Global variability in atmospheric new particle formation mechanisms.

A key challenge in aerosol pollution studies and climate change assessment is to understand how atmospheric aerosol particles are initially formed1,2. Although new particle formation (NPF) mechanisms have been described at specific sites3-6, in most regions, such mechanisms remain uncertain to a large extent because of the limited ability of atmospheric models to simulate critical NPF processes1,7. Here we synthesize molecular-level experiments to develop comprehensive representations of 11 NPF mechanisms and the complex chemical transformation of precursor gases in a fully coupled global climate model. Combined simulations and observations show that the dominant NPF mechanisms are distinct worldwide and vary with region and altitude. Previously neglected or underrepresented mechanisms involving organics, amines, iodine oxoacids and HNO3 probably dominate NPF in most regions with high concentrations of aerosols or large aerosol radiative forcing; such regions include oceanic and human-polluted continental boundary layers, as well as the upper troposphere over rainforests and Asian monsoon regions. These underrepresented mechanisms also play notable roles in other areas, such as the upper troposphere of the Pacific and Atlantic oceans. Accordingly, NPF accounts for different fractions (10-80%) of the nuclei on which cloud forms at 0.5% supersaturation over various regions in the lower troposphere. The comprehensive simulation of global NPF mechanisms can help improve estimation and source attribution of the climate effects of aerosols.

In women with epilepsy, use of valproate in the second half of pregnancy was linked to autism in offspring.

SOURCE CITATION: Hernández-Díaz S, Straub L, Bateman BT, et al. Risk of autism after prenatal topiramate, valproate, or lamotrigine exposure. N Engl J Med. 2024;390:1069-1079. 38507750.

Antidepressants that increase mitochondrial energetics may elevate risk of treatment-emergent mania.

Preclinical evidence suggests that antidepressants (ADs) may differentially influence mitochondrial energetics. This study was conducted to investigate the relationship between mitochondrial function and illness vulnerability in bipolar disorder (BD), specifically risk of treatment-emergent mania (TEM). Participants with BD already clinically phenotyped as TEM+ (n = 176) or TEM- (n = 516) were further classified whether the TEM associated AD, based on preclinical studies, increased (Mito+, n = 600) or decreased (Mito-, n = 289) mitochondrial electron transport chain (ETC) activity. Comparison of TEM+ rates between Mito+ and Mito- ADs was performed using generalized estimating equations to account for participants exposed to multiple ADs while adjusting for sex, age at time of enrollment into the biobank and BD type (BD-I/schizoaffective vs. BD-II). A total of 692 subjects (62.7% female, 91.4% White, mean age 43.0 ± 14.0 years) including 176 cases (25.3%) of TEM+ and 516 cases (74.7%) of TEM- with previous exposure to Mito+ and/or Mito- antidepressants were identified. Adjusting for age, sex and BD subtype, TEM+ was more frequent with antidepressants that increased (24.7%), versus decreased (13.5%) mitochondrial energetics (OR = 2.21; p = 0.000009). Our preliminary retrospective data suggests there may be merit in reconceptualizing AD classification, not solely based on monoaminergic conventional drug mechanism of action, but additionally based on mitochondrial energetics. Future prospective clinical studies on specific antidepressants and mitochondrial activity are encouraged. Recognizing pharmacogenomic investigation of drug response may extend or overlap to genomics of disease risk, future studies should investigate potential interactions between mitochondrial mechanisms of disease risk and drug response.

Optical Coherence Tomography Predictors of SIde Branch REstenosis after unprotected Left Main bifurcation angioplasty using double kissing crush technique (OP-SIBRE LM Study).

