI, 1.85 to 4.06; P = 2.9 × 10-7). Restricting to genes previously associated with schizophrenia risk strengthened the enrichment with 8.9% of individuals with severe, extremely treatment-resistant schizophrenia carrying a damaging missense or loss-of-function variant compared to 2.3% of typical schizophrenia (odds ratio, 5.48; 95% CI, 1.52 to 19.74; P = 0.02) and 1.6% of controls (odds ratio, 5.82; 95% CI, 3.00 to 11.28; P = 2.6 × 10-8). These results demonstrate the power of extreme phenotype case selection in psychiatric genetics and an approach to augment schizophrenia gene discovery efforts.

Aged↗
PubMed2005

Association study of 12 polymorphisms spanning the dopamine D(2) receptor gene and clozapine treatment response in two treatment refractory/intolerant populations.

RATIONALE: Dopamine D(2) receptor blockade is the major basis for the antipsychotic action of typical antipsychotic drugs (AP) and a necessary but not sufficient basis for the antipsychotic action of atypical APs such as clozapine and other multireceptor antagonists which rely, in part, upon 5-HT(2A) antagonism. Genetic factors affecting the density and/or function of D(2) receptors may therefore affect AP response. OBJECTIVES: This exploratory study investigates the effect of 12 single nucleotide polymorphisms (SNPs) spanning the entire dopamine D(2) gene on clozapine response in two distinct schizophrenic populations (Caucasian and African-American) refractory or intolerant to conventional APs. METHODS: This study included 183 Caucasian and 49 African-American DSM-III-R or DSM-IV schizophrenics. Genotyping was determined by 5'-exonuclease fluorescence assays. Within each population genotype, allele, allele +/-, and haplotype frequencies were compared between responders and non-responders by X (2) tests. Linkage disequilibrium analysis was also performed. RESULTS: In the Caucasian sample, no significant associations were found for individual SNP tests; however, two haplotypes were identified as having significant protective effects on treatment outcome. In the African-American sample, individual SNP tests identified the Taq1A, Taq1B, and rs1125394 markers as being predictive of clozapine response. Haplotype analyses identified four protective haplotypes containing these SNPs. In addition, no association between the -141C Ins/Del site and clozapine response was found in either population. CONCLUSIONS: Interindividual variability in clozapine response among treatment refractory/intolerant patients is still not fully understood and likely involves multiple factors. This exploratory analysis suggests that the D(2) receptor gene may be one such factor.

Adult↗
PubMed2005

Quality of life during treatment with haloperidol or olanzapine in the year following a first psychotic episode.

OBJECTIVES: Schizophrenia causes significant impairments of quality of life. As treatment approaches have advanced, more attention has been given to re-integrating patients into their psychosocial environments, rather than simply monitoring psychotic symptoms. The development of the second-generation antipsychotics raised hope that these medications would provide better quality of life improvement than conventional antipsychotics. This improvement is particularly relevant early in the course of schizophrenia. METHODS: To address these considerations, improvements in measures of general health and social function (determined using the SF-36) were assessed in 195 patients with first-episode schizophrenia for up to one year following randomization to either olanzapine or haloperidol in a double blind clinical trial. We hypothesized that olanzapine would demonstrate better improvement on these measures than haloperidol. In order to test this hypothesis, we used a repeated measure model with SF-36 scores as the outcome, and treatment group, time, time2, time-by-treatment group interaction, and time2-by-treatment group interaction as fixed effects. RESULTS: Both treatments demonstrated similar changes on the SF-36. Independent of treatment, patients demonstrated significant improvements in most of the SF-36 subscales, which approached normative scores by the end of one year of treatment. Forty-six of 100 olanzapine-treated patients and 37 of 95 haloperidol-treated patients completed the one year of this study (p<.4). CONCLUSIONS: These results suggest an important initial treatment goal for patients with new onset schizophrenic disorders, namely that they can expect to recover significant quality of life and social function at least initially in treatment.

