Outcomes of heparinized adult veno-arterial extracorporeal membrane oxygenation patients managed with low and high activated partial thromboplastin time targets: A systematic review and meta-analysis.

INTRODUCTION: There are no randomized controlled trials comparing low and high activated partial thromboplastin time (aPTT) targets in heparinized adult veno-arterial (VA) extracorporeal membrane oxygenation (ECMO) patients. Our systematic review and meta-analysis summarized complication rates in adult VA ECMO patients treated with low and high aPTT targets. METHODS: Studies published from January 2000 to May 2022 were identified using Pubmed, Embase, Cochrane Library, and LILACS (Latin American and Caribbean Health Sciences Literature). Studies were included if aPTT was primarily used to guide heparin anticoagulation. For the low aPTT group, we included studies where aPTT goal was ≤60 seconds and for the high aPTT group, we included studies where aPTT goal was ≥60 seconds. Proportional meta-analysis with a random effects model was used to calculate pooled complication rates for patients in the two aPTT groups. RESULTS: Twelve studies met inclusion criteria (5 in the low aPTT group and 7 in the high aPTT group). The pooled bleeding complication incidence for low aPTT studies was 53.6% (95% CI = 37.4%-69.4%, I2 = 60.8%) and for high aPTT studies was 43.8% (95% CI = 21.7%-67.1%, I2 = 91.8%). No studies in the low aPTT group reported overall thrombosis incidence, while three studies in the high aPTT group reported overall thrombosis incidence. The pooled thrombosis incidence for high aPTT studies was 16.1% (95% CI = 9.0%-24.5%, I2 = 13.1%). CONCLUSIONS: Adult ECMO patients managed with low and high aPTT goals appeared to have similar bleeding and other complication rates further highlighting the need for a randomized controlled trial.

In vitro comparison of spatiotemporal fibrin clot formation dynamics in plasma treated with different protamine-heparin ratios.

INTRODUCTION: Our study aim was to explore how different protamine-heparin ratios impacted enzymatic coagulation and acellular fibrin clot growth in plasma using an in vitro model. We hypothesized that a low protamine-heparin ratio would be associated with superior fibrin clot growth dynamics. METHODS: We performed an in vitro study using 15 plasma samples from a commercial supplier. Different protamine-heparin ratios were added to each donor plasma sample: low ratio (0.7-1), traditional ratio (1-1), and high ratio (1.3-1) and clot formation dynamics were evaluated using a Thrombodynamics analyzer. Study outcomes were initial clot growth velocity and clot size at 30 min. RESULTS: Plasma samples treated with a one-to-one protamine-heparin ratio had significantly lower mean initial clot growth velocity compared to samples treated with a low protamine-heparin ratio; mean difference -2.3 µm/min (95% CI = -4.0 to -0.7, p = .004). Plasma samples treated with a one-to-one protamine-heparin ratio also had significantly smaller mean clot size at 30 min compared to samples treated with a low protamine-heparin ratio; mean difference -54.0 µm (95% CI = -107.6 to -0.4, p = .048). There were no significant differences in mean initial clot growth velocity or clot size at 30 min between plasma samples treated with a high protamine-heparin ratio and those treated with a one-to-one or low protamine-heparin ratio (all p > .05). CONCLUSIONS: Plasma samples treated with a low protamine-heparin ratio had superior clot growth velocity and larger clot size at 30 min compared to a one-to-one ratio, supporting the notion that a low protamine-heparin ratio may optimize enzymatic coagulation after cardiopulmonary bypass.

Utilization of submandibular ultrasound in assessing upper airway changes following the administration of propofol.

