Papers by Lawrence Kegeles
Rationale Schizotypal personality disorder (SPD) is associated with working memory (WM) impairmen... more Rationale Schizotypal personality disorder (SPD) is associated with working memory (WM) impairments that are similar to those observed in schizophrenia. Imaging studies have suggested that schizophrenia is associated with alterations in dopamine D1 receptor availability in the prefrontal cortex (PFC) that may be related to the WM impairments that characterize this disorder. Objectives The aim of this study was to characterize prefrontal D1 receptor availability and its relation to WM performance in SPD. Methods We used positron emission tomography (PET) and the radiotracer [ 11 C]NNC112 with 18 unmedicated SPD and 21 healthy control participants; as an index of D1 receptor availability, binding potential (BP) measures (BP F , BP ND , and BP P ) were calculated for prefrontal and striatal subregions. To assess WM, SPD participants completed the 2-back and Paced Auditory Serial Addition Test (PASAT). Results There were no significant group differences in PFC BP. BP F and BP P in the medial PFC were significantly negatively related to PASAT performance (r s =-0.551, p=.022 and r s =-0.488, p=.047, respectively), but BP was not related to 2back performance. Conclusions In contrast to what has been found in schizophrenia, SPD was not associated with significant alterations in prefrontal D1 receptor availability. Similar to previous schizophrenia findings, however, higher prefrontal D1 receptor availability was associated with poorer WM performance (as measured by the PASAT) in SPD. These findings suggest that schizophrenia and SPD may share a common pathophysiological feature related to prefrontal dopamine functioning that contributes to WM dysfunction, but that in SPD, alterations in D1 may occur only in a subset of individuals and/or to an extent that is minor relative to what occurs in schizophrenia.
Journal of Psychopharmacology, Mar 10, 2016
Evidence from preclinical and human studies indicates the presence of reduced dopamine-1 receptor... more Evidence from preclinical and human studies indicates the presence of reduced dopamine-1 receptor (D1R) signaling in the cortex, where D1Rs predominate, in patients with schizophrenia (SCZ), which may contribute to their cognitive deficits. Furthermore, studies in nonhuman primates (NHP) have suggested that intermittent administration of low doses of D1R agonists produce long-lasting reversals in cognitive deficits. The purpose of this trial was to test whether a similar design, involving subacute intermittent administration of low doses of a full, selective agonist at D1Rs, DAR-0100A, would improve cognitive deficits in SCZ. We randomized 49 clinically stable individuals with SCZ to three weeks of intermittent treatment with 0.5 mg or 15 mg of DAR-0100A, or placebo (normal saline). Functional magnetic resonance imaging (fMRI) BOLD was used to evaluate the effects of drug administration on brain activity during a working memory (WM) task. Effects on cognition were also assessed using the MATRICS and the N-back task as primary endpoints. The CogState battery was used as a secondary endpoint. There were no observed treatment effects on either the BOLD fMRI signal during WM tasks or the WM domains of the MATRICS. Moderate improvement was detected on the CogState battery and on the attention domain of the MATRICS. These results suggest that low doses of D1 agonists that do not result in measureable occupancy of the D1R do not reliably improve cognition in SCZ, unlike the observations in NHP. As this drug is limited by its pharmacokinetic profile, better D1R agonists that can achieve adequate levels of D1R occupancy are needed to test the efficacy of this mechanism for cognitive enhancement in SCZ.