Adult↗
PubMed2005

Auditory P300 in high-risk, recent-onset and chronic schizophrenia.

BACKGROUND: The present study examined the integrity of the P300 component of the event-related potential (ERP) in patients at high imminent risk for schizophrenia in relation to healthy comparison subjects and patients in the recent-onset and chronic stages of schizophrenia. METHODS: The P300 was recorded by using an auditory oddball task in 10 patients clinically considered at risk of being prodromally symptomatic for schizophrenia, 10 patients with recent-onset schizophrenia, 14 patients with chronic schizophrenia, 14 young healthy comparison subjects, who were age-matched to the high-risk and recent-onset schizophrenia groups, and 14 older healthy comparison subjects, who were age-matched to the chronic schizophrenia group. RESULTS: High-risk subjects displayed smaller than normal P300 amplitudes at the parietal, centroparietal and central scalp locations. The observed P300 amplitude abnormalities in high-risk subjects were severe, being comparable in magnitude to the abnormalities seen in recent-onset and chronic schizophrenia subjects. However, whereas high-risk subjects showed P300 amplitude abnormalities that were bilaterally symmetrical, subjects with recent-onset schizophrenia and, particularly, subjects with chronic schizophrenia exhibited abnormalities that were markedly larger over the left temporal scalp sites. CONCLUSIONS: Patients at high imminent risk for developing a first florid psychotic episode seem to manifest auditory P300 amplitude abnormalities that are similar, but not identical, to those observed in patients in the recent-onset and chronic stages of schizophrenia. These results support the idea that auditory P300 abnormalities in schizophrenia reflect a primary cognitive and pathophysiological feature of the illness.

Adult↗
PubMed2005

Morphometric analysis of lateral ventricles in schizophrenia and healthy controls regarding genetic and disease-specific factors.

The structural variability of lateral ventricles is poorly understood notwithstanding that enlarged size has been identified as an unspecific marker for psychiatric illness, including schizophrenia. This paper explores the effects of heritability and genetic risk for schizophrenia reflected in ventricular size and structure. We examined ventricular size and shape in the MRI studies of monozygotic (MZ) twin pairs discordant for schizophrenia (DS), healthy MZ twin pairs, healthy dizygotic twin pairs, and healthy nonrelated subject pairs. Heritability and effect due to disease were analyzed in two tests. First, heritability was examined by ventricle similarity between pairs of co-twins. Results show that co-twin ventricle shape similarity decreases with decreasing genetic identity, an effect not seen in the volume analysis. Co-twin shape similarity of healthy MZ twins did not differ from DS MZ twins. Second, the disease effect was examined through the ventricular differences of DS subjects to a template shape representing healthy subjects. Affected DS twins showed shape differences from healthy subjects on the left and right sides. Interestingly, unaffected DS twins also showed significant shape differences from healthy subjects for both sides. Volume comparisons did not show differences between these groups. Locality of shape difference suggests that the ventricular shape of the anterior and posterior regions is under genetic influence in both healthy controls and schizophrenia patients. Affected and unaffected groups demonstrate main shape differences, compared with healthy controls, only in the posterior region. Our results suggest that genetics have a stronger influence on the shape of lateral ventricles than do the disease-related changes in schizophrenia.

Adult↗
PubMed2005

The SNAP-25 gene may be associated with clinical response and weight gain in antipsychotic treatment of schizophrenia.

