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.

Is a vegetarian diet beneficial for bipolar disorder? Relationship between dietary patterns, exercise and pharmacological treatments with metabolic syndrome and course of disease in bipolar disorder.

BACKGROUND: Lifestyle factors are being increasingly studied in bipolar disorder (BD) due to their possible effects on both course of disease and physical health. The aim of this study was to jointly describe and explore the interrelations between diet patterns, exercise, pharmacological treatment with course of disease and metabolic profile in BD. METHODS: The sample consisted of 66 euthymic or mild depressive individuals with BD. Clinical and metabolic outcomes were assessed, as well as pharmacological treatment or lifestyle habits (diet and exercise). Correlations were explored for different interrelations and a factor analysis of dietary patterns was performed. RESULTS: Adherence to the Mediterranean diet was low, seen in 37.9% of the patients and was positively associated with perceived quality of life. The amount of exercise was negatively associated with cholesterol levels, with 32.8% of participants rated as low active by International Physical Activity Questionnaire. There was a high prevalence of obesity (40.6%) and metabolic syndrome (29.7%). Users of lithium showed the best metabolic profile. Interestingly, three dietary patterns were identified: "vegetarian," "omnivore" and "Western." The key finding was the overall positive impact of the "vegetarian" pattern in BD, which was associated with reduced depression scores, better psychosocial functioning, and perceived quality of life, decreased body mass index, cholesterol, LDL and diastolic blood pressure. Nuts consumption was associated with a better metabolic profile. CONCLUSIONS: A vegetarian diet pattern was associated with both, better clinical and metabolic parameters, in patients with BD. Future studies should prioritize prospective and randomized designs to determine causal relationships, and potentially inform clinical recommendations.

Impact of chronic lithium treatment on brain oxidative stress and anxiety-like behaviors in rats: Dose-dependent effects.

Lithium (Li) is a mood-stabilizing drug. Although one of the potential mechanisms underlying the neuroprotective effects of lithium is related to its antioxidative effect, its mechanisms of action are not fully understood. Herein we aimed to investigate the impact of varied dosages of long-term lithium therapy on oxidative stress parameters in the brains of healthy rats, and on anxiety-like behaviors, and whether any changes in behavior can be attributed to modifications in oxidative stress levels within the brain. Thirty-two adult Wistar albino male rats were randomly assigned to four treatment groups. While the control (C) group was fed with a standard diet, low Li (1.4 g/kg/diet), moderate Li (1.8 g/kg/diet), and high Li (2.2 g/kg/diet) groups were fed with lithium bicarbonate (Li2CO3) for 30 days. Malondialdehyde increased, while superoxide dismutase and catalase levels decreased in the brains of the high Li group animals. In addition, anxiety-like behaviors of animals increased in the high Li group considering fewer entries to and less time spent in the open arms of the elevated plus maze test. Our findings underscore the potential adverse effects of prolonged lithium treatment, especially at doses approaching the upper therapeutic range. The induction of toxicity, manifested through heightened oxidative stress, appears to be a key mechanism contributing to the observed increase in anxiety-like behaviors. Consequently, caution is warranted when considering extended lithium therapy at higher doses, emphasizing the need for further research to delineate the precise mechanisms underlying these effects and to inform safer therapeutic practices.

Electrocardiographic Changes During Initiation of Lithium Augmentation of Antidepressant Pharmacotherapy.

PURPOSE/BACKGROUND: Lithium augmentation of antidepressants represents a common strategy to overcome treatment resistance in patients with major depressive disorder. The use of lithium has been associated with cardiovascular adverse effects such as QTc prolongation and tachyarrhythmia. Although the previous studies investigated monotherapy with lithium, the aim of this study was to investigate electrocardiographic changes in LA. METHODS/PROCEDURES: A 12-lead surface electrocardiogram (ECG) was obtained from 38 patients with major depressive disorder before and during LA. Changes in heart rate, PQ, QRS and QTc interval, QT dispersion, ST segment, and T- and U-wave alterations were analyzed using a linear mixed model. FINDINGS/RESULTS: The ECG readings of 33 patients were evaluated. Lithium augmentation was not significantly associated with changes in heart rate, QTc, PQ, or QRS interval. We found a significant decrease in QT dispersion. These results were independent of sex, age, stable comedication, and comorbidities. During LA, we observed 9 cases of T-wave alterations and 2 cases of new U waves. CONCLUSIONS: Our data provide no evidence for serious ECG abnormalities at therapeutic serum lithium levels in patients treated with LA. In particular, we did not find evidence for QTc time lengthening or tachyarrhythmia, such as torsades des pointes. The recommended intervals for ECG checks should be considered to detect long-term effects of LA.

Pharmacotherapy Prescriptions for Relapse Prevention of Psychotic Depression After Electroconvulsive Therapy.

