Lithium Exposure and Risk of Major Neurocognitive Disorders: A Systematic Review and Meta-analysis.

BACKGROUND: Published studies on the association between lithium use and the decreased risk of major neurocognitive disorders (MNCDs) have shown disparities in their conclusions. We aimed to provide updated evidence of this association. METHODS: A comprehensive literature search was performed in PubMed, EMBASE, and Cochrane Library from inception until August 31, 2023. All the observational studies evaluating the association between lithium use and MNCD risk were eligible for inclusion. Pooled odds ratios (ORs) and 95% prediction intervals were computed using random-effects models. RESULTS: Eight studies with 377,060 subjects were included in the analysis. In the general population on the association between lithium use versus nonuse and dementia, the OR was 0.94 (95% confidence interval [CI] = 0.77-1.24). Further analysis also demonstrated that lithium use was not associated with an increased risk of Alzheimer's disease (OR = 0.69, 95% CI: 0.31-1.65). When the analysis was restricted to individuals with bipolar disorder to reduce the confounding by clinical indication, lithium exposure was also not associated with a decreased risk of MNCD (OR = 0.9, 95% CI = 0.71-1.15). CONCLUSION: The results of this systematic review and meta-analysis do not support a significant association between lithium use and the risk of MNCD.

Surgical strategy in lithium-associated hyperparathyroidism: A population-based study.

BACKGROUND: The extent of parathyroidectomy (PTX) recommendation in patients with lithium-associated hyperparathyroidism (LAH) remains controversial. The primary objectives of this study were to analyze extent of surgery, complications, and long-term outcomes. METHODS: A population-based study, including all primary hyperparathyroidism (PHPT) patients who underwent PTX in Sweden between 2008 and 2017. Data on exhibited lithium prescriptions, morbidity, surgical approach, and outcomes were collected from relevant national registers and the Scandinavian Quality Register of Thyroid, Parathyroid, and Adrenal Surgery. Patients with lithium exposure before PTX were defined as having LAH. Descriptive summary statistics and regression models were used to evaluate differences in comorbidities, surgical approach, and outcomes between LAH and PHPT not exposed to lithium (non-LAH). RESULTS: Lithium exposure was significantly more common among PHPT (n = 202, 2.3%) than in controls (n = 416, 0.5%); OR 5.0 (95% CI 4.2-5.9). The risk of LAH correlated to the length of lithium exposure. In the LAH-group, the surgical procedures were more extensive and associated with a higher risk of postoperative bleeding, wound infections, persistent hypercalcemia, and hypocalcemia that remained after adjustment for the higher percentage of multiglandular disease. However, the cumulative risk of re-admission for PHPT was similar the first years after PTX and primarily elevated for patients with >5 years duration of lithium exposure prior to surgery. CONCLUSIONS: The findings support the perception of LAH as a complex entity. We recommend a functionally oriented approach, aimed to obtain and maintain normocalcemia for as long as possible, minimizing the risk of permanent hypoparathyroidism, and accepting some risk of recurrence.

Lithium versus anticonvulsants and the risk of physical disorders - Results from a comprehensive long-term nation-wide population-based study emulating a target trial.

Bipolar disorder is associated with increased rates of many physical disorders, but the effects of medication are unclear. We systematically investigated the associations between sustained use of first line maintenance agents, lithium versus lamotrigine and valproate, and the risk of physical disorders using a nation-wide population-based target trial emulation covering the entire 5.9 million inhabitants in Denmark. We identified two cohorts. Cohort 1: patients with a diagnosis of bipolar disorder prior to first purchase (N = 12.607). Cohort 2: all 156.678 adult patients who had their first ever purchase (since 1995) of either lithium, lamotrigine or valproate between 1997 and 2021 regardless of diagnosis. Main analyses investigated the effect of sustained exposure defined as exposure for all consecutive 6-months periods during a 10-year follow-up. Outcomes included a diagnosis of incident stroke, arteriosclerosis, angina pectoris, myocardial infarction, diabetes mellitus, myxedema, osteoporosis, dementia, Parkinson's disease, chronic kidney disease and cancer (including subtypes). In both Cohorts 1 and 2, there were no systematic statistically significant differences in associations between sustained use of lithium versus lamotrigine and valproate, respectively, and any physical disorder, including subtypes of disorders, except myxedema, for which exposure to lithium increased the absolute risk of myxedema with 7-10 % compared with lamotrigine or valproate. In conclusion, these analyses emulating a target trial of "real world" observational register-based data show that lithium does not increase the risk of developing any kind of physical disorders, except myxedema, which may be a result of detection bias.

