The role of dissociation in ketamine’s antidepressant effects

Ballard, Elizabeth D.; Zarate, Carlos A.

doi:10.1038/s41467-020-20190-4

Cited by 123 publications

(72 citation statements)

References 76 publications

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“…Our findings may have implications for the potential therapeutic use of ketamine. There are mixed findings and views as to whether dissociation is necessary to achieve antidepressant effects of ketamine [7, 8] or whether these effects are considered as adverse events. An answer may lie in the personalized responses of each individual person, which might require in-depth analysis of individual variation.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Acute Ketamine Modulated Functional Brain Coupling and Dissociative and Affective States in Human Subjects: Interim Analyses

Hack

Warthen

Zhang

et al. 2021

Preprint

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Ketamine is a non-competitive antagonist of the N-methyl-D-aspartate (NMDA) glutamate receptor that is both a drug of abuse and an FDA-approved anesthetic used off-label for treatment-resistant depression. Despite its growing clinical use for depression and pain, the relationships between the acute dissociative and affective effects of ketamine that contribute to its abuse liability and therapeutic potential, along with the neural mechanisms underlying these effects, are not well established. To address this need, we have implemented a randomized, double-blinded, placebo-controlled, within-subjects mechanistic trial. Healthy adult subjects undergo infusion with two fixed doses of subanesthetic racemic intravenous (IV) ketamine and placebo and their acute responses are assessed with self-report questionnaires, behavioral measures, hormone levels, and neuroimaging. As planned in our analysis strategy, we present interim results for the first 7 subjects of our study, focusing on dissociative and affective states and resting functional brain coupling signatures of these states. The first key finding was that ketamine induced dose-dependent increases in dissociation and related intoxication. Ketamine also altered affective states, reducing emotional insensitivity but increasing stress assessed by cortisol. Second, ketamine had an effect on altering brain connectivity, particularly for specific connections between regions of the reward and negative affect circuits and involving thalamic sub-regions. Third, regarding brain-response associations, ketamine-induced increases in amygdala-anteroventral thalamus coupling were correlated with greater dissociation and intoxication, whereas decreases in the coupling of the anteromedial thalamus and posterior parietal thalamus were correlated with increased sensory aspects of reward responsiveness. Additional specific correlations were observed between affective measures relevant to reward responsiveness or its absence and drug-altered changes in localized functional connections involving the nucleus accumbens (NAcc), amygdala, and thalamic sub-regions. We also discovered a consistent profile of negative associations between ketamine altered connectivity involving the NAcc and specific thalamic sub-regions and effects of anxiety. Further, drug-altered increases in the coupling of the amygdala and anteroventral thalamus were associated with increases in cortisol, an indicator of biochemical stress. The findings highlight the utility of integrating self-reports, objective measures, and functional neuroimaging to disentangle the brain states underlying specific acute responses induced by ketamine. With the likely continued expansion of FDA indications for ketamine, understanding acute responses and underlying neural mechanisms is important for maximizing the therapeutic potential of ketamine while minimizing the risk of promoting misuse or abuse of this substance. Clinical Trial Registration ID #: NCT03475277

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Section: Discussionmentioning

confidence: 99%

“…There is mixed evidence as to whether dissociation is necessary for ketamine's antidepressant effect. For example, a meta-analysis showed it was not necessary [7], whereas another study demonstrated a correlation between reduction in depression scores and the depersonalization aspect of ketamine-induced dissociation in particular [8].…”

Section: Introductionmentioning

confidence: 99%

Acute Ketamine Modulated Functional Brain Coupling and Dissociative and Affective States in Human Subjects: Interim Analyses

Hack

Warthen

Zhang

et al. 2021

Preprint

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“…In fact it has been reported that dissociation could predict a robust and sustained antidepressant effect (Luckenbaugh et al, 2014;Niciu et al, 2018). However, one must consider that the latter correlation is debated (Ballard and Zarate, 2020) and that dissociative effects and sleep effects occur at different times (Vande Voort et al, 2017). Furthermore it is possible that ketamine may produce different effects in depressed and suicidal patients than in individuals without these conditions; in fact, ketamine can cause unpleasant dreams in healthy volunteers over the three post-administration nights (Blagrove et al, 2009) and has not decreased delirium in older adults undergoing negative experiences after major surgery (Avidan et al, 2017).…”