Background and Aims: Our study aimed to use submandibular ultrasound to measure upper airway parameters before and after induction dose of propofol in order to further understand upper airway changes that occur during induction of anesthesia. Measuring the changes that occur in airway anatomy due to the hypotonic effects of induction agents will allow for a deeper understanding of airway management. Material and Methods: We enrolled 39 patients between November 2021 and January 2022. Submandibular ultrasound was used to measure tongue thickness, geniohyoid muscle thickness, the distance between the lingual arteries (DLA), lateral pharyngeal wall thickness, and hyomental distance before and after administration of induction doses of the commonly used, sedative-hypnotic agent, propofol. Results: The mean DLA increased significantly after propofol administration, from 3.62 ± 0.63 cm to 3.79 ± 0.56 cm (P < 0.001). The mean tongue thickness was 4.89 ± 0.51 cm and decreased significantly to a mean of 4.62 ± 0.50 cm after propofol administration (P < 0.001). The change in DLA measurements after propofol administration decreased significantly as STOP-BANG score increased (r = -0.344, P = 0.037). However, DLA measurements when patients were awake increased significantly with an increase in the STOP-BANG score (r = 0.351, P = 0.031). Conclusion: These findings suggest that propofol widens and flattens the tongue, which are changes that may contribute to difficult airway management. Given the quick and non-invasive nature of ultrasound, further studies should evaluate the role of submandibular ultrasound for understanding the upper airway and airway management in various populations.

Health care utilization and costs of systemic lupus erythematosus in the United States: A systematic review.

OBJECTIVES: To evaluate health care utilization and costs for patients with systemic lupus erythematosus (SLE) by disease severity. METHODS: We searched PubMed and Embase from January 2000 to June 2020 for observational studies examining health care utilization and costs associated with SLE among adults in the United States. Two independent reviewers reviewed the selected full-text articles to determine the final set of included studies. Costs were converted to 2020 US $. RESULTS: We screened 9224 articles, of which 51 were included. Mean emergency department visits were 0.3-3.5 per year, and mean hospitalizations were 0.1-2.4 per year (mean length of stay 0.4-13.0 days). Patients averaged 10-26 physician visits/year. Mean annual direct total costs were $17,258-$63,022 per patient and were greater for patients with moderate or severe disease ($19,099-$82,391) compared with mild disease ($12,242-$29,233). Mean annual direct costs were larger from commercial claims ($24,585-$63,022) than public payers (Medicare and Medicaid: $18,302-$27,142). CONCLUSIONS: SLE remains a significant driver of health care utilization and costs. Patients with moderate to severe SLE use more health care services and incur greater direct and indirect costs than those with mild disease.

Role of Submandibular Ultrasound in Airway Management of a Patient With Angioedema.

Angioedema is one of several life-threatening clinical scenarios that lacks clarity on when a patient requires intubation. We present a case of angiotensin-converting enzyme-inhibitor-induced angioedema with peri-oral swelling and normal airway measurements on ultrasound, who was intubated with an abundance of caution and extubated successfully. Current tests for intubation and extubation, such as traditional bedside assessments and the cuff leak test, vary in reliability for angioedema and similar urgent situations. Submandibular ultrasound is a quick, low-cost, non-invasive method for determining quantitative criteria for and assessing when intubation and extubation is indicated, which may lead to improved quality of care and patient safety.

Healthcare Utilization and Costs of Systemic Lupus Erythematosus by Disease Severity in the United States.