Efficacy and Safety of Adding Lurasidone to Ongoing Therapy With Lithium or Valproate for the Treatment of an Acute Bipolar Depressive Episode: A Post Hoc Analysis of 2 Placebo-Controlled Trials.

PURPOSE: The aim of this study was to compare the efficacy and safety profile of lurasidone combined with either lithium or valproate, in the short-term treatment of patients with bipolar depression. METHODS: Data were pooled from two 6-week, double-blind, placebo-controlled trials of patients with bipolar depression on stable doses of lithium or valproate randomized to lurasidone (20-120 mg/d) or placebo. Efficacy measures included the Montgomery-Åsberg Depression Rating Scale, Clinical Global Impressions Bipolar Scale, and the Quick Inventory of Depressive Symptomatology via self-assessment and were analyzed using a mixed model for repeated measures approach. RESULTS: Notably larger week 6 effect sizes were observed when lurasidone was added to lithium, compared with when lurasidone was added to valproate, on 2 of the 3 depression outcome measures, Montgomery-Åsberg Depression Rating Scale total score (d = 0.45 vs 0.22) and Quick Inventory of Depressive Symptomatology via self-assessment (d = 0.63 vs 0.29); the efficacy advantage was smaller on the Clinical Global Impressions Bipolar Scale depression score (d = 0.34 vs 0.29). Similar adverse event profiles were observed for lurasidone treatment in combination with either lithium or valproate. The most frequently reported events (≥5%) in both groups were nausea, parkinsonism, somnolence, akathisia, and insomnia. Minimal changes in weight, lipids, and measures of glycemic control were observed during treatment with lurasidone combined with either lithium or valproate. CONCLUSIONS: Lurasidone added to either lithium or valproate was found to be an effective treatment for bipolar depression, with a larger antidepressant effect observed when lurasidone was combined with lithium. There were no clinically meaningful differences in the safety or tolerability of lurasidone when used adjunctively with lithium or valproate.

A case of pregnancy with severe polyhydramnios related to long-term use of lithium.

OBJECTIVES: Severe polyhydramnios during pregnancy may be associated with long-term lithium use and presents considerable challenges. This complication, which has been linked to induced nephrogenic diabetes insipidus (NDI), underscores the necessity for cautious management of pregnant women with bipolar disorder. This case report aims to elucidate the relationship between long-term lithium use, pregnancy, and the development of severe polyhydramnios, emphasizing the importance of diagnosing NDI in order to prevent obstetric and neonatal complications. METHODS: We present the case of a 42-year-old primigravida undergoing long-term lithium treatment for bipolar disorder type I, who developed severe polyhydramnios at 34 weeks of gestation. Clinical data including obstetric monitoring and neonatal outcomes were analyzed. RESULTS: This case emphasizes the need for heightened awareness and proactive measures to mitigate the risk associated with lithium treatment during pregnancy. Close monitoring and timely interventions are essential to ensure optimal outcomes for both mother and fetus. CONCLUSIONS: Our article puts forth the hypothesis that there is a link between lithium use during pregnancy and the occurrence of polyhydramnios and Nephrogenic Diabetes Insipidus (NDI), which may lead to severe obstetric and neonatal complications. This case report contributes to the limited literature on the subject and gives doctors practical advice that may help them make a better risk-benefit analysis. Further research is warranted in order to refine risk assessment protocols and management strategies in this complex clinical scenario.

Possible association between lithium intoxication and Takotsubo syndrome.

More than 25 years after being diagnosed with bipolar disorder and receiving continuous treatment with lithium, a woman develops Takotsubo syndrome.

Syndrome of Irreversible Lithium-Effectuated Neurotoxicity (SILENT): A Preventable Cerebellar Disorder.

