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Background: Lithium is effective in the long-term treatment of bipolar disorder. Concerns have been raised about non-responsiveness after discontinuation and resuming previously effective lithium prophylaxis. We reviewed the available literature on this so-called lithium-discontinuation-induced treatment refractoriness (LDITR). Results: We found 11 case reports and six cohort studies including 403 patients addressing LDITR, and one nation-wide register study providing some additional data on LDITR. Pooling all cohort studies, the percentages of non-responders during re-treatment with lithium ranged from 3.6 to 27.7%, with an average of 17.3%. Non-responsiveness was associated with longer duration of lithium treatment before discontinuation, longer duration of bipolar disorder before start of lithium, faster tapering off lithium, and longer duration of discontinuation. Conclusions: There may be a subgroup in whom lithium discontinuation-induced treatment refractoriness exists. However, the vast majority of people respond when lithium is restarted. Moreover, it may be necessary to continue lithium beyond the first relapses to restore long-term prophylactic efficacy. [ABSTRACT FROM AUTHOR]

Background: Lithium stands as the gold standard in treating bipolar disorders (BD). Despite numerous clinical factors being associated with a favorable response to lithium, comprehensive studies examining the collective influence of clinical variables alongside psychopathological dimensions are lacking. Our study aims to enhance comprehension of lithium response in individuals with BD by integrating clinical variables with psychopathological traits and early adverse events. Methods: We assessed 201 patients with BD for clinical characteristics, childhood trauma, temperament traits, impulsivity, and aggression. Lithium response was evaluated using the gold standard Alda scale, and predictors of lithium response were estimated through a multivariate model. Results: On the total sample, 61 (30.3%) patients were lithium responders according to the Alda scale. Comparatively, lithium responders, in contrast to non-responders, demonstrated a higher prevalence of the mania-depression-interval (MDI) cycle, a more frequent diagnosis of BD type I, and reported an earlier age of onset. They also exhibited less lifetime substance abuse, emotional, physical, and sexual abuse, while scoring higher on hyperthymic and irritable temperament scales. In multivariate analyses, only the MDI cycle (OR,3.47; 95%CI,1.61–7.50) hyperthymic (OR,1.20; 95%CI,1.02–1.41) and irritable temperament (OR,1.28; 95%CI,1.08–1.52) persisted as significant predictors of a positive response to lithium treatment, while emotional (OR,0.87; 95%CI,0.76–0.98) and physical abuse (OR,0.83; 95%CI,0.70–0.98) were predictors of non-response. Conclusions: In evaluating lithium response in BD, our study highlights the importance of considering clinical variables alongside temperament and childhood adversities. The assessment of hyperthymic and irritable temperament, emotional and physical abuse together with the type of cycle is of particular importance. Furthermore, our findings underscore the significance of systematically assessing the type of cycle in patients with BD through the use of life charts. [ABSTRACT FROM AUTHOR]

Background: The phenomenon of preventing the recurrences of mood disorders by the long-term lithium administration was discovered sixty years ago. Such a property of lithium has been unequivocally confirmed in subsequent years, and the procedure makes nowadays the gold standard for the pharmacological prophylaxis of bipolar disorder (BD). The efficacy of lithium prophylaxis surpasses other mood stabilizers, and the drug has the longest record as far as the duration of its administration is concerned. The continuation of lithium administration in case of good response could be a lifetime and last for several decades. The stability of lithium prophylactic efficacy in most patients is pretty steady. However, resuming lithium after its discontinuation may, in some patients, be less efficient. Main body: In the article, the clinical and biological factors connected with the prophylactic efficacy of long-term lithium administration are listed. Next, the adverse and beneficial side effects of such longitudinal treatment are presented. The main problems of long-term lithium therapy, which could make an obstacle to lithium continuation, are connected with lithium's adverse effects on the kidney and, to lesser extent, on thyroid and parathyroid functions. In the paper, the management of these adversities is proposed. Finally, the case reports of three patients who have completed 50 years of lithium therapy are described. Conclusions: The authors of the paper reckon that in the case of good response, lithium can be given indefinitely. Given the appropriate candidates for such therapy and successful management of the adverse effects, ultra-long term lithium therapy is possible and beneficial for such patients. [ABSTRACT FROM AUTHOR]

Suicidal behavior is more prevalent in bipolar disorders than in other psychiatric illnesses. In the last thirty years evidence has emerged to indicate that long-term treatment of bipolar disorder patients with lithium may reduce risk of suicide and attempts, with possibly similar benefits in recurrent major depressive disorder. We review and update selected research literature on effects of lithium treatment in reducing suicidal behavior and consider proposals that higher levels of lithium in drinking water may be associated with lower suicide rates. We summarize results of a growing number of randomized, controlled studies of lithium treatment for suicide prevention including comparisons with placebos or alternative treatments, and comment on the severe challenges of such trials. The basis of a proposed protective effect of lithium against suicidal behaviors remains uncertain but may include protective effects against recurrences of depressive phases of mood disorders, especially with mixed features or agitation, and possibly through beneficial effects on impulsivity, agitation and dysphoric mood. [ABSTRACT FROM AUTHOR]

Background: Lithium is an essential psychopharmaceutical, yet side effects and concerns about severe renal function impairment limit its usage. Aims: Our objectives were to quantify the occurrence of chronic kidney disease stage 4 or higher (CKD4 +) within a lithium-treated population, using age- and time-specific cumulative incidence and age-specific lifetime risk as measures of disease occurrence. Additionally, we aimed to investigate the association between the duration of lithium treatment and the risk of CKD4 +. Methods: We identified patients from the Sahlgrenska University Hospital's laboratory database. We conducted a retrospective cohort study employing cumulative incidence functions that account for competing deaths to estimate cumulative and lifetime risk of CKD4 +. A subdistribution hazards model was employed to explore baseline covariates. For measuring the association between the duration of lithium treatment and CKD4 + occurrence, we used a matched 1:4 case–control study design and logistic regression. Results: Considering a 90-year lifetime horizon, the lifetime risk of CKD4 + for patients initiating lithium treatment between ages 55 and 74 ranged from 13.9% to 18.6%. In contrast, the oldest patient group, those starting lithium at 75 years or older, had a lower lifetime risk of 5.4%. The 10-year cumulative risk for patients starting lithium between ages 18 and 54 was minimal, ranging from 0% to 0.7%. Pre-treatment creatinine level was a predictive factor, with a hazard ratio of 4.6 (95% CI 2.75–7.68) for values within the upper third of the reference range compared to the lower third. Moreover, twenty or more years of lithium exposure showed a strong association with an increased risk of CKD4 + compared to 1–5 years of lithium use, with an odds ratio of 6.14 (95% CI 2.65–14.26). Conclusions: The risk of CKD4 + among lithium-treated patients exhibited significant age-related differences. Patients under 55 years old had negligible 10-year risk, while the lifetime risk for those aged 75 and older was limited. Duration of lithium treatment, especially exceeding 20 years, emerged as a significant risk factor. For individual risk assessment and prediction, consideration of age, pre-treatment creatinine levels, and the chosen time horizon for prediction is essential. [ABSTRACT FROM AUTHOR]

