Glutamate Modulation of Dopamine Measured in Vivo with Positron Emission Tomography (PET) and 11C-Raclopride in Normal Human Subjects

Smith, Gwenn S.; Schloesser, R.; Brodie, Jonathan D.; Dewey, Stephen L.; Logan, Jean; Vitkun, Stephen A.; Simkowitz, Philip; Hurley, Arlene; Cooper, Thomas B.; Volkow, Nora D.; Cancro, Robert

doi:10.1016/s0893-133x(97)00092-4

Cited by 177 publications

(18 citation statements)

References 43 publications

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“…However, Adams et al (2002) found that ketamine did not stimulate dopamine release in non-human primates. In humans, ketamine’s effect on dopaminergic neuro-transmission is even more controversial (Aalto et al, 2005, 2002; Breier et al, 1998; Smith et al, 1998; Kegeles et al, 2002; Vernaleken et al, 2013). With regard to psychotomimetic effects, (Sos et al, 2013) BPRS subscales were not correlated with antidepressant response in depressed subjects.…”

Section: Discussionmentioning

confidence: 99%

Do the dissociative side effects of ketamine mediate its antidepressant effects?

Luckenbaugh

Niciu

Ionescu

et al. 2014

Journal of Affective Disorders

249

175

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Background The N-methyl-D-aspartate receptor antagonist ketamine has rapid antidepressant effects in major depression. Psychotomimetic symptoms, dissociation and hemodynamic changes are known side effects of ketamine, but it is unclear if these side effects relate to its antidepressant efficacy. Methods Data from 108 treatment-resistant inpatients meeting criteria for major depressive disorder and bipolar disorder who received a single subanesthetic ketamine infusion were analyzed. Pearson correlations were performed to examine potential associations between rapid changes in dissociation and psychotomimesis with the Clinician-Administered Dissociative States Scale (CADSS) and Brief Psychiatric Rating Scale (BPRS), respectively, manic symptoms with Young Mania Rating Scale (YMRS), and vital sign changes, with percent change in the 17-item Hamilton Depression Rating scale (HDRS) at 40 and 230 min and Days 1 and 7. Results Pearson correlations showed significant association between increased CADSS score at 40 min and percent improvement with ketamine in HDRS at 230 min (r= −0.35, p=0.007) and Day 7 (r=−0.41, p=0.01). Changes in YMRS or BPRS Positive Symptom score at 40 min were not significantly correlated with percent HDRS improvement at any time point with ketamine. Changes in systolic blood pressure, diastolic blood pressure, and pulse were also not significantly related to HDRS change. Limitations Secondary data analysis, combined diagnostic groups, potential unblinding. Conclusions Among the examined mediators of ketamine’s antidepressant response, only dissociative side effects predicted a more robust and sustained antidepressant. Prospective, mechanistic investigations are critically needed to understand why intra-infusion dissociation correlates with a more robust antidepressant efficacy of ketamine.

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Section: Discussionmentioning

confidence: 99%

Do the dissociative side effects of ketamine mediate its antidepressant effects?

Luckenbaugh

Niciu

Ionescu

et al. 2014

Journal of Affective Disorders

249

175

View full text Add to dashboard Cite

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“…Dopamine (DA) neurotransmission and neural circuits involving the dorsolateral prefrontal cortex (DLPFC) and the striatum have been most consistently implicated in processing speed, psychomotor and executive functioning. Ketamine has been observed to modulate DA transmission (Krystal et al 2005; Smith et al 1998; Vollenweider et al 2000), although the extent to which this is related to its antidepressant activity is not known. Beyond DA, preclinical studies have implicated alterations in neuroplasticity via several mechanisms – including modulation of brain-derived neurotrophic factor (BDNF) – as critical to ketamine’s antidepressant action (Autry et al 2011; Duman 2012).…”

Section: Discussionmentioning

confidence: 99%

Neurocognitive effects of ketamine in treatment-resistant major depression: association with antidepressant response

