Modulatory effects of ketamine, risperidone and lamotrigine on resting brain perfusion in healthy human subjects

Shcherbinin, Sergey; Doyle, Orla; Zelaya, Fernando; Simoni, Sara De; Mehta, Mitul A.; Schwarz, Adam J.

doi:10.1007/s00213-015-4021-z

Cited by 20 publications

(30 citation statements)

References 38 publications

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“…The decreases in CBF observed in the cerebellum following risperidone are in line with our previous observation [Shcherbinin et al, ]. These effects of risperidone differ from the effects of aripiprazole, a partial D2 agonist that increased CBF in the cerebellum [Handley et al, ].…”

Section: Discussionsupporting

confidence: 90%

An investigation of regional cerebral blood flow and tissue structure changes after acute administration of antipsychotics in healthy male volunteers

Hawkins

Wood

Vernon

et al. 2017

Human Brain Mapping

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Chronic administration of antipsychotic drugs has been linked to structural brain changes observed in patients with schizophrenia. Recent MRI studies have shown rapid changes in regional brain volume following just a single dose of these drugs. However, it is not clear if these changes represent real volume changes or are artefacts ("apparent" volume changes) due to drug-induced physiological changes, such as increased cerebral blood flow (CBF). To address this, we examined the effects of a single, clinical dose of three commonly prescribed antipsychotics on quantitative measures of T1 and regional blood flow of the healthy human brain. Males (n 5 42) were randomly assigned to one of two parallel groups in a double-blind, placebo-controlled, randomized, three-period cross-over study Additional Supporting Information may be found in the online version of this article. design. One group received a single oral dose of either 0.5 or 2 mg of risperidone or placebo during each visit. The other received olanzapine (7.5 mg), haloperidol (3 mg), or placebo. MR measures of quantitative T1, CBF, and T1-weighted images were acquired at the estimated peak plasma concentration of the drug. All three drugs caused localized increases in striatal blood flow, although drug and region specific effects were also apparent. In contrast, all assessments of T1 and brain volume remained stable across sessions, even in those areas experiencing large changes in CBF. This illustrates that a single clinically relevant oral dose of an antipsychotic has no detectable acute effect on T1 in healthy volunteers. We further provide a methodology for applying quantitative imaging methods to assess the acute effects of other compounds on structural MRI metrics. Hum Brain Mapp 39:319-331, 2018.V C 2017 Wiley Periodicals, Inc.

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Section: Discussionsupporting

confidence: 90%

An investigation of regional cerebral blood flow and tissue structure changes after acute administration of antipsychotics in healthy male volunteers

Hawkins

Wood

Vernon

et al. 2017

Human Brain Mapping

Self Cite

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“…Interestingly, a study combining ketamine administration with other potential glutamate release modulators suggests that, at least with ketamine, connectivity changes occur due to NMDAR blockade rather than downstream glutamatergic effects(136). This finding is consistent with arterial spin labeling studies on this topic(137). It may have important implications for identifying drug targets related to altered NMDAR signaling in SCZ, which likely contribute to E/I imbalance(138).…”

Section: Looking Forward: Pharmacological Tms Genetic Disorders Ansupporting

confidence: 92%

Searching for Cross-Diagnostic Convergence: Neural Mechanisms Governing Excitation and Inhibition Balance in Schizophrenia and Autism Spectrum Disorders

Foss‐Feig

Adkinson

et al. 2017

Biological Psychiatry

247

183

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Recent theoretical accounts have proposed excitation (E) and inhibition (I) imbalance as a possible mechanistic, network-level hypothesis underlying neural and behavioral dysfunction across neurodevelopmental disorders, particularly autism spectrum disorder (ASD) and schizophrenia (SCZ). These two disorders share some overlap in their clinical presentation as well as convergence in their underlying genes and neurobiology. However, there are also clear points of dissociation in terms of phenotypes and putatively affected neural circuitry. Here we highlight emerging work from the clinical neuroscience literature examining neural correlates of E/I imbalance across children and adults with ASD and adults with both chronic and early-course SCZ. We discuss findings from diverse neuroimaging studies across distinct modalities, conducted with EEG, MEG, 1H-MRS, and fMRI, including effects observed both during task and at rest. Throughout this review we discuss points of convergence and divergence in the ASD and SCZ literature, with a focus on disruptions in neural E/I balance. We also consider these findings in relation to predictions generated by theoretical neuroscience, particularly computational models predicting E/I imbalance across disorders. Finally, we discuss how human non-invasive neuroimaging can benefit from pharmacological challenge studies to reveal mechanisms in ASD and SCZ. Collectively, we attempt to shed light on shared and divergent neuroimaging effects across disorders with the goal of informing future research examining the mechanisms underlying the E/I imbalance hypothesis across neurodevelopmental disorders. We posit that such translational efforts are vital to facilitate development of neurobiologically informed treatment strategies across neuropsychiatric conditions.