For over half a century, it has been widely known that lithium is the most efficacious maintenance treatment for bipolar disorder. Despite thorough research on the long-term effects of lithium on renal function, a number of important questions relevant to clinical practice remain. The risk of polyuria, reflecting renal tubular dysfunction, is seen in a substantial proportion of patients treated with long term lithium therapy. The duration of lithium may be the most important risk factor for lithium-induced polyuria. Most, but not all, studies find that lithium is associated with higher rates of chronic kidney disease compared to either age matched controls or patients treated with other mood stabilizers. Age, duration of lithium therapy and medical disorders such as hypertension and diabetes mellitus are risk factors for chronic kidney disease in lithium-treated patients. The relationship between polyuria and chronic kidney disease is inconsistent but poorly studied. Although not all studies agree, it is likely that lithium may increase the risk for end stage renal disease but in a very small proportion of treated patients. Patients whose renal function is relatively preserved will show either no progression or improvement of renal function after lithium discontinuation. In contrast, patients with more renal damage frequently show continued deterioration of renal function even after lithium discontinuation. Optimal management of lithium treatment requires obtaining a baseline measure of renal function (typically estimated glomerular filtration rate [eGFR]) and regular monitoring of eGFR during treatment. Should the eGFR fall rapidly or below 60 ml/minute, patients should consider a consultation with a nephrologist. A decision as to whether lithium should be discontinued due to progressive renal insufficiency should be made using a risk/benefit analysis that takes into account other potential etiologies of renal dysfunction, current renal function, and the efficacy of lithium in that individual patient. [ABSTRACT FROM AUTHOR]

Background: The impact of long-term lithium treatment on weight gain has been a controversial topic with conflicting evidence. We aim to assess reporting of weight gain associated with lithium and other mood stabilizers compared to lamotrigine which is considered free of metabolic adverse drug reactions (ADRs). Methods: We conducted a case/non-case pharmacovigilance study using data from the AMSP project (German: "Arzneimittelsicherheit in der Psychiatrie"; i.e., Drug Safety in Psychiatry), which collects data on ADRs from patients treated in psychiatric hospitals in Germany, Austria, and Switzerland. We performed a disproportionality analysis of reports of weight gain (> 10% of baseline body weight) calculating reporting odds ratio (ROR). We compared aripiprazole, carbamazepine, lithium, olanzapine, quetiapine, risperidone, and valproate to lamotrigine. Additional analyses related to different mood stabilizers as reference medication were performed. We also assessed sex and age distributions of weight-gain reports. Results: We identified a total of 527 cases of severe drug-induced weight gain representing 7.4% of all severe ADRs. The ROR for lithium was 2.1 (95%CI 0.9–5.1, p > 0.05), which did not reach statistical significance. Statistically significant disproportionate reporting of weight gain was reported for olanzapine (ROR: 11.5, 95%CI 4.7–28.3, p < 0.001), quetiapine (ROR: 3.4, 95%CI 1.3–8.4, p < 0.01), and valproate (ROR: 2.4, 95%CI 1.1–5.0, p = 0.03) compared to lamotrigine. Severe weight gain was more prevalent in non-elderly (< 65 years) than in elderly patients, with an ROR of 7.6 (p < 0.01) in those treated with lithium, and an ROR of 14.7 (p < 0.01) in those not treated with lithium. Conclusions: Our findings suggest that lithium is associated with more reports of severe weight gain than lamotrigine, although this difference did not reach statistical significance. However, lithium use led to fewer reports of severe weight gain than some alternative drugs for long-term medication (olanzapine, quetiapine, and valproate), which is consistent with recent studies. Monitoring of weight gain and metabolic parameters remains essential with lithium and its alternatives. [ABSTRACT FROM AUTHOR]

Background: The distinction between bipolar I and bipolar II disorder and its treatment implications have been a matter of ongoing debate. The aim of this study was to examine differences between patients with bipolar I and II disorders with particular emphasis on the early phases of the disorders. Methods: 808 subjects diagnosed with bipolar I (N = 587) or bipolar II disorder (N = 221) according to DSM-IV criteria were recruited between April 1994 and March 2022 from tertiary-level mood disorder clinics. Sociodemographic and clinical variables concerning psychiatric and medical comorbidities, family history, illness course, suicidal behavior, and response to treatment were compared between the bipolar disorder types. Results: Bipolar II disorder patients were more frequently women, older, married or widowed. Bipolar II disorder was associated with later "bipolar" presentation, higher age at first (hypo)mania and treatment, less frequent referral after a single episode, and more episodes before lithium treatment. A higher proportion of first-degree relatives of bipolar II patients were affected by major depression and anxiety disorders. The course of bipolar II disorder was typically characterized by depressive onset, early depressive episodes, multiple depressive recurrences, and depressive predominant polarity; less often by (hypo)mania or (hypo)mania-depression cycles at onset or during the early course. The lifetime clinical course was more frequently rated as chronic fluctuating than episodic. More patients with bipolar II disorder had a history of rapid cycling and/or high number of episodes. Mood stabilizers and antipsychotics were prescribed less frequently during the early course of bipolar II disorder, while antidepressants were more common. We found no differences in global functioning, lifetime suicide attempts, family history of suicide, age at onset of mood disorders and depressive episodes, and lithium response. Conclusions: Differences between bipolar I and II disorders are not limited to the severity of (hypo)manic syndromes but include patterns of clinical course and family history. Caution in the use of potentially mood-destabilizing agents is warranted during the early course of bipolar II disorder. [ABSTRACT FROM AUTHOR]