We report a case study of a 60-year-old man with bipolar disorder on stable lithium treatment who developed severe toxicity while admitted to ICU with sepsis and multiorgan failure. Despite unchanged lithium administration, his serum levels escalated due to renal dysfunction, resulting in lithium toxicity. After regaining consciousness, he exhibited a cerebellar syndrome marked by ataxia, tremor, and scanning speech. MRI revealed cerebellar atrophy. Following discontinuation of lithium and hemodialysis, the patient's symptoms remained static. The patient was diagnosed with syndrome of irreversible lithium-effectuated neurotoxicity (SILENT), a chronic cerebellar disorder characterized by persistent ataxia, nystagmus, and gait abnormalities extending beyond two months post-lithium exposure. The disorder has a predilection for cerebellar and basal ganglia dysfunction. MRI findings include cerebellar gliosis and atrophy and leptomeningeal enhancement. This case report highlights that SILENT is both preventable and permanent, urging heightened awareness among clinicians to facilitate early detection and intervention. Patients on lithium with compromised renal function or fever necessitate vigilant lithium level monitoring, dose adjustment, or cessation, to forestall enduring morbidity. This case emphasizes the significance of recognizing and managing SILENT, particularly in critical care settings, to mitigate long-term cerebellar impairment and optimize patient outcomes.

Chronic kidney disease incidences in Thai outpatients diagnosed with psychiatric illnesses receiving lithium maintenance therapy: a university hospital-based study.

BACKGROUND: There has been no previous study in Thailand regarding the incidence of lithium-induced abnormal renal function. Hence, this study aimed to assess the effect of lithium maintenance therapy on chronic kidney disease, and associated factors among outpatients diagnosed with a psychiatric illness within Southern Thailand. METHODS: This was a retrospective study, using an information review from the electronic medical records of Songklanagarind Hospital computer system in the last ten years; from 1 January 2013 until 31 September 2022. Chronic kidney disease was defined as an estimated glomerular filtration rate of less than 60 mL/min/1.73 m2 and persisted for three months or more. There were 461 outpatients diagnosed with a psychiatric illness who received lithium maintenance therapy. From this, 154 outpatients were excluded: 153 received lithium therapy for less than three months and 1 presented with a baseline chronic kidney disease. All data were analyzed using Rstudio 4.3.1. The incidence of lithium-induced chronic kidney disease was analyzed by survival analysis. RESULTS: Of the 307 outpatients diagnosed with a psychiatric illness and received lithium maintenance therapy, the most common diagnosis was bipolar disorder (59.3%). Most were female (52.8%), with the median (IQR) age of 39.0 (27.5-54.0) years. The median (IQR) age onset of lithium therapy and duration of lithium maintenance therapy were 28.0 (21.0-41.5) years, and 2.97 (0.9-9.2) years, respectively. This study identified six outpatients (1.9%) that developed chronic kidney disease stage 3 or more and one of them (0.3%) presented with chronic kidney disease stage 5 or end-stage. The incidence of lithium-induced chronic kidney disease was 0.0023 cases per exposed patient-year. When comparing outpatients who had received lithium maintenance therapy and developed chronic kidney disease with those who did not develop chronic kidney disease, this study identified that most of the group with chronic kidney disease had a lithium maintenance therapy for more than ten years, had an older age onset of lithium therapy, reported history of psychiatric hospitalization and lithium intoxication, and presented with physical illness. The associated factors between the effect of lithium maintenance therapy and chronic kidney disease could not be identified due to a limited number of outpatients having developed chronic kidney disease. CONCLUSIONS: Lithium-induced chronic kidney disease was identified as a minor incidence, and it was likely safe for maintenance therapy with careful and regular monitoring. However, older patients or those receiving lithium for a longer time and present with comorbid physical illnesses should be prescribed with caution. IRB / IEC CERTIFICATION: 65-389-3-4.

Association between lithium treatment and renal, thyroid and parathyroid function: A cohort study of 6659 patients with bipolar disorder.

OBJECTIVES: Although potential adverse effects of lithium treatment on renal and endocrine systems have been extensively investigated, most prior studies are limited by selected populations and short follow-up. METHODS: Within the Psychiatric Services of the Central Denmark Region, we identified all patients with bipolar disorder and ≥1 serum-lithium (se-Li) measurements between January 1, 2013, and July 20, 2022, and reference patients with bipolar disorder matched on age, sex, and baseline creatinine. Outcomes were diagnoses of renal, thyroid and parathyroid disease, and blood tests measuring creatinine, estimated glomerular filtration rate (eGFR), thyroid-stimulating hormone (TSH), parathyroid hormone (PTH) and calcium. Analyses included unadjusted multilevel regression to describe changes in biochemical markers, and adjusted Cox regression to compare rates of disease/biochemical outcomes between lithium users and reference patients. RESULTS: Among 1646 lithium users (median age 36 years, 63% women) and 5013 reference patients, lithium users had decreasing TSH and eGFR, stable PTH, and increasing calcium levels over time. Lithium use was associated with increased rates of renal, thyroid and parathyroid disease, and levels of biochemical markers outside normal ranges (hazard rate ratios: 1.07-11.22), but the absolute number of severe outcomes was low (e.g., chronic kidney disease: N = 10, 0.6%). Notably, the rate of blood testing was substantially higher among lithium users than among reference patients (e.g., mean number of creatinine tests during the second year of follow-up: lithium users = 2.5, reference patients = 1.4). CONCLUSIONS: Severely adverse renal and endocrine outcomes are rare during lithium treatment. Observational studies of long-term lithium treatment are prone to detection bias.