BACKGROUND: Among the two stent strategies, contemporary evidence favors double kissing crush technique (DKC) for complex unprotected distal left main bifurcation (UdLMB) lesions. However one of the major challenges to these lesions is side branch (SB) restenosis. AIMS: Our aim was to identify optical coherence tomographic (OCT) characteristics that may predict SB restenosis (SBR) after UdLMB angioplasty using DKC technique. METHODS: This was a single-center, retrospective study that included 60 patients with complex UdLMB disease, who underwent OCT-guided angioplasty using DKC technique. Angiographic follow-up was performed in all patients at 1 year to identify patients with SBR. Patients with SBR group were compared with patients without SBR (NSBR group) for OCT parameters during index procedure. RESULTS: Twelve (20%) patients developed SBR at 1-year follow-up. The SBR group had longer SB lesion (18.8 ± 3.2 vs. 15.3 ± 3.7 mm, p = 0.004) and neo-metallic carinal length (2.1 vs. 0.1 mm, p < 0.001) when compared to the NSBR group. Longer neo-metallic carinal length was associated with the absence of the dumbbell sign, presence of hanging stent struts across the SB ostium on OCT of final MB pullback. On multivariate regression analysis, SB distal reference diameter (DRD) and SB stent expansion were identified as independent predictors of SBR with SB-DRD of ≤2.8 mm (area under curve-0.73, sensitivity-83.3%, and specificity-62.5%) and SB stent expansion of ≤89% (area under curve-0.88, sensitivity-83.3%, and specificity- 81.2%) as the best cut off values to predict SBR. CONCLUSIONS: SB DRD and SB stent expansion are the OCT predictors of future SBR after UdLMB angioplasty using DKC technique.

Safety, efficacy, and optical coherence tomography insights into intravascular lithotripsy for the modification of non-eruptive calcified nodules: A prospective observational study.

BACKGROUND: Non-eruptive calcium nodules (CNs) are commonly seen in heavily calcified coronary artery disease. They are the most difficult subset for modification, and may result in stent damage, malapposition and under-expansion. There are only limited options available for non-eruptive CN modification. Intravascular lithotripsy (IVL) is being explored as a potentially safe and effective modality in these lesions. AIMS: This study aimed to investigate the safety and efficacy of the use of IVL for the modification of non-eruptive CNs. The study also explored the OCT features of calcium nodule modification by IVL. METHODS: This is a single-center, prospective, observational study in which patients with angiographic heavy calcification and non-eruptive CN on OCT and undergoing PCI were enrolled. The primary safety endpoint was freedom from perforation, no-reflow/slow flow, flow-limiting dissection after IVL therapy, and major adverse cardiac events (MACE) during hospitalization and at 30 days. MACE was defined as a composite of cardiac death, myocardial infarction (MI), and ischemia-driven target lesion revascularization (TLR). The primary efficacy endpoint was procedural success, defined as residual diameter stenosis of <30% on angiography and stent expansion of more than 80% as assessed by OCT. RESULTS: A total of 21 patients with 54 non-eruptive CNs undergoing PCI were prospectively enrolled in the study. Before IVL, OCT revealed a mean calcium score of 3.7 ± 0.5 and a mean MLA at CN of 3.9 ± 2.1 mm2. Following IVL, OCT revealed calcium fractures in 40 out of 54 (74.1%) CNs with an average of 1.05 ± 0.72 fractures per CN. Fractures were predominantly observed at the base of the CN (80%). Post IVL, the mean MLA at CN increased to 4.9 ± 2.3 mm2. After PCI, the mean MSA at the CN was 7.9 ± 2.5 mm2. Optimal stent expansion (stent expansion >80%) at the CN was achieved in 85.71% of patients. All patients remained free from MACE during hospitalization and at the 30-day follow-up. At 1-year follow-up, all-cause death had occurred in 3 (14.3%) patients. CONCLUSIONS: This single-arm study demonstrated the safety, efficacy, and utility of the IVL in a subset of patients with non-eruptive calcified nodules. In this study, minimal procedural complications, excellent lesion modifications, and favorable 30-day and 1-year outcomes were observed.

Effects of long-term lithium therapy on kidney functioning in mood disorders: A population-based historical cohort study.