Background: Lithium has long been considered the gold-standard pharmacological treatment for the maintenance treatment of bipolar disorders (BD) which is supported by a wide body of evidence. Prior research has shown a steady decline in lithium prescriptions during the last two decades. We aim to identify potential factors explaining this decline across the world with an anonymous worldwide survey developed by the International Society for Bipolar Disorders (ISBD) Task Force "Role of Lithium in Bipolar Disorders" and distributed by diverse academic and professional international channels. Results: A total of 886 responses were received of which 606 completed the entire questionnaire while 206 completed it partially. Respondents were from 43 different countries comprising all continents. Lithium was the most preferred treatment option for the maintenance of BD patients (59%). The most relevant clinical circumstances in which lithium was the preferred option were in patients with BD I (53%), a family history of response (18%), and a prior response during acute treatment (17%). In contrast, Lithium was not the preferred option in case of patients´ negative beliefs and/or attitudes towards lithium (13%), acute side-effects or tolerability problems (10%) and intoxication risk (8%). Clinicians were less likely to prefer lithium as a first option in BD maintenance phase when practising in developing economy countries [X2 (1, N = 430) = 9465, p = 0.002) ] and private sectors [X2 (1, N = 434) = 8191, p = 0.004)]. Conclusions: Clinicians' preferences and attitudes towards the use of lithium in the maintenance treatment of bipolar disorders appear to be affected by both the patients' beliefs and the professional contexts where clinicians provide their services. More research involving patients is needed for identifying their attitudes toward lithium and factors affecting its use, particularly in developing economies. [ABSTRACT FROM AUTHOR]

Background: Lithium is one of the most consistently effective treatment for mood disorders. However, patients may show a high level of heterogeneity in treatment response across the lifespan. In particular, the benefits of lithium use may vary in special clinical conditions. The aim of this study was to test this hypothesis by conducting an umbrella review on the efficacy and safety of lithium in childhood and adolescence, peripartum and old age. Methods: We applied the Preferred Reporting Items for Systematic Reviews and Meta-analyses criteria (PRISMA) to identify systematic reviews/meta-analyses on the efficacy and/or safety of lithium in mood disorders in special clinical conditions: (i) childhood and adolescence; (ii) peripartum (pregnancy, postpartum and lactation); (iii) old age. The Risk of Bias Assessment Tool for Systematic Reviews (ROBIS) tool was used to assess the risk of bias. Overlap in primary studies across systematic reviews was calculated through the Corrected Covered Area (CCA). Results: We included 20 independent studies, for a total of 8209 individuals treated with lithium. Regarding paediatric age, efficacy and safety results suggested that lithium may be superior to placebo in bipolar disorders (BD) and not associated with serious adverse events. Nevertheless, primary available data are very limited. Efficacy in paediatric major depressive disorder (MDD) is not clear. During peripartum, lithium use was superior to non-lithium in preventing mood episodes and it was associated with low risk of congenital anomalies and with normal child neurodevelopment. Regarding old age, limited evidence supported lithium as an effective treatment in BD and resistant MDD; low doses should be used in this population. Systematic reviews on paediatric age showed the lowest risk of bias (80% of the studies at low risk). The CCA range of included studies was 13–47%. Conclusions: This umbrella review supports the use of lithium across the lifespan, including special clinical condition. Nevertheless, more studies with increased methodological homogeneity are needed. [ABSTRACT FROM AUTHOR]

Background: Lithium is well recognized as the first-line maintenance treatment for bipolar disorder (BD). However, besides therapeutic benefits attributed to lithium therapy, the associated side effects including endocrinological and renal disorders constitute important parameters in prescribing patterns and patient adherence. The objectives of this study is to (i) determine whether long-term lithium therapy is associated with a decrease in renal function, hyperparathyroidism and hypercalcemia and (ii) identify risk factors for lithium-induced chronic kidney disease (CKD). Methods: We conducted a single-centered cohort study of adult patients (≥ 18 years) treated with lithium, who were enrolled at Rennes University Hospital in France between January 1, 2018 and June 1, 2020. Required data were collected from the patient's medical records: demographics characteristics (age, sex, body mass index), biologic parameters (GFR, lithium blood level, PTH and calcium), medical comorbidities (hypertension and diabetes), lithium treatment duration and dosage, and length of hospitalization. Results: A total of 248 patients were included (mean age: 60.2 ± 16.5 years). Duration of lithium treatment correlated with (i) deterioration of renal function estimated at − 2.9 mL/min/year (p < 0.0001) and (ii) the development of hyperparathyroidism (p < 0.01) and hypercalcemia (p < 0.01). We also noted that patients with lithium blood level > 0.8 mEq/mL had significantly lower GFR than patients with lithium blood level < 0.8 mEq/mL (61.8 mL/min versus 77.6 mL/min, respectively, p = 0.0134). Neither diabetes mellitus nor hypertension was associated with more rapid deterioration of renal function. Conclusion: This study suggests that the duration of lithium treatment contribute to the deterioration of renal function, raising the question of reducing dosages in patients with a GFR < 60 mL/min. Overdoses has been identified as a risk factor for CKD, emphasizing the importance of regular re-evaluation of the lithium dose regimen. Also, long-term lithium therapy was associated with hyperparathyroidism and hypercalcemia. Particular vigilance is required on these points in order to limit the occurrence of endocrinological and renal lithium adverse effects. [ABSTRACT FROM AUTHOR]

Background: Lithium is the gold standard prophylactic treatment for bipolar disorder. Most clinical practice guidelines recommend regular calcium assessments as part of monitoring lithium treatment, but easy-to-implement specific management strategies in the event of abnormal calcium levels are lacking. Methods: Based on a narrative review of the effects of lithium on calcium and parathyroid hormone (PTH) homeostasis and its clinical implications, experts developed a step-by-step algorithm to guide the initial management of emergent hypercalcemia during lithium treatment. Results: In the event of albumin-corrected plasma calcium levels above the upper limit, PTH and calcium levels should be measured after two weeks. Measurement of PTH and calcium levels should preferably be repeated after one month in case of normal or high PTH level, and after one week in case of low PTH level, independently of calcium levels. Calcium levels above 2.8 mmol/l may require a more acute approach. If PTH and calcium levels are normalized, repeated measurements are suggested after six months. In case of persistent PTH and calcium abnormalities, referral to an endocrinologist is suggested since further examination may be needed. Conclusions: Standardized consensus driven management may diminish the potential risk of clinicians avoiding the use of lithium because of uncertainties about managing side-effects and consequently hindering some patients from receiving an optimal treatment. [ABSTRACT FROM AUTHOR]