The synaptosomal-associated protein of 25 kDa (SNAP-25) is an essential component of the core complex that mediates presynaptic vesicle trafficking. Thus, SNAP-25 is directly involved in the release of neurotransmitters. Quantitative alterations of SNAP-25 expression have been reported in brain regions and cerebrospinal fluid (CSF) of schizophrenics and in haloperidol treated rats. This observed altered expression may be influenced by genetic variants of SNAP-25. We hypothesized that polymorphisms of the SNAP-25 gene (sites DdeI, MnlI and TaiI in the 3'UTR) are associated with antipsychotic drug response and induced weight gain. A sample of 59 patients with prior suboptimal response to antipsychotic treatment and diagnosed with DSM-IV schizophrenia or schizoaffective disorder was examined. Patients were administered clozapine, haloperidol, olanzapine or risperidone for up to 14 weeks. Clinical response was defined as the difference between the baseline and the endpoint total scores on the Positive and Negative Syndrome Scale (PANSS). Weight was assessed at baseline and at study endpoint. ANOVA revealed that the MnlI and TaiI polymorphisms were associated with response (F[2,53] = 4.57, p = 0.01 and F[2,52] = 3.53, p = 0.03) and with weight gain (F[2,52] = 4.28, p = 0.01 and F[2,51] = 3.38, p = 0.04). When covariates were included, the MnlI polymorphism remained significantly associated with changes of PANSS scores, but not with weight gain. The DdeI polymorphism was not associated with response or weight gain. These findings suggest that SNAP-25 gene variants affect clinical response in patients with prior poor response to antipsychotics. Weight changes do not seem to be associated with polymorphism of the SNAP-25 gene, however, replication in independent samples is warranted.

Adult↗
PubMed2005

Imaging frontostriatal function in ultra-high-risk, early, and chronic schizophrenia during executive processing.

CONTEXT: Individuals experiencing prodromal symptoms of schizophrenia (ultra-high-risk group) demonstrate impaired performance on tasks of executive function, attention, and working memory. The neurobiological underpinnings of such executive deficits in ultra-high-risk individuals remains unclear. OBJECTIVE: We assessed frontal and striatal functions during a visual oddball continuous performance task, in ultra-high-risk, early, and chronic schizophrenic patients with the use of functional magnetic resonance imaging. DESIGN: Cross-sectional case-control design. SETTING: Community; outpatient clinic. Patients Fifty-two individuals (control, n = 16; ultra-high risk, n = 10; early, n = 15; chronic, n = 11) from a referred clinical sample and age- and sex-matched control volunteers underwent scanning. MAIN OUTCOME MEASURES: Percentage of active voxels and percentage signal change calculated for the anterior cingulate gyrus (ACG), middle frontal gyrus (MFG), inferior frontal gyrus (IFG), basal ganglia, and thalamus. Performance on the visual oddball task was measured with percentage of hits and d' (a measure based on the hit rate and the false-alarm rate). RESULTS: The ultra-high-risk group showed significantly smaller differential activation between task-relevant and task-irrelevant stimuli in the frontal regions (ACG, IFG, MFG) than the control group. Frontostriatal activation associated with target stimuli in the early and chronic groups was significantly lower than the control group, while the ultra-high-risk group showed a trend toward the early group. CONCLUSIONS: Our findings suggest that prefrontal function begins to decline before the onset of syndromally defined illness and hence may represent a vulnerability marker in assessing the risk of developing psychotic disorders among ultra-high-risk individuals.

Adolescent↗
PubMed2005

Antipsychotic drug effects on brain morphology in first-episode psychosis.