AIMS: Lithium is Food and Drug Administration-approved for bipolar disorder (BD) and is also used in depressive disorders but is underutilized due to concerns about chronic kidney disease (CKD). We explored clinical and demographic profiles of patients on long-term lithium therapy (LTLT) and assessed kidney function. Our aims were to identify the predictors for CKD stage ≥3 and the impact of lithium discontinuation post-CKD diagnosis. METHODS: We conducted a population-based historical cohort study of adult patients with mood disorders on LTLT at the Marshfield Clinical Health System from 1990 to 2019. Data on lithium therapy and kidney-related information (estimated glomerular filtration rate and CKD) were extracted from electronic medical records. RESULTS: Among 1603 patients with mood disorders (mean age 42.1 years, 60% females), 15.3% (n = 246) developed CKD stage ≥3. Patients without CKD were on lithium for 4.5 years, compared to 6.6 years for those with CKD. Hypertension, age, and BD were significant CKD risk factors. Kidney function declined linearly with lithium duration, returning to pre-treatment trajectory in patients without CKD but showed no improvement in those with CKD after lithium discontinuation. CONCLUSION: The findings suggest that CKD occurs in 15% of patients with mood disorder receiving LTLT, with its progression potentially influenced by existing comorbidities rather than lithium alone. These results underscore the importance of monitoring kidney function in patients on LTLT and considering individual risk factors for CKD development. In patients who developed CKD, Li discontinuation did not impact change in kidney function.

Metabolomic biomarkers for (R, S)-ketamine and (S)-ketamine in treatment-resistant depression and healthy controls: A systematic review.

BACKGROUND: Ketamine is increasingly used for treatment-resistant depression (TRD) while its mechanism of action is still being investigated. In this systematic review, we appraise the current evidence of metabolomic biomarkers for racemic ketamine and esketamine in patients with TRD and healthy controls (HCs). METHODS: A comprehensive search of several databases (Ovid MEDLINE®, Embase, and Epub Ahead of Print) was performed from each database's inception to June 29, 2022, in any language, was conducted. We included studies wherein the metabolomic biomarkers for racemic ketamine or esketamine were investigated in TRD or HCs. Our main outcomes were to examine changes in metabolites among patients treated with ketamine/esketamine and explore the association with response to ketamine/esketamine. RESULTS: A total of 1859 abstracts were screened of which 11 were included for full-text review. Of these, a total of five articles were included (N = 147), including three RCTs (n = 129) and two open-label trials (n = 18). All studies used racemic ketamine; one study additionally used esketamine. The included studies evaluated patients with treatment-resistant bipolar depression (n = 22), unipolar depression (n = 91), and HCs (n = 34). The included studies reported alteration in several metabolites including acylcarnitines, lipids, kynurenine (KYN), and arginine with ketamine in TRD. Studies suggest the involvement of energy metabolism, KYN, and arginine pathways. In HCs, acetylcarnitine decreased post-infusion, whereas inconsistent findings were observed after the ketamine infusion in TRD patients. CONCLUSIONS: This systematic review provides preliminary evidence that ketamine may cause changes in several important pathways involved in energy metabolism and inflammation. Larger and more rigorous studies are needed.

Patterns of pharmacotherapy for bipolar disorder: A GBC survey.

