Ketamine in Bipolar Disorder: A Review

Bipolar disorder (BD) is a recurrent, highly morbid psychiatric illness affecting over 1% of the population and carrying the highest lifetime suicide risk among psychiatric disorders. Patients with BD spend a large proportion of their lives depressed, and bipolar depression shows higher treatment-failure rates than major depressive disorder; longer depressive episodes are associated with neuroprogression, structural brain changes, and cognitive deficits. Given these unmet needs, novel treatments for refractory bipolar depression are required. Ketamine has demonstrated rapid antidepressant and antisuicidal effects in treatment‑resistant populations, but most research has focused on unipolar depression and bipolar patients are underrepresented in clinical trials. Wilkowska and colleagues set out to review the existing clinical, molecular, and preclinical evidence regarding ketamine’s potential benefits and mechanisms in BD. The review aims to summarise single- and multiple‑dose clinical data, discuss risks such as affective switch, and examine molecular pathways (for example glutamatergic signalling, BDNF, synaptogenesis, epigenetics, inflammation, and the microbiome) that could underlie ketamine’s effects in bipolar illness, with a view to informing future trials and clinical practice.

The extracted text identifies this paper as a review of current evidence on ketamine in bipolar disorder but does not provide a methods section describing a search strategy, eligibility criteria, databases searched, or formal meta-analytic procedures. Therefore, the review should be characterised as a narrative synthesis rather than a systematic review or formal meta-analysis based on the provided extraction. Content in the review integrates findings from randomized, placebo‑controlled and open‑label clinical studies, meta-analyses cited by the authors, retrospective case series, and preclinical (animal and in vitro) studies. The authors draw on clinical trial reports of single and repeated ketamine (and esketamine) administrations, observational data on side effects and suicidality, and mechanistic studies addressing receptors, intracellular signalling, neuroplasticity, immunology, epigenetics, and the gut microbiota. The extracted text does not report explicit inclusion/exclusion criteria, quality or risk-of-bias assessment methods, or any quantitative pooling strategy applied by the authors.