NeuroImage, May 1, 1998
Changes in levels of synaptic dopamine COA) have been shown to affect the in vivo binding of vari... more Changes in levels of synaptic dopamine COA) have been shown to affect the in vivo binding of various DA2 receptor (02) radiotracers such as [llCJraclopride and (l23I]IBZM 0, 2). This phenomenon can be used to measure changes in synaptic OA following pharmacological challenge tests (3). However, the use of O 2 radiotracers practically restricts these measurements to regions of high O 2 density e.g., the striatum. Given the widespread distribution of D1 receptors in the brain, the use of a 0 1 instead of a O 2 radiotracer may allow measurement of DA release in both subcortical and cortical areas. We studied the impact of amphetamine, a potent OA releaser, on the in vivo binding of the D 1 radiotracer
Neuropsychopharmacology, Feb 3, 2020
Despite their theoretical rationale, nicotinic alpha-7 acetylcholine (nα 7 ) receptor agonists, h... more Despite their theoretical rationale, nicotinic alpha-7 acetylcholine (nα 7 ) receptor agonists, have largely failed to demonstrate efficacy in placebo-controlled trials in schizophrenia. AVL-3288 is a nα 7 positive allosteric modulator (PAM), which is only active in the presence of the endogenous ligand (acetylcholine), and thus theoretically less likely to cause receptor desensitization. We evaluated the efficacy of AVL-3288 in a Phase 1b, randomized, double-blind, placebo-controlled, triple cross-over study. Twenty-four non-smoking, medicated, outpatients with schizophrenia or schizoaffective disorder and a Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) ≥62 were randomized. Each subject received 5 days of AVL-3288 (10, 30 mg) and placebo across three separate treatment weeks. The primary outcome measure was the RBANS total scale score, with auditory P50 evoked potential suppression the key target engagement biomarker. Secondary outcome measures include task-based fMRI (RISE task), mismatch negativity, the Scale for the Assessment of Negative Symptoms of Schizophrenia (SANS) and the Brief Psychiatric Rating Scale (BPRS). Twenty-four subjects were randomized and treated without any clinically significant treatment emergent adverse effects. Baseline RBANS (82 ± 17) and BPRS (41 ± 13) scores were consistent with moderate impairment. Primary outcomes were negative, with nonsignificant worsening for both active groups vs. placebo in the P50 and minimal between group changes on the RBANS. In conclusion, the results did not indicate efficacy of the compound, consistent with most prior results for the nα 7 target.
Springer eBooks, 2002
The classical dopamine hypothesis of schizophrenia proposes that positive symptoms of the disorde... more The classical dopamine hypothesis of schizophrenia proposes that positive symptoms of the disorder are a result of hyperactivity of dopamine transmission.1 This hypothesis has received new support from brain imaging studies that have shown an exaggerated response to acute amphetamine challenge in untreated patients with schizophrenia compared with healthy subjects using dopamine D2 receptor SPECT (single photon emission computed tomography) or PET (positron emission tomography).2–4
NeuroImage, May 1, 1998
West 168th Street, Unit 28, New Ybrk, NY, 10m2 aadar®neuron.cpmc.columbia.edu We have previously ... more West 168th Street, Unit 28, New Ybrk, NY, 10m2 aadar®neuron.cpmc.columbia.edu We have previously demonstrated that amphetamine-induced dopamine release is increased in patients with schizophrenia (1, 2). While these studies indicated an abnormal response of DA neurons to amphetamine exposure, it remains unknown if baseline levels of DA are increased in schizophrenia. Baseline levels are physiologically more interesting, and potentially better related to severity of illness and prognosis, than amphetamine-stimulated levels. We recently developed a new imaging protocol that provides measurement of intrasynaptic DA in the resting state by comparing D 2 receptors availability before and after acute dopamine depletion, as induced by the reversible tyrosine hydroxylase inhibitor alpha-methyl-para-tyrosine (AMIYJ') (1 g PO QID for 2 days) (3). The purpose of this study was to evaluate "resting" or baseline dopamine release in patients with schizophrenia and matched controls. Nine patients with schizophrenia (5 males and 4 females, 4 African-American, 4 Hispanics, 1 Caucasian, age: 35 ± 12 y) and nine matched healthy controls (5 males and 4 females, 3 African-Americans, 1 Hispanic, 3 Caucasian and 1 Asian, age 35 ± 9 y) were included. Patients met DSM-IVcriteria for schizophrenia, without lifetime comorbid axis I diagnosis. Four patients were drug naive, and 5 were neuroleptic-free for at least 21 days. D 2 receptors availability was measured with SPECT and the radiotracer (l231]IBZM, using the constant infusion / sustained equilibrium technique and the PRISM 3000. The l1lean increase in D 2 receptors availability induced by AMPT was significantly larger in schizophrenic patients (32 ± 29%)compared to controls (10 ± 6%) (repeated measureANOVA,AMPT effect: p = 0.001, diagnosis *AMPT effect interaction: p = 0.044). The variance of the AMPT effect was also significantly larger in schizophrenics than Controls (F test, p = 0.004). AMPT induced an improvement in positive symptoms (PANSS positive symptoms SCore: baseline: 19 ± 8; post-AMP'!': 14 ± 7, P = 0.012, repeated measure ANOVA) and no significant changes in negative symptoms (PANSS negative symptoms score: baseline: 12 ± 5; post-AMPT: 15 ± 9, P = 0.30). If these findings are confirmed in a larger sample, the data would indicate a larger D 2 receptor occupancy by DA at baseline in patients with schizophrenia (assuming that the AMPT challenge results in equally negligible synaptic DA concentration in both groups, an assumption supported by plasma HVA measurements). These results nrc compatible with an increased "resting" synaptic DA concentration in untreated schizophrenic patients and Congruent with the D2 antagonism properties of antipsychotic drugs.