OBJECTIVE: To quantify healthcare utilization and costs by disease severity for patients with systemic lupus erythematosus (SLE) in the United States. METHODS: We conducted descriptive analyses of Humedica electronic health record (EHR) data from 2011 to 2015 (utilization analysis) and integrated Optum administrative claims/Humedica EHR data from 2012 to 2015 (cost analysis) for patients with SLE. All-cause utilization outcomes examined were hospitalizations, outpatient visits, emergency department (ED) visits, and prescription drug use. Analyses of costs stratified by disease severity were limited to patients enrolled in an Optum-participating health insurance plan for ≥ 1 year after the earliest observed SLE diagnosis date. Costs were converted to 2016 US dollars (US$). RESULTS: Healthcare utilization was evaluated in 17,257 patients with SLE. Averaged over the 2011-2015 study period, 13.7% of patients had ≥ 1 hospitalization per year, 25.7% had ≥ 1 ED visit, and 94.4% had ≥ 1 outpatient visit. Utilization patterns were generally similar across each year studied. Annually, 88.0% of patients had ≥ 1 prescription, including 1.3% who used biologics. Biologic treatment doubled between 2011 (0.7%) and 2015 (1.4%). Cost analyses included 397 patients. From 2012 to 2015, patients with severe SLE had mean annual costs of $52,951, compared with $28,936 and $21,052 for patients with moderate and mild SLE, respectively. Patients with severe SLE had increased costs in all service categories: inpatient, ED, clinic/office visits, and pharmacy. CONCLUSION: Patients from the US with SLE, especially individuals with moderate or severe disease, utilize significant healthcare resources and incur high medical costs.

Association between organ damage and mortality in systemic lupus erythematosus: a systematic review and meta-analysis.

OBJECTIVE: At least half of patients with systemic lupus erythematosus (SLE) develop organ damage as a consequence of autoimmune disease or long-term therapeutic steroid use. This study synthesised evidence on the association between organ damage and mortality in patients with SLE. DESIGN: Systematic review and meta-analysis. METHODS: Electronic searches were performed in PubMed, Embase, Cochrane Library and Latin American and Caribbean Health Sciences Literature for observational (cohort, case-control and cross-sectional) studies published between January 2000 and February 2017. Included studies reported HRs or ORs on the association between organ damage (measured by the Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index (SDI) score) and mortality. Study quality was assessed using the modified Newcastle-Ottawa assessment. Pooled HRs were obtained using the DerSimonian and Laird random-effects model. Heterogeneity was assessed using the Cochrane Q (Q) and I2 statistics. RESULTS: The search yielded 10 420 articles, from which 21 longitudinal studies were selected. Most studies (85%) were of high quality. For 10 studies evaluating organ damage (SDI) as a continuous variable and reporting HR as a measure of association, a 1-unit increase in SDI was associated with increased mortality; pooled HR was 1.34 (95% CI: 1.24 to 1.44, p<0.001; Q p=0.027, I2=52.1%). Exclusion of one potential outlying study reduced heterogeneity with minimal impact on pooled HR (1.33 (95% CI: 1.25 to 1.42), p<0.001, Q p=0.087, I2=42.0%). The 11 remaining studies, although they could not be aggregated because of their varying patient populations and analyses, consistently demonstrated that greater SDI was associated with increased mortality. CONCLUSIONS: Organ damage in SLE is consistently associated with increased mortality across studies from various countries. Modifying the disease course with effective therapies and steroid-sparing regimens may reduce organ damage, improve outcomes and decrease mortality for patients with SLE.

Clinical Development of Biologics Approved by the US Food and Drug Administration, 2003-2016.

BACKGROUND: Biological therapies are increasingly common in the United States. Although their clinical development may deviate significantly from the classic paradigm used for small molecule drugs, there has been little systematic analysis of these programs. We describe the development programs and factors associated with approval in the first review cycle for biologics approved by the US Food and Drug Administration's Center for Drug Evaluation and Research (FDA CDER) between 2003 and 2016. METHODS: We conducted a retrospective analysis of publicly available approval packages including clinical pharmacology/biopharmaceutics, medical and summary reviews, and approval letters for biologics approved by FDA CDER. We evaluated characteristics of the development program (eg, use of expedited pathways, clinical pharmacology studies, number and type of pivotal trials) and the prevalence and correlates of first cycle approval, a key indicator of successful product development. RESULTS: We assessed 81 development programs for 75 unique therapies. Most programs (67%) made use of at least 1 expedited designation and about half (49%) were designated as orphan products. The clinical pharmacology programs were highly variable and one in four (25%) did not include an ascending dose study, where the tolerability of the therapeutic is typically determined before pivotal trials. Since 2003, an increasing proportion of biologics have been approved on first cycle approval and with fewer than 2 pivotal clinical trials (P < .001 for trend). Of the approximately three-fourths (76%) of products that were approved on the first review cycle, the likelihood of such approval was greater among development programs that performed an ascending dose study (84% vs 55%, P = .01) or held an End of Phase 2 meeting (85% vs 57%, P = .01). CONCLUSION: Considerable regulatory flexibility, with respect to the number of pivotal trials and data supporting dosing, coincides with a growing number of biologics approved on an annual basis.