et al. 2013

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Rationale The N-methyl-d-aspartate (NMDA) glutamate receptor antagonist ketamine has demonstrated rapid antidepressant effects in patients with treatment-resistant depression (TRD). Despite the promise of a novel and urgently needed treatment for refractory depression, concerns regarding potential adverse neurocognitive effects of ketamine remain. Objectives Although extensive research has been conducted in healthy volunteers, there is a paucity of studies examining the neurocognitive effects of ketamine in depressed patients. Therefore, the aims of the current study were to characterize the relationship between baseline neurocognition and antidepressant response to ketamine, measure the acute impact of ketamine on neurocognition, and investigate the relationship between acute neurocognitive effects of ketamine and antidepressant response. Methods Neurocognitive functioning was assessed in 25 patients with TRD using a comprehensive battery: estimated premorbid IQ, current IQ, and tests from the MATRICS battery (MCCB). A subset of the MCCB was repeated immediately following a 40-min intravenous infusion of ketamine (0.5 mg/kg). Results Patients who responded to ketamine 24 hours following treatment had poorer baseline neurocognitive performance relative to non-responders, and in particular slower processing speed (F=8.42, df=23, p=0.008). Ketamine was associated with selective impairments in memory recall and the degree of cognitive change carried negative prognostic significance (e.g. negative cognitive effects immediately after ketamine predicted lower response rate at 24 hours; Fisher’s Exact Test 2-sided p=0.027). Conclusions Taken together, our findings suggest a potential baseline neurocognitive predictor of ketamine response and an inverse relationship between the cognitive effects of ketamine and antidepressant efficacy.

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“…This is well known for neurological applications and many reports describe the effect of anaesthetics, mostly barbiturates, on brain function [4], [5], [6]. However, less is published on the general impact of anaesthesia on extracerebral metabolism, especially in nuclear medicine applications.…”

Section: Introductionmentioning

confidence: 99%

Hypoxia Imaging Using PET and SPECT: The Effects of Anesthetic and Carrier Gas on [64Cu]-ATSM, [99mTc]-HL91 and [18F]-FMISO Tumor Hypoxia Accumulation

et al. 2011

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BackgroundPreclinical imaging requires anaesthesia to reduce motion-related artefacts. For direct translational relevance, anaesthesia must not significantly alter experimental outcome. This study reports on the effects of both anaesthetic and carrier gas upon the uptake of [64Cu]-CuATSM, [99mTc]-HL91 and [18F]-FMISO in a preclinical model of tumor hypoxia.Methodology/Principal FindingsThe effect of carrier gas and anaesthetic was studied in 6 groups of CaNT-bearing CBA mice using [64Cu]-CuATSM, [99mTc]-HL91 or [18F]-FMISO. Mice were anaesthetised with isoflurane in air, isoflurane in pure oxygen, with ketamine/xylazine or hypnorm/hypnovel whilst breathing air, or in the awake state whilst breathing air or pure oxygen. PET or SPECT imaging was performed after which the mice were killed for organ/tumor tracer quantitation. Tumor hypoxia was confirmed. Arterial blood gas analysis was performed for the different anaesthetic regimes. The results demonstrate marked influences on tumor uptake of both carrier gas and anaesthetic, and show differences between [99mTc]-HL91, [18F]-FMISO and [64Cu]-CuATSM. [99mTc]-HL91 tumor uptake was only altered significantly by administration of 100% oxygen. The latter was not the case for [18F]-FMISO and [64Cu]-CuATSM. Tumor-to-muscle ratio (TMR) for both compounds was reduced significantly when either oxygen or anaesthetics (isoflurane in air, ketamine/xylazine or hypnorm/hypnovel) were introduced. For [18F]-FMISO no further decrease was measured when both isoflurane and oxygen were administered, [64Cu]-CuATSM did show an additional significant decrease in TMR. When using the same anaesthetic regimes, the extent of TMR reduction was less pronounced for [64Cu]-CuATSM than for [18F]-FMISO (40–60% versus 70% reduction as compared to awake animals breathing air).Conclusions/SignificanceThe use of anaesthesia can have profound effects on the experimental outcome. More importantly, all tested anaesthetics reduced tumor-hypoxia uptake. Anaesthesia cannot be avoided in preclinical studies but great care has to be taken in preclinical models of hypoxia as anaesthesia effects cannot be generalised across applications, nor disease states.

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Glutamate Modulation of Dopamine Measured in Vivo with Positron Emission Tomography (PET) and 11C-Raclopride in Normal Human Subjects

Abstract: Subanesthetic doses of the noncompetitive N-methyl-

Cited by 177 publications

References 43 publications

Do the dissociative side effects of ketamine mediate its antidepressant effects?

Do the dissociative side effects of ketamine mediate its antidepressant effects?

Neurocognitive effects of ketamine in treatment-resistant major depression: association with antidepressant response

Hypoxia Imaging Using PET and SPECT: The Effects of Anesthetic and Carrier Gas on [64Cu]-ATSM, [99mTc]-HL91 and [18F]-FMISO Tumor Hypoxia Accumulation

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