Glutamatergic dysfunction is implicated in the pathoaetiology of schizophrenia, but this may vary... more Glutamatergic dysfunction is implicated in the pathoaetiology of schizophrenia, but this may vary in extent between patients. It is unclear whether inter-individual variability in glutamate is greater in schizophrenia than the general population. We conducted meta-analyses to assess (1) variability of glutamate measures in patients relative to controls, using the log coefficient of variation ratio (CVR); (2) standardised mean differences (SMD) using Hedges g; (3) modal distribution of individual-level glutamate data using Hartigan’s unimodality dip test. MEDLINE and EMBASE databases were searched from inception to October 2021 for proton magnetic resonance spectroscopy (1H-MRS) studies reporting glutamate, glutamine or Glx in schizophrenia patients compared to controls. 116 studies reporting on 7,844 patients and 7,305 controls were included. Compared with controls, patients demonstrated greater variability in glutamatergic metabolites in the medial frontal cortex (MFC, glutamate: C...
Schizophrenia is a chronic neuropsychiatric disorder that causes distinct structural alterations ... more Schizophrenia is a chronic neuropsychiatric disorder that causes distinct structural alterations within the brain. We hypothesize that deep learning applied to a structural neuroimaging dataset could detect disease-related alteration and improve classification and diagnostic accuracy. We tested this hypothesis using a single, widely available, and conventional T1-weighted MRI scan, from which we extracted the 3D whole-brain structure using standard post-processing methods. A deep learning model was then developed, optimized, and evaluated on three open datasets with T1-weighted MRI scans of patients with schizophrenia. Our proposed model outperformed the benchmark model, which was also trained with structural MR images using a 3D CNN architecture. Our model is capable of almost perfectly (area under the ROC curve = 0.987) distinguishing schizophrenia patients from healthy controls on unseen structural MRI scans. Regional analysis localized subcortical regions and ventricles as the m...
Translational Psychiatry, 2021
Glutamate (Glu) and gamma-aminobutyric acid (GABA) are implicated in the pathophysiology of major... more Glutamate (Glu) and gamma-aminobutyric acid (GABA) are implicated in the pathophysiology of major depressive disorder (MDD). GABA levels or GABAergic interneuron numbers are generally low in MDD, potentially disinhibiting Glu release. It is unclear whether Glu release or turnover is increased in depression. Conversely, a meta-analysis of prefrontal proton magnetic resonance spectroscopy (1H MRS) studies in MDD finds low Glx (combination of glutamate and glutamine) in medicated MDD. We hypothesize that elevated Glx or Glu may be a marker of more severe, untreated MDD. We examined ventromedial prefrontal cortex/anterior cingulate cortex (vmPFC/ACC) Glx and glutamate levels using1H MRS in 34 medication-free, symptomatic, chronically ill MDD patients and 32 healthy volunteers, and GABA levels in a subsample. Elevated Glx and Glu were observed in MDD compared with healthy volunteers, with the highest levels seen in males with MDD. vmPFC/ACC GABA was low in MDD. Higher Glx levels correlat...
Neuropsychopharmacology, 2020
Glutamate neurotransmission is a prioritized target for antipsychotic drug development. Two metab... more Glutamate neurotransmission is a prioritized target for antipsychotic drug development. Two metabotropic glutamate receptor 2/3 (mGluR2/3) agonists (pomaglumetad [POMA] and TS-134) were assessed in two Phase Ib proof of mechanism studies of comparable designs and using identical clinical assessments and pharmacoBOLD methodology. POMA was examined in a randomized controlled trial under double-blind conditions for 10-days at doses of 80 or 320 mg/d POMA versus placebo (1:1:1 ratio). The TS-134 trial was a randomized, single-blind, 6-day study of 20 or 60 mg/d TS-134 versus placebo (5:5:2 ratio). Primary outcomes were ketamine-induced changes in pharmacoBOLD in the dorsal anterior cingulate cortex (dACC) and symptoms reflected on the Brief Psychiatric Rating Scale (BPRS). Both trials were conducted contemporaneously. 95 healthy volunteers were randomized to POMA and 63 to TS-134. High-dose POMA significantly reduced ketamine-induced BPRS total symptoms within and between-groups (p <...