Causes, clinical characteristics, and outcomes of high lithium levels and intoxications: Retrospective analysis of patient records.

BACKGROUND: The mood stabilizer lithium has a narrow therapeutic index with a relevant risk of intoxication. We used real-world hospital data to identify causes, treatment courses, and outcomes of high lithium levels and intoxications. METHODS: Retrospective chart review of patients with a lithium concentration of ⩾1.1 mmol/L, who were treated at Charité University Medical Center Berlin. RESULTS: We identified 136 patients (58% women; mean age: 54.7 years) with high lithium levels or intoxication. 66.9% were chronic (stable lithium dose but changes in other variables such as co-medication). 40.4% took at least one risk medication with a relative contraindication for concurrent lithium treatment. 11.1% of the cases with a high therapeutic level showed moderate to severe intoxications. Feverish infections were significantly associated with severe intoxications. Overall, 97.1% (132/136) of patients fully recovered, two had residual but mild symptoms and two died during hospitalization (unlikely related to the intoxication). In 37.5% of patients, no psychiatrist was involved in the management of high lithium levels or intoxication. In these patients, lithium treatment was adjusted or discontinued in 37.3% of the cases compared to 64.7% when a psychiatrist was involved (χ²(1) = 9.683, p = 0.002). CONCLUSIONS: Patients and medical doctors should be aware of the increased risk of lithium intoxication already within the high therapeutic range and should consider alternative medications without relative contraindications for concurrent lithium use. Involving psychiatrists during or after an intoxication event is associated with more frequent adjustment of the maintenance lithium dose and should be considered in most cases.

Lithium Therapy in Old Age: Recommendations from a Delphi Survey.

INTRODUCTION: While lithium (Li) has been well established for the treatment of bipolar disorder, geriatric patients require special attention when it comes to issues of drug safety. Declining renal function, amongst other medical conditions, and polypharmacy may pose increased risks. Only a few previous studies have addressed the management of Li in geriatric patients. METHODS: Twenty-four German medical experts on geriatric medicine and Li treatment participated in a Delphi survey, consisting of two rounds of questionnaires and a final formulation of treatment recommendations. Three major issues of Li therapy were outlined: initiation of treatment, monitoring of ongoing therapy, and withdrawal due to medical reasons. Final recommendations were consented to at a threshold of at least 80% expert agreement. RESULTS: Final consensus was achieved on 21 clinical recommendations. The approved recommendations covered aspects of necessary laboratory checks, concomitant medication, and target Li serum concentration in geriatric patients. Concerning the termination of Li therapy, an agreement was reached on the appropriate time span for tapering and on potential alternatives to Li. No consensus was achieved on whether concomitant dementia or frailty should be considered contraindications for Li treatment and the appropriate threshold of the estimated glomerular function rate for withdrawing Li. CONCLUSION: According to the view of German experts, Li may be used in geriatric patients, but it should be monitored carefully. However, the lack of consent in several specific treatment situations underlines the need for research on specific issues of Li therapy.

[Lithium treatment for affective disorders in old age]. / Lithiumtherapie zur Behandlung affektiver Störungen im höheren Lebensalter.

BACKGROUND: Lithium is considered the gold standard for the treatment of bipolar affective disorder for the prevention of recurrence of manic and depressive episodes and for augmentation treatment in unipolar severe depressive episodes. The indications for treatment with lithium do not differ for older or younger patients. Nevertheless, there are a number of aspects to be considered with respect to drug safety in the group of old patients. OBJECTIVE: The aim was to give an overview of the current literature on lithium treatment in old age and from this to derive recommendations for action. MATERIAL AND METHODS: A selective literature review on lithium treatment in old age was conducted to answer questions on drug safety, monitoring (particularly with respect to comorbidities) and potential alternatives to lithium. RESULTS AND DISCUSSION: Lithium is an effective and, if used correctly, safe drug also in old people; however, with respect to somatic comorbidities that increase with age, special caution is required when using lithium in order to prevent nephropathy and intoxication.