The Correction Notice from the International Journal of Bipolar Disorders addresses an error in the original article by Ferensztajn-Rochowiak et al. regarding the affiliation of author Ute Lewitzka. The correct affiliation for Ute Lewitzka is provided as the Department of Psychiatry and Psychotherapy at Universitätsklinikum Carl Gustav Carus, Dresden, Germany, and TUD Dresden University of Technology, Dresden, Germany. The notice also includes the authors' names and a link to the original article for reference. [Extracted from the article]

Background: The efficacy and safety of adjunctive therapy are unclear in bipolar depression. In this systematic review and meta-analysis, we aimed to evaluate the efficacy and safety of second-generation antipsychotic, lamotrigine, lithium, or valproate therapy used in adjunction with lamotrigine, lithium, or valproate monotherapy in bipolar depression. A literature search of major electronic databases was conducted in February 2021, and all articles published until then were eligible. Two researchers independently screened relevant publications, extracted data, and evaluated methodological quality according to the Cochrane criteria. Results: Five studies met the inclusion criteria. The meta-analysis revealed significant differences in the following outcomes: (i) remission rates from depressive episodes (risk ratio [RR]: 1.23, 95% confidence interval [CI] 1.01–1.50, p = 0.04), (ii) improvement in depressive symptoms (standardized mean difference [SMD]: 0.21, 95% CI 0.09–0.34, p = 0.001), (iii) improvement in quality of life (SMD: 0.22, 95% CI 0.06–0.37, p = 0.005), and (iv) rate of adverse events during the study period (RR: 1.12, 95% CI 1.03–1.22, p = 0.008). There was no significant difference between adjunctive therapy and monotherapy in the emergence of suicide-related behaviors, dropout rate during the study period, or rate of manic switching. Conclusions: Our results suggest that adjunctive second-generation antipsychotics, lamotrigine, lithium, or valproate increase both the benefits and risks in patients with bipolar depression, although there is no significant difference in severe adverse events. Adjunctive therapy should be provided through shared decision-making while considering the patients' condition in clinical settings. [ABSTRACT FROM AUTHOR]

Background: Lithium-induced nephrotoxicity has long been debated. However, it has been rarely explored in Asian populations. The aim of the present study was to assess the effect of lithium maintenance therapy on estimated glomerular filtration rate (eGFR) in Korean patients diagnosed with a psychiatric illness. Methods: This was a single-centered, retrospective study that included patients treated with lithium or comparator drug (valproate) in Samsung Seoul Medical Center between November 1994 and July 2020. Patients diagnosed with ICD codes F20-33 who had ≥ 6 months of exposure to lithium or valproate were included. Patients had to have ≥ 1 baseline and ≥ 2 post-baseline eGFR data with post-baseline data having an interval of at least 30 days. Chronic kidney disease (CKD) was defined as CKD stage 3 (eGFR < 60 mL/min/1.732). To be considered as CKD, the threshold had to be met at two consecutive post-baseline measurements. Those treated with both lithium and valproate, diagnosed with CKD stages 3–5, diagnosed with a renal disease, or received kidney transplantation were excluded. Results: A total of 766 patients were included (242 treated with lithium and 524 with valproate). Two (0.8%) in the lithium group and 8 (1.5%) in the valproate group developed CKD stage 3. None developed CKD stages 4–5. Median yearly eGFR change was − 1.3 mL/min/1.732 (IQR: − 6.8, 1.7) for the lithium group and − 1.1 mL/min/1.732 (IQR: − 4.5, 1.5) for the valproate group, showing no significant difference between the two groups (p = 0.389). The rate of decline was more rapid for those with CKD in both groups. eGFR values of lithium and valproate groups did not show significant differences during a follow-up duration of 15 years or more. A significant negative correlation between baseline eGFR and yearly eGFR change was identified in a linear regression analysis. Conclusions: In Korean patients, treatment with lithium did not increase the risk of developing CKD compared to treatment with valproate. Prevalence of CKD was lower than those previously reported in western populations. Low baseline eGFR showed significant correlation with changes in renal function. [ABSTRACT FROM AUTHOR]

Background: Lithium is the best documented maintenance treatment in bipolar disorder, but its use varies considerably across and within countries. It is not known whether regional differences in lithium prescription rates translate to differing regional outcomes. Aims: To estimate associations between county specific lithium prescription rates and county specific recurrence odds of bipolar disorder in Sweden. Method: Data from 14,616 patients with bipolar I disorder, bipolar II disorder, or bipolar disorder not otherwise specified were extracted from the Swedish national quality assurance register for bipolar disorders (BipoläR). Lithium prescription frequencies were calculated for 21 counties. Logistic regression analyses were run adjusted for confounders, with any type of recurrence as primary outcome, and incident elated and depressive episodes as secondary outcomes. Subsets of patients with bipolar I, II and not otherwise specified disorder were also analysed separately. Results: Lithium prescription rates for populations with all bipolar subtypes ranged across counties from 37.7 to 84.9% (mean 52.4%). Higher regional prescription rates were significantly associated with lower rate of any type of recurrence. The association was stronger when bipolar I disorder was analysed separately. Conclusions: The advantages for lithium use long acknowledged for bipolar I disorder are also seen for the rest of the bipolar spectrum. Results suggest that population level outcomes of bipolar disorder could be improved by increasing the number of patients using lithium. [ABSTRACT FROM AUTHOR]