BACKGROUND: Pathomorphologic brain changes occurring as early as first-episode schizophrenia have been extensively described. Longitudinal studies have demonstrated that these changes may be progressive and associated with clinical outcome. This raises the possibility that antipsychotics might alter such pathomorphologic progression in early-stage schizophrenia. OBJECTIVE: To test a priori hypotheses that olanzapine-treated patients have less change over time in whole brain gray matter volumes and lateral ventricle volumes than haloperidol-treated patients and that gray matter and lateral ventricle volume changes are associated with changes in psychopathology and neurocognition. DESIGN: Longitudinal, randomized, controlled, multisite, double-blind study. Patients treated and followed up for up to 104 weeks. Neurocognitive and magnetic resonance imaging (MRI) assessments performed at weeks 0 (baseline), 12, 24, 52, and 104. Mixed-models analyses with time-dependent covariates evaluated treatment effects on MRI end points and explored relationships between MRI, psychopathologic, and neurocognitive outcomes. SETTING: Fourteen academic medical centers (United States, 11; Canada, 1; Netherlands, 1; England, 1). PARTICIPANTS: Patients with first-episode psychosis (DSM-IV) and healthy volunteers. INTERVENTIONS: Random allocation to a conventional antipsychotic, haloperidol (2-20 mg/d), or an atypical antipsychotic, olanzapine (5-20 mg/d). MAIN OUTCOME MEASURES: Brain volume changes assessed by MRI. RESULTS: Of 263 randomized patients, 161 had baseline and at least 1 postbaseline MRI evaluation. Haloperidol-treated patients exhibited significant decreases in gray matter volume, whereas olanzapine-treated patients did not. A matched sample of healthy volunteers (n = 58) examined contemporaneously showed no change in gray matter volume. CONCLUSIONS: Patients with first-episode psychosis exhibited a significant between-treatment difference in MRI volume changes. Haloperidol was associated with significant reductions in gray matter volume, whereas olanzapine was not. Post hoc analyses suggested that treatment effects on brain volume and psychopathology of schizophrenia may be associated. The differential treatment effects on brain morphology could be due to haloperidol-associated toxicity or greater therapeutic effects of olanzapine.

Adult↗
PubMed2005

Aggression and psychopathology in treatment-resistant inpatients with schizophrenia and schizoaffective disorder.

Positive psychotic symptoms, such as threat/"control-override" delusions or command hallucinations, have been related to aggression in patients with schizophrenia. However, retrospective data collection has hampered evaluation of the direct influence of psychopathology on aggressive behavior. In this study, we monitored aggressive behavior and psychopathology prospectively and in close temporal proximity in 157 treatment-resistant inpatients diagnosed with chronic schizophrenia or schizoaffective disorder participating in a 14-week double-blind clinical trial. Aggressive behavior was rated with the overt aggression scale (OAS). Psychopathology was assessed using the positive and negative syndrome scale (PANSS). At baseline, subjects who would be aggressive during the study had higher scores on only two PANSS items: hostility and poor impulse control. During the study PANSS positive subscale scores were significantly higher in aggressive subjects. Total PANSS scores were higher within 3 days of an aggressive incident, as were positive and general psychopathology subscale scores. However, in a smaller subsample for whom PANSS ratings were available within 3 days before aggressive incidents, only scores on the PANSS positive subscale were significantly higher. These findings in chronic, treatment resistant inpatients support the view that positive symptoms may lead to aggression.

Aggression↗
PubMed2005

Identification of a naturally occurring 21 bp deletion in alpha 2c noradrenergic receptor gene and cognitive correlates to antipsychotic treatment.

Neurocognitive deficits are recognized as a cardinal feature of schizophrenia. Atypical antipsychotics have high affinity for many neurotransmitter receptors. Among these receptors, antipsychotics are antagonists of adrenoceptors, and this pharmacological property has been postulated to be involved in the mechanism of action of antipsychotics. We tested the hypotheses that clinical response and cognitive improvement to antipsychotic treatment are associated with genetic variation in adrenergic alpha2C receptor (ADRA2C). Fifty-seven patients with chronic schizophrenia were prospectively assessed for clinical response to antipsychotic treatment. They were subsequently genotyped for a 21 bp insertion/deletion that we identified in the 3' untranslated region (3'UTR) of ADRA2C. With regard to clinical response and cognitive improvement to antipsychotics, there was no significant association observed for this polymorphism. Our results suggest that the novel polymorphism may not play a major role in antipsychotic response.

Alleles↗
PubMed2005

Apoptotic mechanisms in the pathophysiology of schizophrenia.