OBJECTIVES: To understand treatment practices for bipolar disorders (BD), this study leveraged the Global Bipolar Cohort collaborative network to investigate pharmacotherapeutic treatment patterns in multiple cohorts of well-characterized individuals with BD in North America, Europe, and Australia. METHODS: Data on pharmacotherapy, demographics, diagnostic subtypes, and comorbidities were provided from each participating cohort. Individual site and regional pooled proportional meta-analyses with generalized linear mixed methods were conducted to identify prescription patterns. RESULTS: This study included 10,351 individuals from North America (n = 3985), Europe (n = 3822), and Australia (n = 2544). Overall, participants were predominantly female (60%) with BD-I (60%; vs. BD-II = 33%). Cross-sectionally, mood-stabilizing anticonvulsants (44%), second-generation antipsychotics (42%), and antidepressants (38%) were the most prescribed medications. Lithium was prescribed in 29% of patients, primarily in the Australian (31%) and European (36%) cohorts. First-generation antipsychotics were prescribed in 24% of the European versus 1% in the North American cohort. Antidepressant prescription rates were higher in BD-II (47%) compared to BD-I (35%). Major limitations were significant differences among cohorts based on inclusion/exclusion criteria, data source, and time/year of enrollment into cohort. CONCLUSIONS: Mood-stabilizing anticonvulsants, second-generation antipsychotics, and antidepressants were the most prescribed medications suggesting prescription patterns that are not necessarily guideline concordant. Significant differences exist in the prescription practices across different geographic regions, especially the underutilization of lithium in the North American cohorts and the higher utilization of first-generation antipsychotics in the European cohorts. There is a need to conduct future longitudinal studies to further explore these differences and their impact on outcomes, and to inform and implement evidence-based guidelines to help improve treatment practices in BD.

Antidepressant-Associated Treatment Emergent Mania: A Meta-Analysis to Guide Risk Modeling Pharmacogenomic Targets of Potential Clinical Value.

BACKGROUND: The purpose of this study was to review the association between the SLC6A4 5-HTTLPR polymorphism and antidepressant (AD)-associated treatment emergent mania (TEM) in bipolar disorder alongside starting a discussion on the merits of developing risk stratification models to guide when not to provide AD treatment for bipolar depression. METHODS: Studies that examined the association between clinical and genetic risk factors, specifically monoaminergic transporter genetic variation, and TEM were identified. A meta-analysis was performed using the odds ratio to estimate the effect size under the Der-Simonian and Laird model. RESULTS: Seven studies, referencing the SLC6A4 5-HTTLPR polymorphism and TEM (total N = 1578; TEM+ =594, TEM- = 984), of 142 identified articles were included. The time duration between the start of the AD to emergence of TEM ranged from 4 to 12 weeks. There was a nominally significant association between the s allele of the 5-HTTLPR polymorphism and TEM (odds ratio, 1.434; 95% confidence interval, 1.001-2.055; P = 0.0493; I2 = 52%). No studies have investigated norepinephrine or dopamine transporters. CONCLUSION: Although the serotonin transporter genetic variation is commercially available in pharmacogenomic decision support tools, greater efforts, more broadly, should focus on complete genome-wide approaches to determine genetic variants that may contribute to TEM. Moreover, these data are exemplary to the merits of developing risk stratification models, which include both clinical and biological risk factors, to guide when not to use ADs in bipolar disorder. Future studies will need to validate new risk models that best inform the development of personalized medicine best practices treating bipolar depression.

Real-World Clinical Practice Among Patients With Bipolar Disorder and Chronic Kidney Disease on Long-term Lithium Therapy.

PURPOSE: Long-term lithium therapy (LTLT) has been associated with chronic kidney disease (CKD). We investigated changes in clinical characteristics, pharmacotherapeutic treatments for medical/psychiatric disorders, and outcomes among patients with bipolar disorder (BD) and CKD on LTLT in a 2-year mirror-image study design. METHODS: Adult BD patients on LTLT for ≥1 year who enrolled in the Mayo Clinic Bipolar Disorder Biobank and developed CKD (stage 3) were included, and our study was approved by the Mayo Clinic Institutional Review Board. The primary outcome was the time to the first mood episode after CKD diagnosis among the lithium (Li) continuers and discontinuers. Cox proportional hazards models were used to estimate the time to the first mood episode. We tested for differences in other medication changes between the Li continuers and discontinuers group using Mantel-Haenszel χ2 tests (linear associations). RESULTS: Of 38 BD patients who developed CKD, 18 (47%) discontinued Li, and the remainder continued (n = 20). The median age of the cohort was 56 years (interquartile range [IQR], 48-67 years), 63.2% were female, and 97.4% were White. As compared with continuers, discontinuers had more psychotropic medication trials (6 [IQR, 4-6] vs 3 [IQR, 2-5], P = 0.02), a higher rate of 1 or more mood episodes (61% vs 10%, P = 0.002), and a higher risk of a mood episode after CKD diagnoses (Hazard Ratio, 8.38; 95% confidence interval, 1.85-38.0 [log-rank P = 0.001]]. CONCLUSIONS: Bipolar disorder patients on LTLT who discontinued Li had a higher risk for relapse and a shorter time to the first mood episode, suggesting a need for more thorough discussion before Li discontinuation after the CKD diagnosis.