Background: Lithium is considered the gold standard treatment for bipolar disorder (BD). Current clinical guidelines and scientific evidence support its use as a first-line treatment in BD. However, over the last two decades, there has been a downward tendency in lithium's use in several developed countries. Based on a nationwide survey, this study's objective is to analyze in a large sample of psychiatrists relevant issues of the use of lithium salts in BD. Methods: Data were collected through an anonymous survey sent by email among 500 psychiatrists who belong to a National Society of Psychiatry (Spanish Society of Biological Psychiatry). The survey is a self-administered questionnaire consisting of 21 items on the most key aspects of lithium's use (indication, dosage, monitoring, and information for patients). Results: 212 psychiatrists completed the survey. 70% of psychiatrists prescribe lithium to more than 50% of patients diagnosed with BD. Adverse effects are the main reason not to use lithium salts. Over 75% of the participants consider lithium salts the treatment of choice for the maintenance phase of BD, both in women and men. Most of the participants (> 50%) start lithium after the first affective episode, use conservative plasma concentrations (0.6–0.8 mmol/L), and generally prescribe it twice a day. 57% of psychiatrists who treat patients under 18 do not use lithium in this population. About 70% of the survey respondents use official protocols to inform and monitor patients on lithium treatment. Conclusions: From the results of the present study, it can be concluded that the use of lithium in Spain is in line with the recommendations of the main international clinical guidelines and current scientific literature. The first reason not to prescribe lithium in our country is the perception of its adverse effects and not the aspects related to its practical use or its effectiveness. Considering that BD is a chronic disease with a typical onset in adolescence, the low rate of prescription of lithium salts in patients under 18 must be thoroughly studied. [ABSTRACT FROM AUTHOR]

Background: In vitro studies have demonstrated that lithium has antiviral properties, but evidence from human studies is scarce. Lithium is used as a mood stabilizer to treat patients with bipolar disorder. Here, the aim was to investigate the association between lithium use and the risk of respiratory infections in patients with bipolar disorder. To rule out the possibility that a potential association could be due to lithium's effect on psychiatric symptoms, we also studied the effect of valproate, which is an alternative to lithium used to prevent mood episodes in bipolar disorder. Method: We followed 51,509 individuals diagnosed with bipolar disorder in the Swedish Patient register 2005–2013. We applied a within-individual design using stratified Cox regression to estimate the hazard ratios (HRs) of respiratory infections during treated periods compared with untreated periods. Results: During follow-up, 5,760 respiratory infections were documented in the Swedish Patient Register. The incidence rate was 28% lower during lithium treatment (HR 0.73, 95% CI 0.61–0.86) and 35% higher during valproate treatment (HR 1.35, 95% CI 1.06–1.73) compared with periods off treatment. Conclusions: This study provides real-world evidence that lithium is associated with decreased risk for respiratory infections and suggests that the repurposing potential of lithium for potential antiviral or antibacterial effects is worthy of investigation. [ABSTRACT FROM AUTHOR]

Objective: To identify possible socio-demographic and clinical factors associated with Good Outcome (GO) as compared with Poor Outcome (PO) in adult patients diagnosed with Bipolar Disorder (BD) who received long-term treatment with lithium. Methods: A comprehensive search of major electronic databases was performed to identify relevant studies that included adults patients (18 years or older) with a diagnosis of BD and reported sociodemographic and/or clinical variables associated with treatment response and/or with illness outcome during long-term treatment to lithium (> = 6 months). The quality of the studies was scored using the Quality Assessment Tool for Observational Cohort and Cross-Sectional Studies from the National Institute of Health. Results: Following review, 34 publications (from 31 independent datasets) were eligible for inclusion in this review. Most of them (n = 25) used a retrospective design. Only 11 studies were graded as good or borderline good quality. Forty-three potential predictors of outcome to lithium were identified. Four factors were associated with PO to lithium: alcohol use disorder; personality disorders; higher lifetime number of hospital admissions and rapid cycling pattern. Two factors were associated with GO in patients treated with lithium: good social support and episodic evolution of BD. However, when the synthesis of findings was limited to the highest (good or borderline good) quality studies (11 studies), only higher lifetime number of hospitalization admissions remained associated with PO to lithium and no associations remained for GO to lithium. Conclusion: Despite decades of research on lithium and its clinical use, besides lifetime number of hospital admissions, no factor being consistently associated with GO or PO to lithium was identified. Hence, there remains a substantial gap in our understanding of predictors of outcome of lithium treatment indicating there is a need of high quality research on large representative samples. [ABSTRACT FROM AUTHOR]

Background: When evaluating the long-term treatment response to mood stabilizers using the Alda scale, mood stabilizer combination therapy is typically considered a confounding factor, and patients receiving combination therapy are excluded from the analysis. However, this may result in bias if those under combination therapy are worse treatment responders. This study aims to explore whether the Alda scale is applicable to patients taking lithium and valproate combination therapy. We compared long-term treatment response in patients receiving monotherapy and combination therapy of the two drugs, and investigated clinical correlates of the responses to each drug. Methods: The study subjects consisted of 102 patients with bipolar I (BD-I) or bipolar II (BD-II) disorder who had been undergoing maintenance treatment with lithium and/or valproate for more than 2 years at a single specialized bipolar disorder clinic. Long-term treatment response was measured using the Alda scale and compared among the lithium monotherapy group, the valproate monotherapy group, and the mood stabilizer combination group. Clinical correlates of long-term treatment response were evaluated in lithium users and valproate users separately. Results: There were no significant differences in terms of baseline illness characteristics among groups. The combination group showed the worst treatment response for all the response measurements applied. This group also had the higher rate of 'poor responder' with a statistically significant difference compared to valproate group. Older age at onset and (hypo)manic episode at onset showed significant positive associations with total Alda score in lithium users, while comorbid anxiety disorders, obsessive–compulsive disorder and mixed episode showed significant negative associations in valproate users. Conclusions: The combination group had poorer long-term treatment response but did not show distinct clinical characteristics compared to the monotherapy groups. When exploring the long-term effects of mood stabilizers, excluding patients undergoing combination treatment could result in bias because they may represent a poor response group. The long-term treatment responses of lithium and valproate had different clinical correlates. [ABSTRACT FROM AUTHOR]

