A retrospective analysis of ketamine intravenous therapy for depression in real-world care settings

McInnes, L. Alison; Qian, Jimmy; Gargeya, Rishab S.; DeBattista, Charles; Heifets, Boris D.

doi:10.1016/j.jad.2021.12.097

Cited by 33 publications

(16 citation statements)

References 30 publications

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“…7 days post-infusion) impact of IV ketamine on depression symptoms across a wide range of study designs and patient characteristics. Overall response (peak of 46%) and remission (peak of 27%) rates were comparable to those observed retrospectively in clinical settings [ 37 ], but lower than those observed in the earliest published RCTs [ 38 – 40 ], consistent with a waning pattern of effect sizes observed across many disciplines as a field of study matures [ 41 ]. Despite variability in patient outcomes, an exhaustive search for moderators of outcome across 37 variables (Table 2 ) produced very few individual study- or patient-level features that reliably predicted ketamine’s benefit over placebo, suggesting ketamine’s antidepressant impact is highly uniform across heterogeneous patients.…”

Section: Resultssupporting

confidence: 67%

International pooled patient-level meta-analysis of ketamine infusion for depression: In search of clinical moderators

et al. 2022

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Depression is disabling and highly prevalent. Intravenous (IV) ketamine displays rapid-onset antidepressant properties, but little is known regarding which patients are most likely to benefit, limiting personalized prescriptions. We identified randomized controlled trials of IV ketamine that recruited individuals with a relevant psychiatric diagnosis (e.g., unipolar or bipolar depression; post-traumatic stress disorder), included one or more control arms, did not provide any other study-administered treatment in conjunction with ketamine (although clinically prescribed concurrent treatments were allowable), and assessed outcome using either the Montgomery-Åsberg Depression Rating Scale or the Hamilton Rating Scale for Depression (HRSD-17). Individual patient-level data for at least one outcome was obtained from 17 of 25 eligible trials [pooled n = 809]. Rates of participant-level data availability across 33 moderators that were solicited from these 17 studies ranged from 10.8% to 100% (median = 55.6%). After data harmonization, moderators available in at least 40% of the dataset were tested sequentially, as well as with a data-driven, combined moderator approach. Robust main effects of ketamine on acute [~24-hours; β*(95% CI) = 0.58 (0.44, 0.72); p < 0.0001] and post-acute [~7 days; β*(95% CI) = 0.38 (0.23, 0.54); p < 0.0001] depression severity were observed. Two study-level moderators emerged as significant: ketamine effects (relative to placebo) were larger in studies that required a higher degree of previous treatment resistance to federal regulatory agency-approved antidepressant medications (≥2 failed trials) for study entry; and in studies that used a crossover design. A comprehensive data-driven search for combined moderators identified statistically significant, but modest and clinically uninformative, effects (effect size r ≤ 0.29, a small-medium effect). Ketamine robustly reduces depressive symptoms in a heterogeneous range of patients, with benefit relative to placebo even greater in patients more resistant to prior medications. In this largest effort to date to apply precision medicine approaches to ketamine treatment, no clinical or demographic patient-level features were detected that could be used to guide ketamine treatment decisions.Review Registration: PROSPERO Identifier: CRD42021235630

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Section: Resultssupporting

confidence: 67%

International pooled patient-level meta-analysis of ketamine infusion for depression: In search of clinical moderators

et al. 2022

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“…We have also observed that ketamine treatment occasionally increases suicidal ideation in a small fraction of severely depressed individuals (unipolar or bipolar), and this observation has been corroborated by a recent study of ketamine treatment in “real world” clinical treatment ( 67 , 68 ). We are also aware of several completed suicides that occurred during or following a course of ketamine treatment ( 69 ).…”

Section: Discussionsupporting

confidence: 80%

Ketamine for Bipolar Depression: Biochemical, Psychotherapeutic, and Psychedelic Approaches