Prescription Drug Coverage for Treatment of Low Back Pain Among US Medicaid, Medicare Advantage, and Commercial Insurers.

Importance: Despite unprecedented injuries and deaths from prescription opioids, little is known regarding medication coverage policies for the treatment of chronic noncancer pain among US insurers. Objective: To assess medication coverage policies for 62 products used to treat low back pain. Design, Setting, and Participants: A cross-sectional study of health plan documents from 15 Medicaid, 15 Medicare Advantage, and 20 commercial health plans in 2017 from 16 US states representing more than half the US population and 20 interviews with more than 43 senior medical and pharmacy health plan executives from representative plans. Data analysis was conducted from April 2017 to January 2018. Main Outcomes and Measures: Formulary coverage, utilization management, and patient out-of-pocket costs. Results: Of the 62 products examined, 30 were prescription opioids and 32 were nonopioid analgesics, including 10 nonsteroidal anti-inflammatory drugs, 10 antidepressants, 6 muscle relaxants, 4 anticonvulsants, and 2 topical analgesics. Medicaid plans covered a median of 19 opioids examined (interquartile range [IQR], 12-27; median, 63%; IQR, 40%-90%) and a median of 22 nonopioids examined (IQR, 21-27; median, 69%; IQR, 66%-83%). Medicare Advantage plans covered similar proportions (median [IQR], opioids: 17 [15-22]; 57% [50%-73%]; nonopioids: 22 [22-26]; 69% [69%-81%]), while commercial plans covered more opioids (median [IQR], 23 [21-25]; 77% [70%-84%]) and nonopioids (median [IQR], 26 [24-27]; 81% [74%-85%]). Utilization management strategies were common for opioids in Medicaid plans (median [IQR], 15 [11-20] opioids; 91% [74%-97%]), Medicare Advantage plans (median [IQR], 15 [9-18] opioids; 100% [100%-100%]), and commercial plans (median [IQR], 16 [11-20] opioids; 74% [53%-94%]), generally relying on 30-day quantity limits rather than prior authorization. Step therapy was especially uncommon. Many of the nonopioids examined also were subject to utilization management, especially quantity limits (24%-32% of products across payers) and prior authorization (median [IQR], commercial plans: 2 [0-3] nonopioids; 9% [0%-11%]; Medicare Advantage plans: 4 [3-5] nonopioids; 19% [10%-23%]; Medicaid plans: 6 [1-13] nonopioids; 38% [2%-52%]). Among commercial plans, the median plan placed 18 opioids (74%) and 20 nonopioids (81%) in tier 1, which was associated with a median out-of-pocket cost of $10 (IQR, $9-$10) per 30-day supply. Key informant interviews revealed an emphasis on increasing opioid utilization management and identifying high-risk prescribers and patients, rather than promoting comprehensive strategies to improve treatment of chronic pain or better integrating pharmacologic and nonpharmacologic alternatives to opioids. Conclusions and Relevance: Given the effect of coverage policies on drug utilization and health outcomes, these findings provide an important opportunity to evaluate how formulary placement, utilization management, copayments, and integration of nonpharmacologic treatments can be optimized to improve pain care while reducing opioid-related injuries and deaths.

Coverage of Nonpharmacologic Treatments for Low Back Pain Among US Public and Private Insurers.