Background: Since its introduction in modern medicine, naturalistic observations emerged about possible uses of lithium treatment for conditions different from recurring affective disorders, for which it is still a first-line treatment option. Some evidence about the antiviral properties of lithium began in the early 1970s, when some reports found a reduction of labial-herpetic recurrences. The present review aims to present most of the pre-clinical and clinical evidence about lithium's ability to inhibit DNA and RNA viruses, including Coronaviridae, as well as the possible pathways and mechanisms involved in such antiviral activity. Main body: Despite a broad number of in vitro studies, the rationale for the antiviral activity of lithium failed to translate into methodologically sound clinical studies demonstrating its antiviral efficacy. In addition, the tolerability of lithium as an antiviral agent should be addressed. In fact, treatment with lithium requires continuous monitoring of its serum levels in order to prevent acute toxicity and long-term side effects, most notably affecting the kidney and thyroid. Yet lithium reaches heterogeneous but bioequivalent concentrations in different tissues, and the anatomical compartment of the viral infection might underpin a different, lower need for tolerability concerns which need to be addressed. Conclusions: Lithium presents a clear antiviral activity demonstrated at preclinical level, but that remains to be confirmed in clinical settings. In addition, the pleiotropic mechanisms of action of lithium may provide an insight for its possible use as antiviral agent targeting specific pathways. [ABSTRACT FROM AUTHOR]

Background: Concerns about potential adverse effects of long-term exposure to lithium as a mood-stabilizing treatment notably include altered renal function. However, the incidence of severe renal dysfunction; rate of decline over time; effects of lithium dose, serum concentration, and duration of treatment; relative effects of lithium exposure vs. aging; and contributions of sex and other factors all remain unclear. Methods: Accordingly, we acquired data from 12 collaborating international sites and 312 bipolar disorder patients (6142 person-years, 2669 assays) treated with lithium carbonate for 8-48 (mean 18) years and aged 20-89 (mean 56) years. We evaluated changes of estimated glomerular filtration rate (eGFR) as well as serum creatinine, urea-nitrogen, and glucose concentrations, white blood cell count, and body-mass index, and tested associations of eGFR with selected factors, using standard bivariate contrasts and regression modeling. Results: Overall, 29.5% of subjects experienced at least one low value of eGFR (<60 mL/min/1.73 m), most after ≥15 years of treatment and age > 55; risk of ≥2 low values was 18.1%; none experienced end-stage renal failure. eGFR declined by 0.71%/year of age and 0.92%/year of treatment, both by 19% more among women than men. Mean serum creatinine increased from 0.87 to 1.17 mg/dL, BUN from 23.7 to 33.1 mg/dL, glucose from 88 to 122 mg/dL, and BMI from 25.9 to 26.6 kg/m. By multivariate regression, risk factors for declining eGFR ranked: longer lithium treatment, lower lithium dose, higher serum lithium concentration, older age, and medical comorbidity. Later low eGFR was also predicted by lower initial eGFR, and starting lithium at age ≥ 40 years. Limitations: Control data for age-matched subjects not exposed to lithium were lacking. Conclusions: Long-term lithium treatment was associated with gradual decline of renal functioning (eGFR) by about 30% more than that was associated with aging alone. Risk of subnormal eGFR was from 18.1% (≥2 low values) to 29.5% (≥1 low value), requiring about 30 years of exposure. Additional risk factors for low eGFR were higher serum lithium level, longer lithium treatment, lower initial eGFR, and medical comorbidity, as well as older age. [ABSTRACT FROM AUTHOR]

Objectives: To present a new case of adverse cutaneous reaction during lithium treatment and to update the systematic review and meta-analysis of the incidence of this adverse reaction. Methods: We conducted a systematic search (performed in September 2016) for peer-reviewed articles in English indexed in Medline (2011-present). Meta-analytical estimates were obtained using the 'Metafor' package. Case presentation: Ms. H., a 31-year-old Caucasian woman with BD1, was admitted to the inpatient unit for a full-blown psychotic episode and treated with carbamazepine 400 mg q.d., lithium carbonate 450 mg q.d., and risperidone 4 mg q.d. with clinical improvement. After 12 days from the start of psychopharmacological treatment, she manifested a cutaneous reaction that motivated the stop of carbamazepine treatment, as well as the increase in lithium carbonate dose (750 mg q.d.). Risperidone dose remained unvaried. Since the skin lesion persisted after 8 days from withdrawal of carbamazepine, the private practitioner stopped also lithium carbonate treatment (de-challenge), maintaining risperidone treatment. The cutaneous reaction resolved spontaneously after six days from withdrawal of lithium carbonate. Subsequently, the worsening of psychopathological conditions motivated a new admission during which lithium carbonate was reintroduced (16 days after its suspension) (re-challenge). On the following day, we observed an itching erythematous maculopapular rash involving the trunk, the four limbs, and the oral mucosa. Conclusions: Our case of an erythematous maculopapular rash during lithium treatment was the first to present a challenge-de-challenge-re-challenge sequence that suggests causality. Although meta-analysis does not point to an increased rate of adverse skin reaction during lithium treatment, clinicians should not neglect to monitor cutaneous symptoms during lithium treatment. [ABSTRACT FROM AUTHOR]

Background: Epidemiological, clinical, and high-risk studies have provided evidence that the peak period for onset of diagnosable episodes of mania and hypomania starts in mid-to-late adolescence. Moreover, clinically significant manic symptoms may occur even earlier, especially in children at familial risk. Lithium is the gold standard treatment for acute mania in adults, yet to our knowledge, there is no published systematic review assessing lithium treatment of mania in children or adolescents. This is a major gap in knowledge needed to inform clinical practice. Aim: As a working group within the ISBD Task Force on Lithium Treatment (), our aim is to complete a systematic review of the efficacy, tolerability, and acceptability of lithium compared with placebo and other active drugs in treating mania in children and adolescents diagnosed with bipolar disorder. Methods: We will include double- or single-blind randomized controlled trials in patients aged less than 18 years. No restrictions will be made by study publication date or language. Several electronic databases will be searched along with secondary sources such as bibliographies and trial registry websites for published and unpublished studies. Response rates to lithium compared with placebo or other active drugs will be the primary efficacy outcome. Primary tolerability and acceptability outcomes will be rates of serious adverse events and dropouts, respectively. Secondary outcomes will include rates of remission, severity of manic symptoms at different time points, and incidence of specific adverse events. Discussion: Findings from this systematic review are critically needed to inform clinical practice. We should not generalize findings from adult studies, as children and adolescents are undergoing accelerated physiological and brain development. Therefore, efficacy, tolerability, and acceptability of lithium treatment of acute mania in children compared to adults may be very different. This systematic review has been registered in PROSPERO (CRD42017055675). [ABSTRACT FROM AUTHOR]