Antidepressant Augmentation versus Switch in Treatment-Resistant Geriatric Depression.

BACKGROUND: The benefits and risks of augmenting or switching antidepressants in older adults with treatment-resistant depression have not been extensively studied. METHODS: We conducted a two-step, open-label trial involving adults 60 years of age or older with treatment-resistant depression. In step 1, patients were randomly assigned in a 1:1:1 ratio to augmentation of existing antidepressant medication with aripiprazole, augmentation with bupropion, or a switch from existing antidepressant medication to bupropion. Patients who did not benefit from or were ineligible for step 1 were randomly assigned in step 2 in a 1:1 ratio to augmentation with lithium or a switch to nortriptyline. Each step lasted approximately 10 weeks. The primary outcome was the change from baseline in psychological well-being, assessed with the National Institutes of Health Toolbox Positive Affect and General Life Satisfaction subscales (population mean, 50; higher scores indicate greater well-being). A secondary outcome was remission of depression. RESULTS: In step 1, a total of 619 patients were enrolled; 211 were assigned to aripiprazole augmentation, 206 to bupropion augmentation, and 202 to a switch to bupropion. Well-being scores improved by 4.83 points, 4.33 points, and 2.04 points, respectively. The difference between the aripiprazole-augmentation group and the switch-to-bupropion group was 2.79 points (95% CI, 0.56 to 5.02; P = 0.014, with a prespecified threshold P value of 0.017); the between-group differences were not significant for aripiprazole augmentation versus bupropion augmentation or for bupropion augmentation versus a switch to bupropion. Remission occurred in 28.9% of patients in the aripiprazole-augmentation group, 28.2% in the bupropion-augmentation group, and 19.3% in the switch-to-bupropion group. The rate of falls was highest with bupropion augmentation. In step 2, a total of 248 patients were enrolled; 127 were assigned to lithium augmentation and 121 to a switch to nortriptyline. Well-being scores improved by 3.17 points and 2.18 points, respectively (difference, 0.99; 95% CI, -1.92 to 3.91). Remission occurred in 18.9% of patients in the lithium-augmentation group and 21.5% in the switch-to-nortriptyline group; rates of falling were similar in the two groups. CONCLUSIONS: In older adults with treatment-resistant depression, augmentation of existing antidepressants with aripiprazole improved well-being significantly more over 10 weeks than a switch to bupropion and was associated with a numerically higher incidence of remission. Among patients in whom augmentation or a switch to bupropion failed, changes in well-being and the occurrence of remission with lithium augmentation or a switch to nortriptyline were similar. (Funded by the Patient-Centered Outcomes Research Institute; OPTIMUM ClinicalTrials.gov number, NCT02960763.).

Iatrogenic endocrine complications of lithium therapy.

Lithium is a cation, similar to sodium and potassium, affecting ion transport. It is used in the medical field as a treatment of bipolar disorders. The main endocrine complications of lithium treatment affect thyroid and parathyroid glands, in association with renal complications. Thyroid adverse effects, which are more frequent in women, comprise hypothyroidism, goiter, or sometimes hyperthyroidism, through interference with the iodine symporter. The increase in thyroid volume is early. Prevalence of goiter is 4 times higher than in the general population and hypothyroidism (8-20%) more frequent in case of pre-existing thyroid autoimmunity. Hyperthyroidism likely to worsen mood is reported in 5% of cases but the causal link to lithium is unproven. An increase in serum calcium and PTH occurs in 30% of cases, as lithium stimulates parathyroid cell proliferation by activating the Wnt pathway. The risk of hyperparathyroidism, by adenoma and especially by hyperplasia, is 5 times higher than in the general population, with the particularity of frequent low urine calcium by action on the calcium-sensing receptor (CaSR). Renal complications include risk of acute or chronic renal failure and nephrogenic diabetes insipidus, which is a factor for hypernatremia and hypercalcemia through dehydration. Nephrogenic diabetes insipidus is not always reversible after lithium therapy discontinuation. Metabolically, weight gain can be observed, but rather less than with other psychotropic drugs, and lithium does not in itself induce diabetes. At pituitary level, corticotropic activation is frequent, but implicating the disease rather than lithium. Lithium treatment induces little or no hyperprolactinemia. Regular monitoring of serum calcium, the ionogram, creatinine and TSH is recommended in lithium treatment.