Importance: Despite epidemic rates of addiction and death from prescription opioids in the United States, suggesting the importance of providing alternatives to opioids in the treatment of pain, little is known regarding how payers' coverage policies may facilitate or impede access to such treatments. Objective: To examine coverage policies for 5 nonpharmacologic approaches commonly used to treat acute or chronic low back pain among commercial and Medicare Advantage insurance plans, plus an additional 6 treatments among Medicaid plans. Design, Setting, and Participants: Cross-sectional study of 15 commercial, 15 Medicaid, and 15 Medicare Advantage health plans for the 2017 calendar year in 16 states representing more than half of the US population. Interviews were conducted with 43 senior medical and pharmacy health plan executives from representative plans. Main Outcomes and Measures: Medical necessity and coverage status for the treatments examined, as well as the use of utilization management tools and cost-sharing magnitude and structure. Results: Commercial and Medicare insurers consistently regarded physical and occupational therapy as medically necessary, but policies varied for other therapies examined. Payers most commonly covered physical therapy (98% [44 of 45 plans]), occupational therapy (96% [43 of 45 plans]), and chiropractic care (89% [40 of 45 plans]), while transcutaneous electrical nerve stimulation (67% [10 of 15 plans]) and steroid injections (60% [9 of 15 plans]) were the most commonly covered among the therapies examined for Medicaid plans only. Despite evidence in the literature to support use of acupuncture and psychological interventions, these therapies were either not covered by plans examined (67% of all plans [30 of 45] did not cover acupuncture) or lacked information about coverage (80% of Medicaid plans [12 of 15] lacked information about coverage of psychological interventions). Utilization management tools, such as prior authorization, were common, but criteria varied greatly with respect to which conditions and what quantity and duration of services were covered. Interviewees represented 6 Medicaid managed care organizations, 2 Medicare Advantage or Part D plans, 9 commercial plans, and 3 trade organizations (eg, Blue Cross Blue Shield Association). Interviews with plan executives indicated a low level of integration between the coverage decision-making processes for pharmacologic and nonpharmacologic therapies for chronic pain. Conclusions and Relevance: Wide variation in coverage of nonpharmacologic treatments for low back pain may be driven by the absence of best practices, the administrative complexities of developing and revising coverage policies, and payers' economic incentives. Such variation suggests an important opportunity to improve the accessibility of services, reduce opioid use, and ultimately improve the quality of care for individuals with chronic, noncancer pain while alleviating the burden of opioid addiction and overdose.

Exposure- and Dose-response Analyses in Dose Selection and Labeling of FDA-approved Biologics.

PURPOSE: Biological drug products, or products derived from living cells, represent an increasingly important part of the pharmaceutical market. Despite this, little is known about how sponsors determine the dose to be studied in registrational trials or to be proposed in labeling for biologics. We examined how exposure-response and dose-response analyses were used to determine dosing in pivotal trials or the labeling for all biologics approved by the Center for Drug Evaluation and Research, the US Food and Drug Administration (FDA) between 2003 and 2016. METHODS: We extracted relevant characteristics of each biologic from its review package by FDA. We used descriptive statistics to characterize the rationale for the selected dose(s) in registration trials, with a particular focus on the role of exposure-response/dose-response analyses. We also examined how exposure-response/dose-response analyses were used to support the labeling dose and the basis for postmarketing requirements or commitments related to dose optimization. FINDINGS: A total of 79 biologics license applications were examined. Dose selection in registrational trials was more often attributed to clinical efficacy (73% of applications) than to clinical safety (42%). The dosing of products whose dose was apparently selected based on clinical efficacy was often (72%) determined by the dose-response relationship. In support of doses that were described in labeling, exposure-response analyses for efficacy were performed more commonly (53%) than dose-response analyses (21%). This trend was apparent after 2012. IMPLICATIONS: This is the first study to summarize the justification of dose selection and the labeled dose of biologics approved by the FDA. Dose-response analyses have been often used as the rationale for dose selection of registrational studies, although exposure-response analyses are becoming more prevalent in support of the dosing guidelines in labeling.