While schizophrenia is generally considered a neurodevelopmental disorder, evidence for progressive clinical deterioration and subtle neurostructural changes following the onset of psychosis has led to the hypothesis that apoptosis may contribute to the pathophysiology of schizophrenia. Apoptosis (a.k.a. programmed cell death) is a mechanism of cell death that operates in normal neurodevelopment and is increasingly recognized for its role in diverse neuropathological conditions. Activation of apoptosis can lead to rapid and complete elimination of neurons and glia in the central nervous system. Studies also show that in certain settings, pro-apoptotic triggers can lead to non-lethal and localized apoptotic activity that produces neuritic and synaptic loss without causing cell death. Given that the neuropathology of schizophrenia is subtle and includes reduced neuropil (especially synaptic elements), limited and often layer-specific reductions of neurons, as well as neuroimaging data suggesting progressive loss of cortical gray matter in first-episode psychosis, a role for apoptosis in schizophrenia appears plausible. Studies that have examined markers of apoptosis and levels of apoptotic regulatory proteins in postmortem schizophrenia brain tissue will be reviewed in context of this hypothesis. Overall, the data seem to indicate a dysregulation of apoptosis in several cortical regions in schizophrenia, including evidence that the apoptotic vulnerability is increased. Although the exact role of apoptosis in schizophrenia remains uncertain, the potential involvement of non-lethal localized apoptosis is intriguing, especially in earlier stages of the illness.

Apoptosis↗
PubMed2005

Effect of olanzapine on body composition and energy expenditure in adults with first-episode psychosis.

OBJECTIVE: Weight gain is a commonly observed adverse effect of atypical antipsychotic medications, but associated changes in energy balance and body composition are not well defined. The authors report here the effect of olanzapine on body weight, body composition, resting energy expenditure, and substrate oxidation as well as leptin, insulin, glucose, and lipid levels in a group of outpatient volunteers with first-episode psychosis. METHOD: Nine adults (six men and three women) experiencing their first psychotic episode who had no previous history of antipsychotic drug therapy began a regimen of olanzapine and were studied within 7 weeks and approximately 12 weeks after olanzapine initiation. RESULTS: After approximately 12 weeks of olanzapine therapy, the median increase in body weight was 4.7 kg, a significant increase of 7.3% from first observation. Body fat, measured by dual-energy x-ray absorptiometry, increased significantly, with a propensity for central fat deposition. Lean body mass and bone mineral content did not change. Resting energy expenditure, measured by indirect calorimetry, did not change. Respiratory quotient significantly increased 0.12 with olanzapine and was greatest in those who gained >5% of their initial weight. Fasting insulin, C-peptide, and triglyceride levels significantly increased, but there were no changes in glucose levels; total, high density lipoprotein, or low density lipoprotein cholesterol levels; or leptin levels. CONCLUSIONS: Olanzapine appears to have induced an increase in central body fat deposition, insulin, and triglyceride levels, suggesting the possible development of insulin resistance. The decrease in fat oxidation may be secondary or predispose patients to olanzapine-induced weight gain.

Adipose Tissue↗
PubMed2005

Duration of illness and treatment effects on hippocampal volume in male patients with schizophrenia.

BACKGROUND: Reduced hippocampal volume is a consistently described structural abnormality in schizophrenia but its cause and timing are not known. AIMS: To examine the relationship of duration of schizophrenic illness and treatment effects with hippocampal volumes. METHOD: Quantitative 1.5 T magnetic resonance imaging brain scans of young male patients in the early stage of schizophrenic illness were compared with those of chronically ill older patients. Scans were also acquired for controls matched to both patient groups for age and handedness. Duration of illness was recorded and severity of symptoms assessed with the Positive and Negative Syndrome Scale. RESULTS: The patients with schizophrenia had smaller hippocampal volumes than the controls. The volume reduction was larger in older patients than in young, compared with age-matched controls. In the early illness group atypical antipsychotics rather than haloperidol were associated with larger hippocampal volumes even after controlling for differences in illness severity. CONCLUSIONS: The greater reduction of hippocampal volume in people with chronic v. early illness, after controlling for illness severity and age, supports the hypothesis of progressive hippocampal reduction in males with schizophrenia. Atypical antipsychotics early in illness may protect against this.