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“…This trend was similar to a previous study in which risperidone reduced ketamine-induced BOLD signal in multiple regions of the brain (Doyle et al 2013). However, the BOLD resting state results from our study do not align with a previous ASL-based study of ketamine-induced changes in brain perfusion in which risperidone increased ketamine-induced perfusion changes (Shcherbinin et al 2015). Taken together, these results suggest that the attenuation of BOLD changes seen with risperidone, and possibly with TAK-063, is not due to generalized changes in blood flow.…”

Section: Discussionsupporting

confidence: 59%

“…Specifically, ketamine impairs working memory and psychomotor function in healthy volunteers (Driesen et al 2013;Lofwall et al 2006;Morgan et al 2004) and induces changes in blood oxygen leveldependent (BOLD) signal as measured by functional magnetic resonance imaging (fMRI) (De Driesen et al 2013). In previous studies, ketamine-induced changes in BOLD signal have been shown to be reversed by risperidone, a dopamine receptor antagonist and atypical antipsychotic (Doyle et al 2013;Shcherbinin et al 2015).…”

Section: Introductionmentioning

confidence: 99%

A randomized, placebo-controlled, phase 1 study to evaluate the effects of TAK-063 on ketamine-induced changes in fMRI BOLD signal in healthy subjects

et al. 2019

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Rationale Phosphodiesterase 10A inhibitor TAK-063 has shown effects that suggest efficacy in schizophrenia treatment. Objective This randomized, double-blind, placebo-controlled, incomplete-crossover study investigated effects of single oral administration of TAK-063 on ketamine-induced changes in blood oxygen level-dependent (BOLD) signal in healthy males. Methods Healthy men aged 18 to 45 years with normal magnetic resonance imaging (MRI) scans and electroencephalogram measurements at screening were eligible. Each subject was randomized to one of nine treatment schedules: all subjects received placebo and two of three doses of TAK-063 followed by ketamine. The primary endpoint was ketamine-induced brain activity in select regions of the brain during resting state. Secondary endpoints included pharmacokinetic parameters of TAK-063, proportion of subjects with treatment-emergent adverse events (AEs), and percentage of subjects meeting criteria for abnormal safety laboratory tests and vital sign measurements. Results The study comprised 27 subjects. Prior to ketamine infusion, TAK-063 exerted region-specific effects on resting state functional MRI (fMRI) BOLD signal. After ketamine administration, TAK-063 reduced the Cohen's effect size for resting-state fMRI BOLD signal in key brain regions examined, and exerted similar effects on BOLD signal during the working memory task across all doses. TAK-063 was safe and well tolerated. Conclusions Our results are consistent with non-clinical studies of ketamine and TAK-063 and clinical studies of ketamine and risperidone. It is unknown whether these data are predictive of potential antipsychotic efficacy, and further analyses are required.

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Modulatory effects of ketamine, risperidone and lamotrigine on resting brain perfusion in healthy human subjects

Abstract: The findings argue against perfusion changes confounding in the previously described evoked BOLD response to ketamine and emphasise the blockade of the NMDA receptor over neuronal glutamate release in determining the perfusion changes induced by ketamine.

Cited by 20 publications

References 38 publications

An investigation of regional cerebral blood flow and tissue structure changes after acute administration of antipsychotics in healthy male volunteers

An investigation of regional cerebral blood flow and tissue structure changes after acute administration of antipsychotics in healthy male volunteers

Searching for Cross-Diagnostic Convergence: Neural Mechanisms Governing Excitation and Inhibition Balance in Schizophrenia and Autism Spectrum Disorders

A randomized, placebo-controlled, phase 1 study to evaluate the effects of TAK-063 on ketamine-induced changes in fMRI BOLD signal in healthy subjects

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