Determinants of Kidney Function and Accuracy of Kidney Microcysts Detection in Patients Treated With Lithium Salts for Bipolar Disorder

Objectives: Early kidney damage during lithium treatment in bipolar disorder is still hypothetical. We aimed at identifying the determinants of a decreased measured glomerular filtration rate (mGFR) and the accuracy of kidney MRI imaging in its detection.Methods: In this cross-sectional cohort study, 217 consecutive lithium-treated patients underwent mGFR and kidney MRI with half-Fourier turbo spin-echo and Single-shot with long echo time sequences.Results: Median age was 51 [27–62] years, and median lithium treatment duration was 5 [2–14] years. 52% of patients had a stage 2 CKD. In multivariable analysis, the determinants of a lower mGFR were a longer lithium treatment duration (β −0.8 [−1; −0.6] ml/min/1.73 m2 GFR decrease for each year of treatment), a higher age (β −0.4 [−0.6; −0.3] ml/min/1.73 m2 for each year of age, p < 0.001), albuminuria (β −3.97 [−6.6; −1.3], p = 0.003), hypertension (β −6.85 [−12.6; −1.1], p = 0.02) and hypothyroidism (β −7.1 [−11.7; −2.5], p = 0.003). Serum lithium concentration was not associated with mGFR. Renal MRI displayed renal microcyst(s) in 51% of patients, detected as early as 1 year after lithium treatment initiation. mGFR and lithium treatment duration were strongly correlated in patients with microcyst(s) (r = −0.64, p < 0.001), but not in patients with no microcysts (r = −0.24, p = 0.09). The presence of microcysts was associated with the detection of an mGFR <45 ml/min/1.73 m2 (AUC 0.893, p < 0.001, sensitivity 80%, specificity 81% for a cut-off value of five microcysts).Conclusion: Lithium treatment duration and hypothyroidism strongly impacted mGFR independently of age, especially in patients with microcysts. MRI might help detect early lithium-induced kidney damage and inform preventive strategies.

Cardioprotective potential of lithium and role of fractalkine in euthymic patients with bipolar disorder

Objective: Over a half century, lithium has been used as the first-line medication to treat bipolar disorder. Emerging clinical and laboratory studies suggest that lithium may exhibit cardioprotective effects in addition to neuroprotective actions. Fractalkine (CX3CL1) is a unique chemokine associated with the pathogenesis of mood disorders and cardiovascular diseases. Herein we aimed to ascertain whether lithium treatment is associated with favorable cardiac structure and function in relation to the reduced CX3CL1 among patients with bipolar disorder. Methods: We recruited 100 euthymic patients with bipolar I disorder aged over 20 years to undergo echocardiographic study and measurement of plasma CX3CL1. Associations between lithium treatment, cardiac structure and function and peripheral CX3CL1 were analyzed according to the cardiovascular risk. The high cardiovascular risk was defined as (1) age ⩾ 45 years in men or ⩾ 55 years in women or (2) presence of concurrent cardiometabolic diseases. Results: In the high cardiovascular risk group ( n = 61), patients who received lithium as the maintenance treatment had significantly lower mean values of left ventricular internal diameters at end-diastole (Cohen’s d = 0.65, p = 0.001) and end-systole (Cohen’s d = 0.60, p = 0.004), higher mean values of mitral valve E/A ratio (Cohen’s d = 0.51, p = 0.019) and superior performance of global longitudinal strain (Cohen’s d = 0.51, p = 0.037) than those without lithium treatment. In addition, mean plasma levels of CX3CL1 in the high cardiovascular risk group were significantly lower among patients with lithium therapy compared with those without lithium treatment ( p = 0.029). Multiple regression models showed that the association between lithium treatment and mitral value E/A ratio was contributed by CX3CL1. Conclusion: Data from this largest sample size study of the association between lithium treatment and echocardiographic measures suggest that lithium may protect cardiac structure and function in patients with bipolar disorder. Reduction of CX3CL1 may mediate the cardioprotective effects of lithium.

Lithium administered to pregnant, lactating and neonatal rats: entry into developing brain

Background Little is known about the extent of drug entry into developing brain, when administered to pregnant and lactating women. Lithium is commonly prescribed for bipolar disorder. Here we studied transfer of lithium given to dams, into blood, brain and cerebrospinal fluid (CSF) in embryonic and postnatal animals as well as adults. Methods Lithium chloride in a clinically relevant dose (3.2 mg/kg body weight) was injected intraperitoneally into pregnant (E15–18) and lactating dams (birth-P16/17) or directly into postnatal pups (P0–P16/17). Acute treatment involved a single injection; long-term treatment involved twice daily injections for the duration of the experiment. Following terminal anaesthesia blood plasma, CSF and brains were collected. Lithium levels and brain distribution were measured using Laser Ablation Inductively Coupled Plasma-Mass Spectrometry and total lithium levels were confirmed by Inductively Coupled Plasma-Mass Spectrometry. Results Lithium was detected in blood, CSF and brain of all fetal and postnatal pups following lithium treatment of dams. Its concentration in pups’ blood was consistently below that in maternal blood (30–35%) indicating significant protection by the placenta and breast tissue. However, much of the lithium that reached the fetus entered its brain. Levels of lithium in plasma fluctuated in different treatment groups but its concentration in CSF was stable at all ages, in agreement with known stable levels of endogenous ions in CSF. There was no significant increase of lithium transfer into CSF following application of Na+/K+ ATPase inhibitor (digoxin) in vivo, indicating that lithium transfer across choroid plexus epithelium is not likely to be via the Na+/K+ ATPase mechanism, at least early in development. Comparison with passive permeability markers suggested that in acute experiments lithium permeability was less than expected for diffusion but similar in long-term experiments at P2. Conclusions Information obtained on the distribution of lithium in developing brain provides a basis for studying possible deleterious effects on brain development and behaviour in offspring of mothers undergoing lithium therapy.