JAMA Network Open, 2020
IMPORTANCE A single subanesthetic dose of ketamine produces an antidepressant response in patient... more IMPORTANCE A single subanesthetic dose of ketamine produces an antidepressant response in patients with major depressive disorder (MDD) within hours, but the mechanism of antidepressant effect is uncertain. OBJECTIVE To evaluate whether ketamine dose and brain glutamate and glutamine (Glx) and γ-aminobutyric acid (GABA) level responses to ketamine are related to antidepressant benefit and adverse effects. This randomized, parallel-group, triple-masked clinical trial included 38 physically healthy, psychotropic medication-free adult outpatients who were in a major depressive episode of MDD but not actively suicidal. The trial was conducted at
We tested two metabotropic glutamate receptor 2/3 (mGluR2/3) agonist prodrugs: pomaglumetad (POMA... more We tested two metabotropic glutamate receptor 2/3 (mGluR2/3) agonist prodrugs: pomaglumetad (POMA) and TS-134 including a high-dose of POMA that was four times the dose tested in the failed phase schizophrenia III trials in two proof of mechanism, Phase Ib studies using identical pharmacoBOLD target-engagement methodology. The POMA study was a double-blind, NIMH-sponsored, 10-day study of 80 or 320 mg/d POMA or placebo (1:1:1 ratio), designed to detect d>0.8 sd between-group effect-size differences. The TS-134 study was a single-blind, industry-sponsored, 6-day study of 20 or 60 mg/d TS-134 or placebo (5:5:2 ratio), designed to permit effect-size estimation for future studies. Primary outcomes were ketamine-induced changes in pharmacoBOLD in the dorsal anterior cingulate cortex (dACC) and Brief Psychiatric Rating Scale (BPRS). 95 healthy controls were randomized to POMA and 63 to TS-134. High-dose POMA had significant within and between-group reduction in ketamine-induced BPRS to...
Molecular Psychiatry, 2018
Scientists have long sought to characterize the pathophysiologic basis of schizophrenia and devel... more Scientists have long sought to characterize the pathophysiologic basis of schizophrenia and develop biomarkers that could identify the illness. Extensive postmortem and in vivo neuroimaging research has described the early involvement of the hippocampus in the pathophysiology of schizophrenia. In this context, we have developed a hypothesis that describes the evolution of schizophrenia—from the premorbid through the prodromal stages to syndromal psychosis—and posits dysregulation of glutamate neurotransmission beginning in the CA1 region of the hippocampus as inducing attenuated psychotic symptoms and initiating the transition to syndromal psychosis. As the illness progresses, this pathological process expands to other regions of the hippocampal circuit and projection fields in other anatomic areas including the frontal cortex, and induces an atrophic process in which hippocampal neuropil is reduced and interneurons are lost. This paper will describe the studies of our group and oth...
Schizophrenia Research, 2014
NeuroImage: Clinical, 2019
Ketamine is an uncompetitive N-methyl-D-aspartate (NMDA) glutamate receptor antagonist. It induce... more Ketamine is an uncompetitive N-methyl-D-aspartate (NMDA) glutamate receptor antagonist. It induces effects in healthy individuals that mimic symptoms associated with schizophrenia. We sought to root these experiences in altered brain function, specifically aberrant resting state functional connectivity (rsfMRI). In the present study, we acquired rsfMRI data under ketamine and placebo in a between-subjects design and analyzed seed-based measures of rsfMRI using large-scale networks, dorsolateral prefrontal cortex (DLPFC) and sub-nuclei of the thalamus. We found ketamine-induced alterations in rsfMRI connectivity similar to those seen in patients with schizophrenia, some changes that may be more comparable to early stages of schizophrenia, and other connectivity signatures seen in patients that ketamine did not recreate. We do not find any circuits from our regions of interest that correlates with positive symptoms of schizophrenia in our sample, although we find that DLPFC connectivity with ACC does correlate with a mood measure. These results provide support for ketamine's use as a model of certain biomarkers of schizophrenia, particularly for early or at-risk patients.