Blood-based biomarkers of antidepressant response to ketamine and esketamine: A systematic review and meta-analysis.

(R,S)-ketamine (ketamine) and its enantiomer (S)-ketamine (esketamine) can produce rapid and substantial antidepressant effects. However, individual response to ketamine/esketamine is variable, and there are no well-accepted methods to differentiate persons who are more likely to benefit. Numerous potential peripheral biomarkers have been reported, but their current utility is unclear. We conducted a systematic review/meta-analysis examining the association between baseline levels and longitudinal changes in blood-based biomarkers, and response to ketamine/esketamine. Of the 5611 citations identified, 56 manuscripts were included (N = 2801 participants), and 26 were compatible with meta-analytical calculations. Random-effect models were used, and effect sizes were reported as standardized mean differences (SMD). Our assessments revealed that more than 460 individual biomarkers were examined. Frequently studied groups included neurotrophic factors (n = 15), levels of ketamine and ketamine metabolites (n = 13), and inflammatory markers (n = 12). There were no consistent associations between baseline levels of blood-based biomarkers, and response to ketamine. However, in a longitudinal analysis, ketamine responders had statistically significant increases in brain-derived neurotrophic factor (BDNF) when compared to pre-treatment levels (SMD [95% CI] = 0.26 [0.03, 0.48], p = 0.02), whereas non-responders showed no significant changes in BDNF levels (SMD [95% CI] = 0.05 [-0.19, 0.28], p = 0.70). There was no consistent evidence to support any additional longitudinal biomarkers. Findings were inconclusive for esketamine due to the small number of studies (n = 2). Despite a diverse and substantial literature, there is limited evidence that blood-based biomarkers are associated with response to ketamine, and no current evidence of clinical utility.

Efficacy and safety of lamotrigine in pediatric mood disorders: A systematic review.

AIM: To appraise the current evidence on the efficacy and safety of lamotrigine (LAM) in the treatment of pediatric mood disorders (PMD) (i.e., Major Depressive disorder [MDD], bipolar disorder [BD]). METHODS: Major databases were searched for randomized controlled trials (RCTs), open-label trials, and observational studies reporting on pediatric (age < 18 years) patients treated with LAM for mood disorders. RESULTS: A total of 3061 abstracts were screened and seven articles were selected for inclusion. Seven studies (319 BD and 43 MDD patients), including one RCT (n = 173), three prospective (n = 105), and three retrospective (n = 84) studies, met the study criteria with a study duration range from 8 to 60.9 weeks. The mean age of this pooled data is 14.6 ± 2.0 years. LAM daily dosage varied from 12.5 to 391.3 mg/day among the studies. In an important finding, the RCT reported favorable outcomes with LAM (HR = 0.46; p = 0.02) in 13- to 17-year-old age group as compared with 10- to 12-year-old age group (HR = 0.93; p = 0.88). In addition, time to occurrence of a bipolar event trended toward favoring LAM over placebo. All the studies identified LAM as an effective and safe drug in PMDs especially, BDs. Overall, LAM was well tolerated with no major significant side effects and no cases of Stevens-Johnson syndrome. CONCLUSIONS: Most studies suggested that LAM was safe and effective in pediatric patients with mood disorders. However, the data regarding the therapeutic range for LAM are lacking. Based on the data, there is inconsistent evidence to make conclusive recommendations on therapeutic LAM dosage for mood improvement in the pediatric population. Further studies including larger sample sizes are required to address this relevant clinical question.