Lithium Use for Suicide Prevention, Revisited.

The literature on lithium's role in suicide prevention is rife with competing interpretations and diverging opinions, in part stemming from the complexity of the underlying literature base. Conclusions that lithium unequivocally offers suicide prevention benefits do not appear warranted based on the strength of existing studies. Given the evidence along with the indisputable risks associated with lithium (especially in overdose), and the need for sustained therapeutic dosing to achieve any theoretical antisuicide benefit, it seems evident that any potential role for lithium in suicide prevention is far narrower than originally hypothesized. As such, the goal of this article is to provide an evidence-informed, therapeutic risk management approach to clinical decision-making concerning the use of lithium for suicide prevention to ensure that such prescribing is done in a patient-centered fashion that mitigates, to the extent possible, the potential risks of lithium use. This includes a review of potential justifications for not employing lithium for suicide prevention, given the recommendations in the existing guidelines. Clinicians should approach this clinical decision in an individualized fashion with full consideration of the potential risks associated with lithium use and availability, as well as potential alternative treatment options. An individualized risk/benefit analysis must also take into consideration the presence of comorbid conditions; the acuity of suicide risk, and any history of self-directed violence, with special attention to suicide attempts via overdose; treatment adherence, past and present; the presence and/or strength of a therapeutic relationship; and other viable treatment options.

Lithium and risk of cardiovascular disease, dementia and venous thromboembolism.

OBJECTIVE: To determine if long-term lithium treatment is associated with protective effects or increased risk of vascular, neurological, and renal disorders. METHODS: Using nationwide registers, we included all citizens of Finland with dispensations of lithium for three or more consecutive years between 1995 and 2016. We identified 9698 cases and matched 96,507 controls without lithium treatment. Studied outcomes were vascular, neurological, renal disorders, and suicide. Analyses were performed applying Cox proportional hazards modeling in full cohort and in further subcohort analysis of individuals with a comparable diagnosis of mood or psychotic disorder. RESULTS: Lithium users had a significantly higher overall disease burden compared to matched population controls, including a higher risk of cardiovascular and cerebrovascular disorders and dementia. However, compared to individuals with a diagnosis of mood or psychotic disorders without lithium treatment, we observed a lower risk of cardiovascular and cerebrovascular disorders (HR = 0.80, 99% CI = 0.73-0.89), and no significant difference for dementia (HR = 1.15, 99% CI = 0.99-1.33), in lithium users. Pulmonary embolism was more common in the lithium-treated cases both in comparison to the general population (HR = 2.86, 99% CI = 2.42-3.37) and in comparison to the psychiatric subcohort (HR = 1.68, 99% CI = 1.31-2.17). Similarly, the risks of Parkinson's disease and kidney disease were higher in both comparisons. CONCLUSIONS: We conclude that individuals prescribed lithium have a lower risk of cardiovascular and cerebrovascular disease, but no marked effect on dementia, compared to individuals with a mood or psychotic disorder not prescribed lithium. Venous thromboembolism, Parkinson's disease, and kidney disease were significantly more prevalent in individuals prescribed lithium.

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.

Lithium-Induced Dysgeusia and Hyposmia: A Case Report and a Literature Review.

BACKGROUND: Bipolar disorder is a complex psychiatric disorder where long-term treatment is crucial to maintain stabilization. Although largely well tolerated, lithium has a wide spectrum of adverse effects in different organs and seems to also cause taste and smell disorders, which remain rare and not largely described. We aim to present a rare case of hyposmia and dysgeusia secondary to lithium treatment in a bipolar patient and also conduct a review on these rare lithium adverse effects. CASE PRESENTATION: The case is a 43-year-old woman with type I bipolar disorder who became stabilized and fully functional with lithium therapy. After 4 months of treatment, she began to notice progressive hyposmia and dysgeusia. After multiple diagnostic and screening tests, lithium was implicated as the cause of the symptoms, which led to a switch to valproic acid. After 3 months, she was not compensated with valproic acid treatment, returned to lithium therapy despite its adverse effects, and became stabilized again. CONCLUSIONS: There are few data on lithium therapy taste and smell adverse effects. Most studies on this topic are likely to be case reports. Lithium therapy may cause dysgeusia and hyposmia, although mechanisms are not fully understood. These adverse effects can interfere negatively in patient's treatment adherence. Therefore, physicians who prescribe lithium should be aware of them. Further structured studies are needed to better understand these lithium rare adverse effects and the appropriate way to assess and monitoring them.