![Research paper thumbnail of Increased prefrontal cortical D1 receptors in drug naive patients with schizophrenia: a PET study with [11C]NNC112](https://attachments.academia-assets.com/113241419/thumbnails/1.jpg)
Journal of psychopharmacology (Oxford, England), 2011
D(1) receptors are the main mediators of dopamine transmission in the cortex and subserve cogniti... more D(1) receptors are the main mediators of dopamine transmission in the cortex and subserve cognitive functions that are affected in patients with schizophrenia. Prior imaging studies have suggested abnormalities in the expression of these receptors in schizophrenia, but no conclusive picture has emerged yet. One source of discrepancy may have been prior antipsychotic exposure. We used positron emission tomography (PET) and a D1 radiotracer, [(11)C]NNC112, in drug naïve (DN, n = 12) and drug free (DF, n = 13) patients with schizophrenia and 40 healthy control subjects (HC, n = 40 total, n = 24 per comparison group) matched for age, gender, ethnicity, parental socioeconomic status and cigarette smoking. We measured the binding potential BPP, corrected for partial volume effects. The outcome measure was obtained in cortical and striatal subregions outlined on coregistered individual MRIs. Partial volume effect corrected BPP measures were significantly higher in DN vs controls in cortica...
Journal of nuclear medicine : official publication, Society of Nuclear Medicine, 2004
N-11 C-propyl-norapomorphine (11 C-NPA) is a new dopamine agonist PET radiotracer that holds pote... more N-11 C-propyl-norapomorphine (11 C-NPA) is a new dopamine agonist PET radiotracer that holds potential for imaging the high-affinity states of dopamine D 2-like receptors in the living brain. The goal of this study was to develop and evaluate analytic strategies to derive in vivo 11 C-NPA binding parameters. Methods: Two baboons were scanned 4 times after 11 C-NPA injections. The metabolite-corrected arterial input functions were measured. Regional brain time-activity curves were analyzed with kinetic and graphical analyses, using the arterial time-activity curve as the input function. Data were also analyzed with the simplified reference-tissue model (SRTM) and graphical analysis with reference-region input. Results: 11 C-NPA exhibited moderately fast metabolism, with 31% Ϯ 5% of arterial plasma concentration corresponding to the parent compound at 40 min after injection. Plasma clearance was 29 Ϯ 1 L/h, and plasma free fraction (f 1) was 5% Ϯ 1%. For kinetic analysis, a 1-tissue compartment model (1TCM) provided a good fit to the data and more robust derivations of the tissue distribution volumes (V T , in mL/g) than a 2-tissue compartment model (2TCM). Using 1TCM, V T s in the cerebellum and striatum were 3.4 Ϯ 0.4 and 7.5 Ϯ 2 mL/g, respectively, which led to estimates of striatal binding potential (BP) of 4.0 Ϯ 1.1 mL/g and striatal equilibrium specific-to-nonspecific partition coefficient (V 3 Љ) of 1.2 Ϯ 0.2. V T values derived with graphical analysis were well correlated with but slightly lower than V T values derived with kinetic analysis. V 3 Љ values derived with SRTM were well correlated with but slightly higher than V 3 Љ values derived with kinetic analysis. Using any method, a significant difference was detected in BP and V 3 Љ values between the 2 animals. It was determined that 30 min of scanning data were sufficient to derive V 3 Љ values using kinetic, graphical (arterial input and reference-region input), and SRTM analyses. Conclusion: This study indicates that 11 C-NPA is a suitable PET tracer to quantify the agonist high-affinity sites of D 2-like receptors.
![Research paper thumbnail of Prefrontal dopamine D1 receptors and working memory in schizotypal personality disorder: a PET study with [11C]NNC112](https://attachments.academia-assets.com/100983797/thumbnails/1.jpg)
Psychopharmacology, 2014
Rationale-Schizotypal personality disorder (SPD) is associated with working memory (WM) impairmen... more Rationale-Schizotypal personality disorder (SPD) is associated with working memory (WM) impairments that are similar to those observed in schizophrenia. Imaging studies have suggested that schizophrenia is associated with alterations in dopamine D1-receptor availability in the prefrontal cortex (PFC) that may be related to the WM impairments that characterize this disorder. Objectives-To characterize prefrontal D1-receptor availability and its relation to WM performance in SPD. Methods-We used positron emission tomography (PET) and the radiotracer [ 11 C]NNC112 with 18 unmedicated SPD and 21 healthy-control participants; as an index of D1-receptor availability, binding-potential (BP) measures (BP F , BP ND , and BP P) were calculated for prefrontal and striatal subregions. To assess WM, SPD participants completed the 2-back and Paced Auditory Serial Addition Test (PASAT).
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Papers by Lawrence Kegeles