Intranasal (IN) COVID-19 vaccines - a breakthrough.

Emerging variants of COVID-19 have threatened the effectiveness of intramuscular (IM) vaccines since that are made to target only the spike protein. Development of Intranasal (IN) vaccination has been proven to provide both the mucosal and systemic immune responses for broader and long lasting protection. Many IN vaccine candidates (virus-vectored vaccines, recombinant subunit vaccines and live attenuated vaccines) are in different phases of clinical trials and in near future many companies would be releasing their vaccines into the drug market. Potential advantages of IN vaccination over IM vaccination makes them ideal to be administered in children and developing populations of the world. This paper focuses on the very recent developments in intranasal vaccination with a spotlight on their safety and efficacy concerns. IN vaccination can prove to be game-changer in handling COVID-19 and potential viral contagious diseases in future.

The Modernization of Clozapine: A Recapitulation of the Past in the United States and the View Forward.

PURPOSE: Although clozapine was Food and Drug Administration (FDA) approved more than 3 decades ago, major barriers and gaps in knowledge continue to prevent its effective and safe use. We review modern-day problems encountered with clozapine in the United States (US). METHODS: Information surrounding current administrative, clinical, research, and technological gaps or barriers related to clozapine use in the US was reviewed. FINDINGS: The history of how clozapine became FDA approved likely contributes to gaps in knowledge. The frequency of safety warnings added to the FDA prescribing information may add to fears about clozapine, as evidence by numerous published survey studies. The clozapine Risk Evaluation and Mitigation Strategy (REMS) program has been modified several times in the last decade, causing access and safety issues for patients, which are discussed. Evidence may suggest that the FDA REMS requirements for hematologic monitoring are too cumbersome, and there may be ability to safely loosen requirements. The COVID-19 pandemic brought forth the ability for extended interval monitoring but also greater awareness of the clozapine-inflammation interaction. Newer guidelines published describe considerations in personalizing clozapine titration based on principles of ethnopsychopharmacology. Emerging technologies to support the use of clozapine are not widely available. IMPLICATIONS: Clozapine is a unique life-saving drug but it is underused in the US, despite its established efficacy. The 2021 REMS changes led to significant difficulties for providers and patients. We highlight the importance of the clozapine-inflammation interaction, therapeutic drug monitoring, and the ability for individual care based on patient-specific factors. There is an urgent need for advancing technology used for clozapine monitoring, evaluating barriers created by REMS, and establishing consistent practices throughout the US.

Clinical Phenotype of Tardive Dyskinesia in Bipolar Disorder.

PURPOSE: Recognizing the negative impact that antipsychotic-induced movement disorders have on the quality of life and treatment outcomes in bipolar disorder (BD), this study aimed to assess clinical correlates and antipsychotic use patterns of tardive dyskinesia (TD+) in BD. MATERIALS AND METHODS: Participants with and without TD were included. Clinical variables were compared using t-test and χ2 test. Antipsychotic use patterns in TD+, including number of trials, mean doses, and estimated cumulative exposure, were assessed in a case-only analysis. RESULTS: The prevalence rate of TD was 5.1%. In comparison to the TD- group (n = 1074), TD+ participants (n = 58) were older, more likely to be female and have type I bipolar illness. There were 60.3% of the TD+ group that continued using antipsychotics at study entry and had a mean cumulative exposure to antipsychotics of 18.2 ± 15.6 years. Average dose, in haloperidol equivalents, was 5.9 ± 3.5 mg and 77.7% of the trials were second-generation antipsychotics. CONCLUSIONS: This study confirms previously identified TD risk factors, such as age, sex, and bipolar subtype in a large BD cohort. Limitations included a cross-sectional design and the lack of tardive illness severity assessment. As atypical antipsychotics continue to be primary mood stabilization treatment, attempting to harmonize large data sets to identify additional biomarkers of tardive risk will optimize individualized care for patients with BD.

