Overlap and Divergence in Ketamine and Lithium Response in Bipolar Disorder: A Scoping Review
Bibliographic record
Abstract
Background/Objectives: Lithium remains the first choice for long-term prophylaxis of mood episodes in bipolar disorder (BD), but only 30% of patients will respond, and there is no reliable method by which to predict treatment response. Ketamine is a rapid antidepressant therapy which ostensibly yields greater results in patients with clinical phenotypes that are classically associated with lithium non-response. This inspired a scoping review to map the overlapping and divergent clinical and mechanistic evidence for acute ketamine response and long-term prophylactic lithium therapy in BD. Methods: We conducted a scoping review of clinical and preclinical studies that examine convergent and divergent predictors and mechanisms of acute response to ketamine and long-term response to lithium. Results: Data from 19 preclinical studies show mechanistic convergence of ketamine and lithium on the GSK-3β/mTOR pathways, and enhancement of synaptic plasticity. Furthermore, lithium appears to consistently limit ketamine-related oxidative stress and hyperlocomotion. However, data from the 23 clinical studies suggest divergence of predictors of response to ketamine and lithium in BD, with ketamine response associated with metabolic risk factors, anxiety/mixed features, and non-melancholic presentations, which are generally predictors of poorer prophylactic lithium response. No study directly tested ketamine response as a predictor of prophylactic lithium response. An important limitation is that clinical studies of ketamine are enriched for lithium-refractory populations and have often included mixed unipolar and bipolar cases. Conclusions: Overall, existing data support mechanistic overlap but clinical divergence between ketamine and lithium responders, though this is confounded by sampling bias. We must therefore undertake longitudinal studies of prophylactic lithium therapy among patients with BD who received ketamine for acute antidepressant treatment in order to investigate if responsiveness to ketamine predicts response to lithium, and establish control over BD earlier in the course of illness.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.001 | 0.001 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.002 | 0.000 |
| Bibliometrics | 0.000 | 0.001 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.000 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one teacher head, not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".