Bennett¹,

Yavorsky²,

Bravo³

2022

Front. Psychiatry

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Bipolar disorder (type 1) is a serious and chronic psychiatric illness that can be difficult to treat. Many bipolar patients have refractory depressive episodes. Racemic ketamine, a glutamate modulator with prominent dissociate and psychedelic properties, has been demonstrated to have rapid acting antidepressant and anti-obsessional effects which may be useful for treating the symptoms of bipolar depression. Most of the existing research literature on unipolar and bipolar depression has looked at racemic ketamine in the sub-psychedelic dose range given by infusion as a stand-alone treatment (without concurrent psychotherapy). This article expands on the existing research by articulating three different paradigms for ketamine treatment: biochemical, psychotherapeutic, and psychedelic. The authors use composite clinical vignettes to illustrate different ways of working with ketamine to treat bipolar depression, and discuss a variety of clinical considerations for using ketamine with this population, including route, dose, frequency, chemical mitigators, and adverse events. Note that the conceptual paradigms could be applied to any ketamine treatment, with broad applicability beyond bipolar treatment.

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“…These studies used intravenous ketamine and found effects within hours following a single administration ( Price et al, 2009 ; Fava et al, 2018 ; Murrough et al, 2013 ). When ketamine administration is repeated in the following weeks, efficacy can reach 70% ( Bahji et al, 2021 ; Coyle and Laws, 2015 ; Fond et al, 2014 ; Kishimoto et al, 2016 ; McInnes et al, 2022 ). Multiple randomized placebo-controlled trials have shown that the intravenous administration of ketamine at the dose of 0.5 mg/kg has rapid, robust, albeit relatively short-lived antidepressant effects in patients with depression ( Berman et al, 2000 ; Fava et al, 2018 ; Murrough et al, 2013 ; Price et al, 2009 ; Zarate et al, 2006 ).…”

Section: Introductionmentioning

confidence: 99%

A unified model of ketamine’s dissociative and psychedelic properties

Marguilho¹,

Figueiredo

Castro-Rodrigues

2022

J Psychopharmacol

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Ketamine is an N-methyl-d-aspartate antagonist which is increasingly being researched and used as a treatment for depression. In low doses, it can cause a transitory modification in consciousness which was classically labelled as ‘dissociation’. However, ketamine is also commonly classified as an atypical psychedelic and it has been recently reported that ego dissolution experiences during ketamine administration are associated with greater antidepressant response. Neuroimaging studies have highlighted several similarities between the effects of ketamine and those of serotonergic psychedelics in the brain; however, no unified account has been proposed for ketamine’s multi-level effects – from molecular to network and psychological levels. Here, we propose that the fast, albeit transient, antidepressant effects observed after ketamine infusions are mainly driven by its acute modulation of reward circuits and sub-acute increase in neuroplasticity, while its dissociative and psychedelic properties are driven by dose- and context-dependent disruption of large-scale functional networks. Computationally, as nodes of the salience network (SN) represent high-level priors about the body (‘minimal’ self) and nodes of the default-mode network (DMN) represent the highest-level priors about narrative self-experience (‘biographical’ self), we propose that transitory SN desegregation and disintegration accounts for ketamine’s ‘ dissociative’ state, while transitory DMN desegregation and disintegration accounts for ketamine’s ‘ psychedelic’ state. In psychedelic-assisted psychotherapy, a relaxation of the highest-level beliefs with psychotherapeutic support may allow a revision of pathological self-representation models, for which neuroplasticity plays a permissive role. Our account provides a multi-level rationale for using the psychedelic properties of ketamine to increase its long-term benefits.

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A retrospective analysis of ketamine intravenous therapy for depression in real-world care settings

Cited by 33 publications

References 30 publications

International pooled patient-level meta-analysis of ketamine infusion for depression: In search of clinical moderators

International pooled patient-level meta-analysis of ketamine infusion for depression: In search of clinical moderators

Ketamine for Bipolar Depression: Biochemical, Psychotherapeutic, and Psychedelic Approaches

A unified model of ketamine’s dissociative and psychedelic properties

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