Cardiovascular Risks of Exogenous Testosterone Use Among Men: A Systematic Review and Meta-Analysis.

PURPOSE: We sought to evaluate whether exogenous testosterone therapy is associated with increased risk of serious cardiovascular events as compared with other treatments or placebo. METHODS: Study selection included randomized controlled trials (RCTs) and observational studies that enrolled men aged 18 years or older receiving exogenous testosterone for 3 or more days. The primary outcomes were death due to all causes, myocardial infarction, and stroke. Secondary outcomes were other hard clinical outcomes such as heart failure, arrhythmia, and cardiac procedures. Peto odds ratio was used to pool data from RCTs. Risk of bias was assessed using Cochrane Collaboration tool and Newcastle and Ottawa scale, respectively. The strength of evidence was evaluated using the Grades of Recommendation, Assessment, Development, and Evaluation Working Group approach. RESULTS: A total of 39 RCTs and 10 observational studies were included. Meta-analysis was done using data from 30 RCTs. Compared with placebo, exogenous testosterone treatment did not show any significant increase in risk of myocardial infarction (odds ratio [OR] 0.87; 95% CI, 0.39-1.93; 16 RCTs), stroke (OR 2.17; 95% CI, 0.63-7.54; 9 RCTs), or mortality (OR 0.88; 95% CI, 0.55-1.41; 20 RCTs). Observational studies showed marked clinical and methodological heterogeneity. The evidence was rated as very low quality due to the high risk of bias, imprecision, and inconsistency. CONCLUSIONS: We did not find any significant association between exogenous testosterone treatment and myocardial infarction, stroke, or mortality in randomized controlled trials. The very low quality of the evidence precludes definitive conclusion on the cardiovascular effects of testosterone.

Physician attitudes and experiences with Maryland's prescription drug monitoring program (PDMP).

AIMS: Physicians' use of prescription drug monitoring programs (PDMPs) varies by state. Among Maryland physicians, we sought to (1) estimate the PDMP impact on changes in opioid prescribing, (2) approximate the scope of PDMP utility and (3) determine the barriers to PDMP use after its 2013 implementation. DESIGN: Cross-sectional postal survey linking responses to state records of PDMP registration and use, randomly sampling physicians within specialty and registration strata. SETTING: Maryland, USA. PARTICIPANTS: A total of 1000 surveyed primary care, pain and emergency medicine physicians stratified into three subpopulations: PDMP non-registrants, PDMP registrants who were non-users and PDMP users; 405 respondents (44%) of 916 eligible physicians were analysed. MEASUREMENTS: Primary outcome measure was PDMP use. Key predictors were clinic characteristics, including type of practice and number of patients prescribed opioids. FINDINGS: No response-wave bias was identified. Seventy per cent of physicians believed PDMP access decreased their amount and increased their comfort level in prescribing opioids. Three-fourths (74%) of PDMP users reported the data very useful for informing opioid prescribing, although one-fifth (20%) reported difficulty accessing the data. Commonly reported barriers to PDMP use were lack of knowledge regarding its existence and registration process. In multivariable analysis after adjusting for key clinic characteristics, practicing at a managed care organization was associated with lower PDMP use [incidence rate ratio (IRR) = 0.19, 95% confidence interval (CI) = 0.05-0.73]. Conversely, physicians who prescribed opioids for more than 50 patients accessed the PDMP three times as often as those prescribing opioids for fewer than 10 patients monthly (IRR = 3.00, 95 % CI = 1.07-8.43). CONCLUSIONS: In this survey of Maryland, USA physicians, most participants reported that prescription drug monitoring programs (PDMPs) improved their opioid prescribing by decreasing prescription amounts and increasing comfort with prescribing opioids. Common barriers to PDMP use included not knowing about the program, registration difficulties and data access difficulties.

Association between exogenous testosterone and cardiovascular events: an overview of systematic reviews.

