Distinct trajectories of antidepressant response to intravenous ketamine

O’Brien, Brittany; Lijffijt, Marijn; Lee, Jae‐Hoon; Kim, Ye Sil; Wells, Allison; Murphy, Nicholas; Ramakrishnan, Nithya; Swann, Alan C.; Mathew, Sanjay J.

doi:10.1016/j.jad.2021.03.006

Cited by 13 publications

(6 citation statements)

References 45 publications

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“…In M* analyses, comparisons of effect sizes across Tiers 2a-g are complicated by the different subsets of patients and studies available for inclusion in each analysis; however, due to small-to-medium overall effect sizes observed consistently across all tiers, the interpretation of moderator findings as having low overall clinical utility is not impacted. Although previous studies suggest that response to a single, first infusion of ketamine is a fairly robust predictor of response to subsequent, serial infusions [ 45 ], some [ 46 , 47 ] (but not all [ 48 ]) findings suggest enhanced outcomes can be achieved even among first infusion non-responders through sustained treatment. Our analyses cannot account for this possibility.…”

Section: Resultsmentioning

confidence: 99%

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: Resultsmentioning

confidence: 99%

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

et al. 2022

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“…The BIS/BAS Scales (O’Brien et al, 2021 ) consist of a 20-item questionnaire that yields four scales: BIS, BAS-Reward Responsiveness, BAS-Fun Seeking, and BAS-Drive. Items are rated on a 4-point Likert scale ranging from 1 ( strongly agree ) to 4 ( strongly disagree ).…”

Section: Methodsmentioning

confidence: 99%

Biological embedding of early trauma: the role of higher prefrontal synaptic strength

Tamman,

Jiang,

Averill

et al. 2023

European Journal of Psychotraumatology

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Background: Early trauma predicts poor psychological and physical health. Glutamatergic synaptic processes offer one avenue for understanding this relationship, given glutamate’s abundance and involvement in reward and stress sensitivity, emotion, and learning. Trauma-induced glutamatergic excitotoxicity may alter neuroplasticity and approach/avoidance tendencies, increasing risk for psychiatric disorders. Studies examine upstream or downstream effects instead of glutamatergic synaptic processes in vivo , limiting understanding of how trauma affects the brain. Objective: In a pilot study using a previously published data set, we examine associations between early trauma and a proposed measure of synaptic strength in vivo in one of the largest human samples to undergo Carbon-13 ( 13 C MRS) magnetic resonance spectroscopy. Participants were 18 healthy controls and 16 patients with PTSD (male and female). Method: Energy per cycle (EPC), which represents the ratio of neuronal oxidative energy production to glutamate neurotransmitter cycling, was generated as a putative measure of glutamatergic synaptic strength. Results: Results revealed that early trauma was positively correlated with EPC in individuals with PTSD, but not in healthy controls. Increased synaptic strength was associated with reduced behavioural inhibition, and EPC showed stronger associations between reward responsivity and early trauma for those with higher EPC. Conclusion: In the largest known human sample to undergo 13 C MRS, we show that early trauma is positively correlated with EPC, a direct measure of synaptic strength. Our study findings have implications for pharmacological treatments thought to impact synaptic plasticity, such as ketamine and psilocybin.

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“…The strength of treatment-specific modeling is in determining before the fact which patients are likely not to respond to the treatment under study. Treatment-specific modeling is often used to study new treatments . An extension of this approach can help systematize stepped care.…”

Section: Alternative Approaches To Estimating Ptrsmentioning

confidence: 99%

“…Estimate preliminary treatment-specific models using best-practices methods . This can be done either using a single algorithm or stacking multiple algorithms into an ensemble …”

Section: Alternative Approaches To Estimating Ptrsmentioning

confidence: 99%

Pragmatic Precision Psychiatry—A New Direction for Optimizing Treatment Selection

Kessler

Luedtke

2021

JAMA Psychiatry

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lthough many evidence-based treatments exist for mental disorders, none are globally optimal and the best treatment for a specific patient is not always clear. Because of this, clinicians often rely on trial and error in treatment selection, and patients often endure multiple ineffective courses of treatment before being helped. Many patients give up before finding the treatment that would have helped them. These delays, burdens, and missed opportunities have led to an interest in developing clinical decision support tools to help select the best available treatment for each patient. The term precision psychiatry is often used to describe this work, although the same term is used to describe basic neurobiological research designed to develop treatments with more refined targets than those in the DSM diagnostic systems. 1 We use the term pragmatic precision psychiatry to describe the branch of precision psychiatry focused on matching patients to best currently available interventions.At its heart, pragmatic precision psychiatry tries to discover prescriptive predictors; that is, predictors of which treatments are best for which patients. A prescriptive predictor is identified by significant between-patient variation in the association of the predictor with the treatment outcome (ie, mean differences in dimensional outcomes or proportion differences in dichotomous outcomes) across different treatment arms. When a prescriptive predictor exists, there is said to be heterogeneity of treatment effects (HTE) across the treatments based on the predictor for the outcome. Numerous prescriptive predictors have been documented, but none are strong enough alone to guide precision treatment planning. This has prompted growing interest in developing precision treatment rules (PTRs) that combine information across multiple prescriptive predictors. 2 However, this work has been much less successful in studies of mental disorders than some other areas of medicine owing to the weakness and instability of mental disorder PTRs. 3,4 IMPORTANCE Clinical trials have identified numerous prescriptive predictors of mental disorder treatment response, ie, predictors of which treatments are best for which patients. However, none of these prescriptive predictors is strong enough alone to guide precision treatment planning. This has prompted growing interest in developing precision treatment rules (PTRs) that combine information across multiple prescriptive predictors, but this work has been much less successful in psychiatry than some other areas of medicine. Study designs and analysis schemes used in research on PTR development in other areas of medicine are reviewed, key challenges for implementing similar studies of mental disorders are highlighted, and recent methodological advances to address these challenges are described here.OBSERVATIONS Discovering prescriptive predictors requires large samples. Three approaches have been used in other areas of medicine to do this: conduct very large randomized clinical trials, pool individual-level ...

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Distinct trajectories of antidepressant response to intravenous ketamine

Cited by 13 publications

References 45 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

Biological embedding of early trauma: the role of higher prefrontal synaptic strength

Pragmatic Precision Psychiatry—A New Direction for Optimizing Treatment Selection

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