Background: Recent observational studies have focused on lithium treatment in the elderly, with particular reference to safety in terms of thyroid and renal functions. The purpose of this study was to compare the clinical characteristics of patients starting lithium treatment before ( N = 79) or after ( N = 31) the age of 65 years. Patients were followed up for 6 years with focus on renal function and prescription of levothyroxine and methimazole. Results: At baseline, median lithium serum concentration was 0.55 mmol/l. The estimated glomerular filtration rate was lower than 60 ml/min/1.73 m in 43 (39%) patients. In a multiple regression analysis controlling for age and gender, we found a significant effect of duration of lithium treatment on estimated glomerular filtration rate (−0.85 ml/min/1.73 m per year of prior exposure). The annual decline during follow-up was 2.3 ml/min/1.73 m. Two patients were prescribed levothyroxine, and two were prescribed methimazole for the first time during follow-up. Conclusions: Median lithium serum concentration in this cohort of elderly patients with mainly bipolar disorders was lower than the therapeutic range indicated for younger adults. The decline in glomerular filtration rate may be accelerated by long-term lithium use. Thyroid and renal functions continue to require close monitoring throughout the course of lithium treatment. Trial registration NP/2013/3836. Registered 24 June 2013 [ABSTRACT FROM AUTHOR]

Background: Depressive disorders are a leading cause of the global burden of disease and are associated with high recurrent often continuing morbidity and high excess mortality by suicide and cardiovascular disease. Whilst there are established, effective and cost-effective treatments for depression, their long-term management is often neglected: there is continuing controversy over the case of need for long-term treatment including lifelong treatment and safety issues. Objective and methods: In this narrative review, we critically examine the evidence for the effectiveness and safety of lithium salts in the long-term management of unipolar depression. We refer to existing recent international guidelines as well as the scientific literature selectively and against the background of our longstanding experience with patients suffering from unipolar depression who are often under treated or inappropriately treated. Results and discussion: According to many studies mostly dating back to the 1970/1980s, lithium is efficacious in the prophylaxis of unipolar depression particularly depression with melancholia and delusional depression and showing a clearly episodic course. Also the efficacy of lithium maintenance treatment following recovery by ECT has been clearly shown. Moreover, convincing evidence exists that lithium has added value and benefit for its unique anti-suicidal effects as well as reducing mortality by other causes. The anti-suicidal effect has been convincingly demonstrated in bipolar as well as in unipolar patients. Nevertheless its use in the management of patients with unipolar depression has not been properly recognized by a majority of textbooks and guidelines. Whilst it has been well considered as an effective treatment for depression that has not responded to antidepressants as an adjunct treatment, also called augmentation, it has been much less recommended for the prevention of recurrent episodes of unipolar depression. One of the reasons for this neglect is the blurring of the diagnosis 'unipolar depression' by modern diagnostic tools. Lithium will hardly work in a patient with 'unipolar depression spectrum disease'. Conclusions: We conclude that lithium is an effective prophylactic treatment for carefully selected patients with unipolar depression and is safe when prescribed in recommended doses/plasma lithium levels and with regular, careful monitoring. We propose that lithium prophylaxis can be indicated in patients with unipolar depression and that the occurrence of 2 episodes of depression within 5 years is a practical criterion for starting lithium prophylaxis particularly in severe depression with psychotic features and high suicidal risk. Furthermore, an indication might be considered especially in unipolar patients in whom a bipolar background is suspected. In some cases, lithium prophylaxis may be recommended after a single episode of depression that is severe with high suicidal risk and continued life-long. [ABSTRACT FROM AUTHOR]

In their comprehensive and updated guide of clinical use of lithium, Tondo et al. ([12]), also made a historical account of persons who significantly contributed to these guidelines. In this context, it would be appropriate to mention the recently deceased great American supporter of lithium therapy, James Walter (Jeff) Jefferson (1937-2019). 7 Moncrieff J. Lithium revisited. a reexamination of the placebo-controlled trial of lithium prophylaxis in manic-depressive disorder. [Extracted from the article]

Background: Despite various pharmacological and psychological treatment interventions, bipolar disorders rank among the leading causes of global disease burden. Group psychoeducation has been demonstrated an effective add-on to pharmacotherapy, but it may be difficult to implement in practice depending on the clinical setting and available human resources. Methods: Multicenter, rater-blind, randomized controlled trial to investigate the efficacy of a new intervention program consisting of an initial 6-week psychoeducation protocol plus a subsequent structured daily computer-based self-charting program (ChronoRecord) over 54 weeks in remitted patients with bipolar disorders. The control condition included non-structured group sessions followed by daily computer-based self-reports (unstructured like a diary). Both groups received treatment-as-usual. Results: Over 2 years, 41 mood episodes occurred in the experimental group (n = 39) compared to 27 in the control group (n = 34), without reaching statistical significance. Time to recurrence did not significantly differ between the experimental and control group (25% relapsed after 112 and 273 days, respectively). There were no significant group-by-time interactions in mood symptoms, quality of life, self-efficacy expectations or perceived involvement in care. Conclusions: Six weekly psychoeducational group sessions followed by daily self-monitoring via ChronoRecord for 54 weeks may not be superior to non-structured group meetings followed by unstructured self-reporting. Other psychotherapeutic interventions may be needed to optimize the treatment of patients with bipolar disorders, especially for those at later disease stages. Trial registration Retrospectively registered at German Clinical Trials Register on May 24, 2019; DRKS00017319 [ABSTRACT FROM AUTHOR]