Adolescent↗
PubMed2004

Deficits in sensorimotor gating and tests of social behavior in a genetic model of reduced NMDA receptor function.

Reduced NMDA receptor function is hypothesized to contribute to the pathophysiology of schizophrenia. In order to model chronic and developmental NMDA receptor hypofunction, a mouse line was developed that expresses low levels of the NMDA R1 subunit (NR1) of the NMDA receptor. The present study tested the hypothesis that these NR1 hypomorphic mice would exhibit deficits in sensorimotor and conspecific interactions, analogous to deficits observed in schizophrenic patients. F1 hybrid mice homozygous for the NR1 hypomorphic mutation (NR1 -/-) were generated by crossing heterozygous mice (NR1 +/-) from C57BL/6 and 129 Sv/Ev backgrounds. To assess sensorimotor gating, mice were tested in the paradigm of prepulse inhibition of acoustic startle. The NR1 hypomorphic mice exhibited increased acoustic startle responses and also showed deficits in prepulse inhibition. Startle responses were differentially altered by predator odor exposure in the male NR1 -/- mice, in comparison to control mice. In a test of social affiliation, the wild type mice spent significantly more time investigating a novel mouse in comparison to the NR1 -/- mice. In a resident-intruder test, marked deficits were found in sex-specific aggressive behavior between the wild type and mutant mice. These data support the contention that the NR1 hypomorphic mice exhibit alterations in sensorimotor gating and typical conspecific interactions, reminiscent of behavioral disturbances associated with schizophrenia. The NR1 hypomorphic mice could represent a model system to explore novel treatment and preventative strategies for certain symptoms of schizophrenia.

Agonistic Behavior↗
PubMed2004

Neonatal neurosteroid administration alters parvalbumin expression and neuron number in medial dorsal thalamus of adult rats.

The neuroactive steroid 3alpha-hydroxy-5alpha-pregnane-20-one (allopregnanolone) is a potent endogenous modulator of GABAA receptor function. A single neonatal allopregnanolone administration (10 mg/kg, i.p.) was previously shown to alter the localization of parvalbumin-positive neurons in the prefrontal cortex at maturity. Cells in the prefrontal cortex receive the majority of their inputs from the medial dorsal nucleus of the thalamus. We investigated whether neonatal allopregnanolone administration alters the neuronal population of the medial dorsal nucleus of the thalamus. We show that the number of parvalbumin-expressing neurons is increased while the total neuron number is decreased in the medial dorsal nucleus after allopregnanolone administration. EAAT3 (excitatory amino acid transporter type 3, the neuron-specific glutamate reuptake transporter) immunoreactivity was unchanged in adjacent sections. These findings suggest that neonatal allopregnanolone administration disrupts the normal development of the prefrontal cortex and medial dorsal thalamus, indicating that neurosteroid levels are important for proper development of thalamocortical systems and may play a role in neurodevelopmental disorders such as schizophrenia.

Amino Acid Transport System X-AG↗
PubMed2004

COMT158 polymorphism and hostility.

The main study was designed primarily to compare the clinical effects of four antipsychotics in 157 patients with schizophrenia or schizoaffective disorder. The secondary genetic study, reported here, is based on a subset of 60 patients who consented to genotyping assays. Based on previous work with the catechol-O-methyltransferase (COMT) 158 polymorphism, we hypothesized that the Met-Met homozygotes would be more hostile than the heterozygotes and the Val-Val homozygotes. Hostility ratings at baseline were used to test this hypothesis. The Met-Met homozygotes (N = 7) were found to have significantly higher levels of hostility than the other patients (N = 53). The hypothesis was thus supported. The finding should be replicated in a larger sample.

Antipsychotic Agents↗