Lithium Receipt and Risk of Dementia in Older Veterans With Bipolar Disorder in the VA Health System

Older adults with bipolar disorder are at increased risk of developing dementia. The literature suggests lithium treatment may reduce the incidence of dementia. This study sought to inform clinical practice in the Veterans Affairs (VA) health system by estimating the effect of past year lithium receipt on dementia incidence among Veterans with bipolar disorder. Divalproex receipt was used as a comparison. Using VA medical records, 121,094 Veterans aged 50 and older with a diagnosis of bipolar disorder but no dementia diagnosis were identified in fiscal years 2005-2019. Follow-up continued until dementia diagnosis, 36 months from the index date, death, or the end of fiscal year 2020, whichever came first. 4347 (3.6%) were diagnosed with dementia during follow-up. Time-varying indicators of receipt of lithium and divalproex in the prior 365 days were calculated for each day, categorized as 301-365, 61-300, 1-60, or 0 days of receipt. Unadjusted Cox proportional hazards regression analyses indicated reduced dementia incidence with 301-365 (HR=0.86, 95% Confidence Interval [95%CI] 0.75-0.99) and 61-300 (HR=0.75, 95%CI 0.65-0.87) days of lithium receipt, compared to 0 days. For divalproex, 301-365 (HR=1.34, 95%CI 1.23-1.47) and 61-300 (HR=1.13, 95%CI 1.03-1.23) days of receipt were each associated with increased dementia incidence. Lithium effects were not statistically significant after adjusting for age, sex, race, ethnicity, medical comorbidities, and antidepressant, antipsychotic, and anxiolytic medication receipt. Divalproex effects remained statistically significant. Past year divalproex, but not lithium, receipt was significantly associated with dementia incidence among VA patients with bipolar disorder when adjusting for demographics and medical comorbidities.

Neuron-Specific Mechanisms Control the Mitochondrial Regulator PGC-1a

Mitochondrial dysfunction has been proposed as a hallmark of the aging process. Specifically, as a function of aging, mitochondria appear to have decreased enzyme activity and respiratory capacity and increase reactive oxygen species production. Brain aging is associated with morphological and homeostatic changes, including alterations in brain size, cognitive impairment, and white and grey matter integrity. However, the causes of these changes remain an open and actively pursued field of study. The ubiquitously expressed transcriptional coactivator peroxisome proliferator-activated receptor gamma-coactivator 1 (PGC-1a) has been described as the master regulator of mitochondrial function. Despite the emerging connections between PGC-1a and disease vulnerability, the regulation of PGC-1a outside of the skeletal muscle, liver, and adipose tissue is not well defined. This is particularly true in the brain, where PGC-1a is enriched in neurons, and alterations in expression levels have been linked to neurodegenerative disorders. Here we report that astrocytes and neurons differ substantially in mitochondrial status and the transcript variants of PGC-1a expressed, including using a neuron-specific promoter. Taking advantage of the ability of the tau-kinase GSK-3b to influence PGC-1a expression, we investigate how transcript variants are differentially regulated in primary neurons and astrocytes. Neuronal PGC-1a responds robustly to GSK3b inhibition by lithium, switching the dominant promoter, leading to changes in isoform distribution and abundance, while astrocytes are refractory to lithium treatment. The data presented here highlight key mechanisms for neuron-specific metabolic regulation that are likely to be relevant to neurodegenerative diseases that have a link to mitochondrial dysfunction.

Tolerability of Lithium: A Naturalistic Discontinuation Study in Older Adults (≥60 Years)

Lithium is one of the most effective treatment options in both bipolar disorder and treatment-resistant depression. The use of lithium in older adults declined during the last decades, probably resulting in undertreatment of older adults. To investigate how well lithium is tolerated in old age, we aimed to determine the frequency, reasons and possible predictors of discontinuation due to adverse effects in a cohort of hospitalized adults aged 60 years or older who had started with lithium. We performed a retrospective cohort study based on chart reviews. Participants were in treatment at Parnassia Group at The Hague, the Netherlands. After inclusion (between January 2010 and December 2016), participants were followed until April 2017, when we performed data extraction and analysis. In our sample of 135 patients (median age 69 years, median follow-up duration 18 months), 49 (36.3%) participants discontinued lithium. Only a minority (11 (8.1%)) of the participants discontinued solely due to adverse effects. The majority discontinued lithium due to psychiatric (18,5%) reasons, (most commonly mentioned within this subgroup: lack of effectiveness and non-compliance) or a combination of reasons (7.4%). None of the factors we studied (age, gender, Charlson Comorbidity Index (CCI), polypharmacy, renal function and neurological history) were significantly associated with discontinuation due to adverse effects. The frequency of lithium discontinuation in our cohort was in range with frequencies reported in younger patients. Older age itself should not be a reason to withhold lithium treatment.