Given the conflicting evidence regarding the association between exogenous testosterone and cardiovascular events, we systematically assessed published systematic reviews for evidence of the association between exogenous testosterone and cardiovascular events. We searched PubMed, MEDLINE, Embase, Cochrane Collaboration Clinical Trials, ClinicalTrials.gov, and the US Food and Drug Administration website for systematic reviews of randomised controlled trials published up to July 19, 2016. Two independent reviewers screened 954 full texts from 29 335 abstracts to identify systematic reviews of randomised controlled trials in which the cardiovascular effects of exogenous testosterone on men aged 18 years or older were examined. We extracted data for study characteristics, analytic methods, and key findings, and applied the AMSTAR (A Measurement Tool to Assess Systematic Reviews) checklist to assess methodological quality of each review. Our primary outcome measure was the direction and magnitude of association between exogenous testosterone and cardiovascular events. We identified seven reviews and meta-analyses, which had substantial clinical heterogeneity, differing statistical methods, and variable methodological quality and quality of data abstraction. AMSTAR scores ranged from 3 to 9 out of 11. Six systematic reviews that each included a meta-analysis showed no significant association between exogenous testosterone and cardiovascular events, with summary estimates ranging from 1·07 to 1·82 and imprecise confidence intervals. Two of these six meta-analyses showed increased risk in subgroup analyses of oral testosterone and men aged 65 years or older during their first treatment year. One meta-analysis showed a significant association between exogenous testosterone and cardiovascular events, in men aged 18 years or older generally, with a summary estimate of 1·54 (95% CI 1·09-2·18). Our optimal information size analysis showed that any randomised controlled trial aiming to detect a true difference in cardiovascular risk between treatment groups receiving exogenous testosterone and their controls (with a two-sided p value of 0·05 and a power of 80%) would require at least 17 664 participants in each trial group. Therefore, given the challenge of adequately powering clinical trials for rare outcomes, rigorous observational studies are needed to clarify the association between testosterone-replacement therapy and major adverse cardiovascular outcomes.

The mood stabilizer lithium potentiates the antidepressant-like effects and ameliorates oxidative stress induced by acute ketamine in a mouse model of stress.

BACKGROUND: Evidence suggests that mammalian target of rapamycin activation mediates ketamine's rapid but transient antidepressant effects and that glycogen synthase kinase-3ß inhibits this pathway. However, ketamine has associated psychotomimetic effects and a high risk of abuse. The mood stabilizer lithium is a glycogen synthase kinase-3 inhibitor with strong antisuicidal properties. Here, we used a mouse stress model to investigate whether adjunct lithium treatment would potentiate ketamine's antidepressant-like effects. METHODS: Mice received chronic restraint stress and long-term pre- or postketamine lithium treatment in drinking water. The effects of lithium on ketamine-induced antidepressant-like effects, activation of the mammalian target of rapamycin/brain-derived neurotrophic factor signaling pathways, oxidative stress, and dendritic spine density in the brain of mice were investigated. RESULTS: Subtherapeutic (600 mg/L) lithium-pretreated mice exhibited an antidepressant-like response to an ineffective ketamine (2.5 mg/kg, intraperitoneally) challenge in the forced swim test. Both the antidepressant-like effects and restoration of dendritic spine density in the medial prefrontal cortex of stressed mice induced by a single ketamine (50 mg/kg) injection were sustained by postketamine treatment with 1200 mg/L of lithium for at least 2 weeks. These benefits of lithium treatments were associated with activation of the mammalian target of rapamycin/brain-derived neurotrophic factor signaling pathways in the prefrontal cortex. Acute ketamine (50 mg/kg) injection also significantly increased lipid peroxidation, catalase activity, and oxidized glutathione levels in stressed mice. Notably, these oxidative stress markers were completely abolished by pretreatment with 1200 mg/L of lithium. CONCLUSIONS: Our results suggest a novel therapeutic strategy and justify the use of lithium in patients who benefit from ketamine.