Influence of dry air and infrared pre-treatments on oxidative stability, Maillard reaction products and other chemical properties of linseed (Linum usitatissimum L.) oil.

In this study, the influence of dry air and infrared pre-treatments on linseed oil (LO) yield, chemical properties, colour, pigment content, total phenolic content (TPC), Maillard reaction products (MRPs), fatty acid composition (FAC), radical scavenging activity (RSA), and oxidative stability index (OSI) were investigated. An increase in dry air and infrared roasting temperature had increased the LO yield, pigment content, a* value, TPC, RSA, OSI, and browning index (BI) while lowered the L* and b* values of LO. Higher OSI (2.24 h), chlorophylls (2.29 mg/kg), carotenoids (3.87 mg/kg), TPC (63.67 mg GAE/100 g), RSA (62.53%), BI (0.330), and MRPs (2.10 mg/kg) were detected in LO by dry air roasting at 180°C for 10 min. Dry air and infrared roasting had slightly affected the FAC of LO. Both dry air and infrared pre-treatments had influenced the LO quality characteristics. However, dry air roasting of linseed at 180°C for 10 min proved more effective in improving oxidative stability, antioxidant activity and other quality characteristics of LO. SUPPLEMENTARY INFORMATION: The online version of this article at 10.1007/s13197-021-05023-6.

Association of Optimal Lamotrigine Serum Levels and Therapeutic Efficacy in Mood Disorders: A Systematic Review.

PURPOSE: The aim of the study was to appraise the current evidence on the optimal serum level for lamotrigine (LAM) in the treatment of mood disorders (major depressive disorder, bipolar disorder). METHODS: Major databases were searched for randomized controlled trials, open-label trials, and observational studies reporting serum LAM levels in adult patients treated with LAM for mood disorders. RESULTS: A total of 814 abstracts were screened and 24 articles were selected for full-text review. Seven studies (226 bipolar disorder and 17 major depressive disorder patients) including 1 randomized controlled trial (n = 43), 3 prospective (n = 53), and 3 retrospective (n = 147) studies met the study criteria with a study duration range from 6 to 96 weeks. Lamotrigine daily dosage varied from 25 to 425 mg/d among the studies. Studies reported inconsistent findings between LAM concentration and efficacy. Three studies did not identify a relationship between LAM levels and a significant improvement in mood symptoms. Two studies (n = 99) reported higher response rates with LAM serum levels of greater than 3.25 µg/mL and 1 study (n = 25) reported a wide therapeutic window of 5 to 11 µg/mL. Overall, LAM was well tolerated with no major significant adverse effects. CONCLUSIONS: Most studies showed a minimum LAM threshold level of 3 µg/mL in patients with mood disorders; however, the data are inconsistent regarding the therapeutic range for LAM. Based on the pooled data, there is inconsistent evidence to make conclusive recommendations on therapeutic LAM serum levels for mood improvement. Further studies including larger sample sizes are required to address this relevant clinical question.

A Systematic Review on the Efficacy of Intravenous Racemic Ketamine for Bipolar Depression.

BACKGROUND: Ketamine, a glutamate N-methyl-d-aspartate receptor antagonist, has shown rapid antidepressant effects in treatment-resistant depression. We conducted a systematic review of studies evaluating the efficacy of intravenous ketamine augmentation in treatment-resistant depression patients with bipolar disorder. METHODS: Major databases were searched for open-label and randomized controlled trials (RCT). Two independent reviewers screened and selected the studies that met the inclusion criteria. Studies were selected following the standard Cochrane methodology, and the findings are reported according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses. Methodological quality of the included studies was assessed using standardized measures. RESULTS: A total of 1442 articles were screened. Five studies were included in the systematic review (3 RCTs and 2 open-label studies) enrolling 110 subjects (mean age, 45.54 ± 12.65 years; 68.18% female). All the RCTs and open-label studies showed improvement in depressions symptoms after receiving a single infusion of ketamine. Included studies also suggested improvement in suicidal ideation and anhedonia after ketamine infusion. Dissociation and transient increase in blood pressure were the most common reported adverse effects with ketamine. Ketamine infusions did not increase mania symptoms. CONCLUSIONS: Limited data show efficacy and feasibility of intravenous racemic ketamine in treatment-resistant bipolar depression. Further studies with larger sample size are required to strengthen the evidence.