Background: Lithium is recommended as a first line treatment for bipolar disorders. However, only 30% of patients show an optimal outcome and variability in lithium response and tolerability is poorly understood. It remains difficult for clinicians to reliably predict which patients will benefit without recourse to a lengthy treatment trial. Greater precision in the early identification of individuals who are likely to respond to lithium is a significant unmet clinical need. Structure: The H2020-funded Response to Lithium Network (R-LiNK; http://www.r-link.eu.com/) will undertake a prospective cohort study of over 300 individuals with bipolar-I-disorder who have agreed to commence a trial of lithium treatment following a recommendation by their treating clinician. The study aims to examine the early prediction of lithium response, non-response and tolerability by combining systematic clinical syndrome subtyping with examination of multi-modal biomarkers (or biosignatures), including omics, neuroimaging, and actigraphy, etc. Individuals will be followed up for 24 months and an independent panel will assess and classify each participants' response to lithium according to predefined criteria that consider evidence of relapse, recurrence, remission, changes in illness activity or treatment failure (e.g. stopping lithium; new prescriptions of other mood stabilizers) and exposure to lithium. Novel elements of this study include the recruitment of a large, multinational, clinically representative sample specifically for the purpose of studying candidate biomarkers and biosignatures; the application of lithium-7 magnetic resonance imaging to explore the distribution of lithium in the brain; development of a digital phenotype (using actigraphy and ecological momentary assessment) to monitor daily variability in symptoms; and economic modelling of the cost-effectiveness of introducing biomarker tests for the customisation of lithium treatment into clinical practice. Also, study participants with sub-optimal medication adherence will be offered brief interventions (which can be delivered via a clinician or smartphone app) to enhance treatment engagement and to minimize confounding of lithium non-response with non-adherence. Conclusions: The paper outlines the rationale, design and methodology of the first study being undertaken by the newly established R-LiNK collaboration and describes how the project may help to refine the clinical response phenotype and could translate into the personalization of lithium treatment. [ABSTRACT FROM AUTHOR]

Background: Lithium has been used clinically for 70 years, mainly to treat bipolar disorder. Competing treatments and exaggerated impressions about complexity and risks of lithium treatment have led to its declining use in some countries, encouraging this update about its safe clinical use. We conducted a nonsystematic review of recent research reports and developed consensus among international experts on the use of lithium to treat major mood disorders, aiming for a simple but authoritative guide for patients and prescribers. Main text: We summarized recommendations concerning safe clinical use of lithium salts to treat major mood disorders, including indications, dosing, clinical monitoring, adverse effects and use in specific circumstances including during pregnancy and for the elderly. Conclusions: Lithium continues as the standard and most extensively evaluated treatment for bipolar disorder, especially for long-term prophylaxis. [ABSTRACT FROM AUTHOR]

Lithium is an effective treatment in pregnancy and postpartum for the prevention of relapse in bipolar disorder. However, lithium has also been associated with risks during pregnancy for both the mother and the unborn child. Recent large studies have confirmed the association between first trimester lithium exposure and an increased risk of congenital malformations. Importantly, the risk estimates from these studies are lower than previously reported. Tapering of lithium during the first trimester could be considered but should be weighed against the risks of relapse. There seems to be no association between lithium use and pregnancy or delivery related outcomes, but more research is needed to be more conclusive. When lithium is prescribed during pregnancy, lithium blood levels should be monitored more frequently than outside of pregnancy and preferably weekly in the third trimester. We recommend a high-resolution ultrasound with fetal anomaly scanning at 20 weeks. Ideally, delivery should take place in a specialised hospital where psychiatric and obstetric care for the mother is provided and neonatal evaluation and monitoring of the child can take place immediately after birth. When lithium is discontinued during pregnancy, lithium could be restarted immediately after delivery as strategy for relapse prevention postpartum. Given the very high risk of relapse in the postpartum period, a high target therapeutic lithium level is recommended. Most clinical guidelines discourage breastfeeding in women treated with lithium. It is highly important that clinicians inform and advise women about the risks and benefits of remaining on lithium in pregnancy, if possible preconceptionally. In this narrative review we provide an up-to-date overview of the literature on lithium use during pregnancy and after delivery leading to clinical recommendations. [ABSTRACT FROM AUTHOR]

Background: Cancer had never been considered as a relevant problem in patients treated with lithium until 2015, when a document published by the European Medicine Agency concluded that long-term use of lithium might induce renal tumors. A few months later, we observed the case of a woman treated with lithium for 18 years who was diagnosed with both thyroid and renal tumors.Methods: This study aimed to investigate the correlation between lithium treatment and thyroid or renal tumors. We analyzed clinical records in our lithium clinic database, causes of death of patients who had been visited at least once at the lithium clinic, reports of lithium adverse reactions in the European and WHO pharmacovigilance databases, and published cases of thyroid and renal tumors in long-term lithium-treated patients.Results: Of the 1871 lithium patients who had been visited at least once between 1980 and 2013, eight had been diagnosed with thyroid papillary carcinoma and two with clear-cell renal-cell carcinoma. No cases of thyroid cancer and only one case of renal tumor were the cause of death according to the 375 available death certificates. VigiAccess database contained a total of 29 and 14 cases of renal and thyroid tumors, respectively. EudraVigilance database contained 21 cases of renal and 8 of thyroid neoplasms. Literature search yielded 6 published cases of thyroid papillary carcinoma and 25 cases of various renal tumors. However, two population-based studies did not find any increased risks of cancer in patients exposed to lithium, whereas two nationwide studies did not find any excess of renal tumors.Conclusion: So far it has not been possible epidemiologically to confirm an increased risk of thyroid or renal cancers associated with lithium. Such a conclusion is supported by the findings of low rates and mortalities of thyroid or renal cancers from the present lithium clinic data. [ABSTRACT FROM AUTHOR]

Background: Adequate monitoring of patients using lithium is needed for optimal dosing and for early identification of patients with (potential) ADEs. The objective was to internationally assess how health care professionals monitor patients treated with lithium for bipolar disorder.Methods: Using networks of various professional organizations, an anonymous online survey was conducted among health care professionals prescribing lithium. Target lithium serum levels and frequency of monitoring was assessed together with monitoring of physical and laboratory parameters. Reasons to and not to monitor and use of guidelines and institutional protocols, and local monitoring systems were investigated.Results: The survey was completed by 117 health care professionals incorporating responses from twenty-four countries. All prescribers reported to monitor lithium serum levels on a regular basis, with varying target ranges. Almost all (> 97%) monitored thyroid and renal function before start and during maintenance treatment. Reported monitoring of other laboratory and physical parameters was variable. The majority of respondents (74%) used guidelines or institutional protocols for monitoring. In general, the prescriber was responsible for monitoring, had to request every monitoring parameter separately and only a minority of patients was automatically invited.Conclusions: Lithium serum levels, renal and thyroid function were monitored by (almost) all physicians. However, there was considerable variation in other monitoring parameters. Our results help to understand why prescribers of lithium monitor patients and what their main reasons are not to monitor patients using lithium. [ABSTRACT FROM AUTHOR]