Clinical effects — single administration: Several controlled studies have demonstrated rapid antidepressant effects of a single low-dose intravenous ketamine infusion in patients with treatment-resistant depression, and the authors cite randomized, double-blind, placebo-controlled, crossover trials that included bipolar patients or mixed samples. An early randomized crossover trial administering ketamine as an adjunct to mood stabilizers found an antidepressant effect in bipolar depression; a replication in a double-blind randomized crossover study with 15 bipolar patients is reported. Open-label data include a study by Permoda-Osip et al in which 42 patients with bipolar depression had a 52% response rate to a single infusion, and a subsequent study of 53 bipolar patients that replicated a rapid antidepressant effect. An esketamine study (0.25 mg/kg) including 23 unipolar and 4 bipolar patients produced an overall response rate of 48.1% within 1 week and a remission rate of 37.0% within the same period. Two meta-analyses cited by the authors support the effectiveness of a single ketamine infusion across unipolar and bipolar depression. Reported predictors of positive response include higher body mass index and lower baseline adiponectin. Clinical effects — multiple administration and suicidality: Data on repeated dosing in bipolar depression are limited. A reported sublingual very low-dose regimen (every 2–3 days or weekly) produced mood, cognition and sleep improvements in 77% of a mixed unipolar/bipolar group, with mild side effects in 26 patients. An intravenous series of six 0.5 mg/kg infusions in mixed samples (unipolar n=77; bipolar n=20) yielded overall response and remission rates of 68% and 50.5%, respectively, but the bipolar subgroup was not analysed separately. A study focused on 16 bipolar patients receiving six low-dose infusions reported a response rate of 73.7% and remission of 63.2% at 24 hours after the sixth infusion. A larger trial cited (McIntyre) included 213 treatment‑resistant depression patients with 30 bipolar participants but did not present separate subgroup analyses. Several authors did not observe significant side effects in these trials. Regarding suicidal ideation, the review notes consistent evidence of rapid antisuicidal effects. Two open-label studies and a systematic review found that a single intravenous ketamine infusion rapidly reduced suicidal ideation within 1 day, and a meta-analysis reported significant and sustained decreases in suicidality within 4 hours of a single dose. A recent open‑label trial administering six 0.5 mg/kg infusions three times weekly in mixed samples reported reductions in suicidal ideation in 57% of patients at 24 hours after the first infusion and 65% after the sixth infusion. Proposed antisuicidal mechanisms are speculative; the authors note associations with the kynurenine pathway and potential anti‑inflammatory effects, and reference post‑mortem evidence implicating microglia in suicidality. Risk of affective switch: The extracted text indicates that evidence is insufficient to determine whether ketamine induces a persistent affective (manic or hypomanic) switch in BD. Three studies in mixed unipolar/bipolar samples reported transient mood elevation in 7% of placebo and 10% of ketamine recipients, with mood returning to baseline by the next day; authors of those studies concluded these episodes did not represent a persistent substance‑induced syndrome. The review notes that antidepressant treatments and histories of substance abuse increase switch risk but that larger bipolar‑specific datasets are needed to define risk factors. Molecular and preclinical findings: Mechanistic data summarised in the review emphasise glutamatergic modulation. Ketamine’s NMDAR blockade on inhibitory interneurons is proposed to disinhibit pyramidal cells and increase glutamate release; downstream AMPAR activation appears necessary for antidepressant effects in rodents, and non‑NMDAR mechanisms are implicated because other NMDAR antagonists lack similar clinical efficacy. Intracellular signalling pathways highlighted include mTOR and BDNF–TrkB, with animal studies reporting increased BDNF, CREB phosphorylation, PKC and PKA in corticolimbic regions after ketamine. Metabolites such as (2R,6R)-hydroxynorketamine ((2R,6R)-HNK) are reported in mice to activate AMPARs and rapidly upregulate BDNF, acting independently of NMDARs. Neuroplasticity and synaptogenesis: Preclinical evidence indicates rapid induction of synaptogenesis and reversal of stress‑related synaptic deficits following ketamine; examples include increased spine density in medial prefrontal cortex and restoration of stress‑lost dendritic spines observed by two‑photon imaging, with behavioural improvement sometimes preceding spine changes. In vitro and animal data also suggest increased neurogenesis in the dentate gyrus and accelerated maturation of newborn granule cells in ventral hippocampus. The review acknowledges conflicting studies that do not support beneficial effects on synaptic plasticity in some rat models, so the role of neurogenesis in sustained clinical effects remains to be confirmed. Epigenetics: The authors report that epigenetic alterations are implicated across mood states in BD and mention one animal study where ketamine produced antidepressant effects by decreasing histone deacetylase activity in the nucleus accumbens, suggesting a possible epigenetic mechanism. Immunological effects: Bipolar patients exhibit proinflammatory alterations (elevated IL‑1β, IL‑4, IL‑10, TNF‑α and other markers) and high prevalence of autoimmune disease. Limited human data suggest ketamine reduces certain proinflammatory cytokines (IL‑6, G‑CSF, IL‑1α) within 4 hours of infusion; one study linked decreases in TNF‑α to reductions in MADRS scores. Ketamine also appears to modulate the kynurenine pathway by increasing kynurenine and kynurenic acid and decreasing quinolinic acid in bipolar depression. In vitro work indicates ketamine can suppress Th17 differentiation, suggesting potential immunomodulation relevant to BD comorbidity with autoimmune disease. Microbiota: Animal studies indicate ketamine alters gut microbiota composition in depression models, increasing some beneficial genera (for example Lactobacillus) and reducing opportunistic pathogens; (R)-ketamine specifically modulated Bacteroidales, Clostridiales and Ruminococcaceae in stressed mice. The authors propose the microbiome as a plausible mediator of ketamine’s antidepressant effects, but human data in BD are not reported. Lithium interactions and shared mechanisms: Ketamine and lithium may share mechanisms such as GSK‑3 inhibition leading to increased BDNF synthesis, modulation of mTOR/BDNF–TrkB signalling, and immunomodulatory effects. Preclinical data suggest lithium can prolong and maintain ketamine‑induced spine restoration and enhance antidepressant‑like effects, supporting potential adjunctive use, though clinical data are limited. Staging, neuroprogression and cognition: The review summarises staging models of BD and evidence for neuroprogression linked to inflammatory changes, reduced BDNF, oxidative stress, blood–brain barrier leakage and insulin resistance. The authors propose that ketamine could hypothetically modify neuroprogression via BDNF upregulation, epigenetic changes, and metabolic effects; preliminary clinical evidence is cited that single and multiple subanaesthetic ketamine infusions can improve cognitive functions in unipolar and bipolar patients, but definitive evidence on long‑term course modification is lacking.

Wilkowska and colleagues propose that adjunctive ketamine treatment may offer both short‑term and potentially longer‑term benefits in bipolar disorder. They note that available clinical studies, though limited in number and often including mixed samples, consistently demonstrate rapid antidepressant and antisuicidal effects in bipolar patients and report a low observed risk of persistent affective switch. Mechanistically, the authors highlight that ketamine’s modulation of glutamatergic transmission, augmentation of BDNF signalling, activation of intracellular cascades (for example mTOR and CREB), and promotion of synaptogenesis align with pathophysiological processes implicated in BD. Additional potentially relevant actions include epigenetic modulation, anti‑inflammatory effects, alterations in the kynurenine pathway, and beneficial changes to the gut microbiota. The authors are cautious about overinterpretation: most mechanistic and many efficacy data derive from preclinical studies or from research in unipolar depression, and bipolar‑specific evidence remains scarce. They acknowledge limitations including the paucity of bipolar‑targeted trials, frequent mixing of unipolar and bipolar samples without subgroup analysis, reliance on open‑label and small studies for repeated dosing data, and incomplete characterisation of long‑term effects and safety in BD. Consequently, the authors call for more bipolar‑focused clinical trials to confirm efficacy, define predictors of response and risk (including affective switch), and to establish optimal dosing and adjunctive strategies (for example with lithium). They suggest that if confirmed, ketamine’s rapid clinical effects and its actions on neuroplasticity and inflammatory/metabolic pathways could have important implications for treating refractory bipolar depression and potentially modifying neuroprogression.