Long-term lithium therapy and risk of chronic kidney disease in bipolar disorder: A historical cohort study.

AIMS: Long-term lithium therapy (LTLT) has been associated with kidney insufficiency in bipolar disorder (BD). We aimed to investigate the risk factors of chronic kidney disease (CKD) development and progression among BD patients receiving LTLT. METHODS: We included adult patients with BD on LTLT (≥1 year) who were enrolled in the Mayo Clinic Bipolar Biobank, Rochester, Minnesota. We reviewed electronic medical records to extract information related to lithium therapy and kidney-related data to assess changes in the estimated glomerular filtration rate (eGFR). CKD severity was assessed based on eGFR. RESULTS: Among 154 patients who received LTLT, 41 patients (27%) developed CKD, of whom 20 (49%) patients continued lithium (continuers) and 19 (46%) discontinued it (discontinuers). The median time to stage 3 CKD development was 21.7 years from the start of Li treatment. Type-2 diabetes mellitus and benzodiazepine use were independent predictors for CKD development in the survival analysis, after controlling for age. The subsequent CKD progression rate did not differ between continuers and discontinuers (mean GFR 48.6 vs. 44.1, p = 0.13) at the end of follow-up duration (mean duration: 3.5 ± 4.4 years for continuers and 4.9 ± 5.3 years for discontinuers). CONCLUSION: CKD was observed in one fourth of patients with BD receiving LTLT. There was no significant difference in the progression of CKD among Li continuers versus discontinuers, at the mean follow-up duration of 4.2 years, after the CKD diagnosis. Progression of CKD could be influenced by existing comorbidities and may not necessarily be due to lithium alone.

Clinical Profile, Viral Load, Maternal-Fetal Outcomes of Pregnancy With COVID-19: 4-Week Retrospective, Tertiary Care Single-Centre Descriptive Study.

OBJECTIVE: The COVID-19 pandemic raises a major concern about its severity in pregnancy, maternal-fetal outcomes, and risk of vertical transmission. We report a retrospective descriptive study of the clinical course and maternal-fetal outcomes of pregnant women with COVID-19. METHODS: This is a single-centre, retrospective study performed in a tertiary care hospital for pregnant women with COVID-19 in India. The medical records of all women who delivered in the COVID19 facility from May 5, 2020, to June 5, 2020, were reviewed independently. Data extracted from the records included demographic characteristics, obstetric details, comorbidities, disease severity, investigations, management, and information on neonates (birthweight, Apgar score, and perinatal complications). RESULTS: Among 348 women tested for SARS-CoV-2, 57 women (16.3%) were confirmed as positive based on quantitative reverse transcriptase polymerase chain reaction of the nasopharyngeal specimen. Most women (45; 78.9%) had a mild infection with favourable maternal-fetal outcomes. Three maternal deaths were associated with comorbidities. Five neonates tested positive for SARS-CoV-2, remained hemodynamically stable, and were subsequently discharged. CONCLUSIONS: A majority of pregnant women with COVID-19 had mild disease and recovered with good perinatal outcomes. Women with comorbidities may have an increased risk of severe morbidity and mortality. The cycle threshold signifying the viral load and degree of infectivity can modify management during pregnancy. Long-term outcomes and the potential mother-to-child vertical/horizontal transmission need further study.