Section: Ketamine and Suicidal Behaviormentioning

confidence: 99%

Repurposing Ketamine in Depression and Related Disorders: Can This Enigmatic Drug Achieve Success?

et al. 2021

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Repurposing ketamine in the therapy of depression could well represent a breakthrough in understanding the etiology of depression. Ketamine was originally used as an anesthetic drug and later its use was extended to other therapeutic applications such as analgesia and the treatment of addiction. At the same time, the abuse of ketamine as a recreational drug has generated a concern for its psychotropic and potential long-term effects; nevertheless, its use as a fast acting antidepressant in treatment-resistant patients has boosted the interest in the mechanism of action both in psychiatry and in the wider area of neuroscience. This article provides a comprehensive overview of the actions of ketamine and intends to cover: (i) the evaluation of its clinical use in the treatment of depression and suicidal behavior; (ii) the potential use of ketamine in pediatrics; (iii) a description of its mechanism of action; (iv) the involvement of specific brain areas in producing antidepressant effects; (v) the potential interaction of ketamine with the hypothalamic-pituitary-adrenal axis; (vi) the effect of ketamine on neuronal transmission in the bed nucleus of stria terminalis and on its output; (vii) the evaluation of any gender-dependent effects of ketamine; (viii) the interaction of ketamine with the inflammatory processes involved in depression; (ix) the evaluation of the effects observed with single or repeated administration; (x) a description of any adverse or cognitive effects and its abuse potential. Finally, this review attempts to assess whether ketamine’s use in depression can improve our knowledge of the etiopathology of depression and whether its therapeutic effect can be considered an actual cure for depression rather than a therapy merely aimed to control the symptoms of depression.

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“…Then proceed with inhibition of glutamatergic input to GABA interneurons and result in glutamatergic disinhibition resulting in decreased feedback and increased glutamatergic excitatory transmission. 5,6 Non-NMDA Mediators…”

Section: Nmda Receptors As Mediatorsmentioning

confidence: 99%

“…Another component involved in the antidepressant effect is the eukaryotic elongation factor 2 kinase (eEF2K), which is the key to mediating the effects of fast-acting antidepressants. 5,6,7 Potential mechanism of antidepressant of ketamine 2…”

Section: The Neurochemical Cascades and Other Mechanismsmentioning

confidence: 99%

The Use of Ketamine as Therapy for Depression

Lovina¹

2021

OAIJMR

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Depressive disorder is still a significant problem in several developed countries and is morbidity caused by mental disorders. With the development of science, now discovered the unique pharmacodynamic properties of ketamine, which is used as an antidepressant. As we know in clinical practice, ketamine is used for anaesthesia, analgesia, sedation, and chronic pain management. Rapid-onset antidepressants resulted from increased levels of BDNF in the hippocampus. Extracellular glutamate agents are not new for the treatment of depression. According to the neurobiology view, depression is a monoaminergic phenomenon, so this is the impetus for discovering a new generation of antidepressants. Ketamine can be given intravenously in subanesthetic doses. Still, monitoring must be carrying in therapy administration because of the possible side effects such as hypersalivation, tachycardia, increased systemic arterial pressure, and intracranial pressure.

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The role of dissociation in ketamine’s antidepressant effects

Cited by 123 publications

References 76 publications

Acute Ketamine Modulated Functional Brain Coupling and Dissociative and Affective States in Human Subjects: Interim Analyses

Acute Ketamine Modulated Functional Brain Coupling and Dissociative and Affective States in Human Subjects: Interim Analyses

Repurposing Ketamine in Depression and Related Disorders: Can This Enigmatic Drug Achieve Success?

The Use of Ketamine as Therapy for Depression

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