PURPOSE/BACKGROUND: Electroconvulsive therapy (ECT) is effective in the treatment of acute episodes of psychotic depression. However, no adequately powered studies have directly investigated the efficacy of antipsychotic pharmacotherapy in relapse prevention of psychotic depression after ECT. In the absence of such literature, we reviewed the clinical practice of 4 academic medical centers that have made research contributions in the treatment of psychotic depression over the past 20 years. METHODS/PROCEDURES: We reviewed medical records of patients with a diagnosis of psychotic depression who received 1 or more acute courses of ECT over the span of 3 years. Chi-square tests were used to compare pharmacotherapy prescribed at the time of completion of ECT. FINDINGS/RESULTS: A total of 163 patients received 176 courses of ECT for separate episodes of psychotic depression. The combination of an antidepressant plus an antipsychotic was the most common regimen, ranging from 61.9% to 85.5% of all prescriptions. One center added lithium in 45.5% of cases treated with the combination of an antidepressant plus an antipsychotic. An antipsychotic alone was prescribed in less than 10% of cases. An antidepressant alone or other drug combinations were rare. IMPLICATIONS/CONCLUSIONS: The combination of an antidepressant plus an antipsychotic was the most commonly prescribed regimen at the completion of ECT for relapse prevention in patients with psychotic depression acutely treated with ECT. Although this report offers a view of the clinical practice of 4 academic medical centers, it also points to the need of randomized controlled trials on continuation pharmacotherapy after treatment of psychotic depression with ECT.

A Single-Blind Randomized Comparison of Lithium and Lamotrigine as Maintenance Treatments for Managing Bipolar II Disorder.

PURPOSE/BACKGROUND: No study to date has compared lithium and lamotrigine as maintenance mood stabilizers for bipolar II disorder. The aim of this study was to evaluate and compare these two medications in terms of their maintenance efficacy and side effect profile, thus evaluating their comparative cost/benefit profile. METHODS/PROCEDURES: Forty-four subjects with a newly diagnosed bipolar II disorder were randomly assigned to receive either lithium or lamotrigine treatment in a 20-week single-blinded study. Subjects received either slow-release lithium progressively up-titrated to achieve a serum level of 0.8 mEq/L, or lamotrigine increased progressively to a maintenance dose of 200 mg/d. Our primary outcome measure examined daily data on hypomanic and depressive symptoms. Secondary measures evaluated hypomanic and depressive symptom severity, global functioning, and global improvement in hypomanic and depressive symptoms. FINDINGS/RESULTS: We terminated the trial principally because of severe ongoing side effects experienced by many of those receiving lithium, and with additional concerns about initial severe side effects (including psychosis) experienced by several assigned to lamotrigine. Analyses of study completer data for 28 participants suggested comparable efficacy of both medications; however, lamotrigine had a distinctly lower rate of severe side effects across the study. We calculated that if study trends on outcome measures were valid, then an extremely large sample would be required to demonstrate superiority of either drug, thus making it unlikely that any such adequately powered study will be mounted in the future. IMPLICATIONS/CONCLUSIONS: The small sample size limits any definitive conclusions, but our data suggest that lithium and lamotrigine are likely to have equal efficacy as mood stabilizers for those with a bipolar II condition but that, as maintenance treatments, lithium has more distinctive side effects.

Chronic lithium treatment alters the excitatory/ inhibitory balance of synaptic networks and reduces mGluR5-PKC signalling in mouse cortical neurons.

Background: Bipolar disorder is characterized by cyclical alternation between mania and depression, often comorbid with psychosis and suicide. Compared with other medications, the mood stabilizer lithium is the most effective treatment for the prevention of manic and depressive episodes. However, the pathophysiology of bipolar disorder and lithium's mode of action are yet to be fully understood. Evidence suggests a change in the balance of excitatory and inhibitory activity, favouring excitation in bipolar disorder. In the present study, we sought to establish a holistic understanding of the neuronal consequences of lithium exposure in mouse cortical neurons, and to identify underlying mechanisms of action. Methods: We used a range of technical approaches to determine the effects of acute and chronic lithium treatment on mature mouse cortical neurons. We combined RNA screening and biochemical and electrophysiological approaches with confocal immunofluorescence and live-cell calcium imaging. Results: We found that only chronic lithium treatment significantly reduced intracellular calcium flux, specifically by activating metabotropic glutamatergic receptor 5. This was associated with altered phosphorylation of protein kinase C and glycogen synthase kinase 3, reduced neuronal excitability and several alterations to synapse function. Consequently, lithium treatment shifts the excitatory­inhibitory balance toward inhibition. Limitations: The mechanisms we identified should be validated in future by similar experiments in whole animals and human neurons. Conclusion: Together, the results revealed how lithium dampens neuronal excitability and the activity of the glutamatergic network, both of which are predicted to be overactive in the manic phase of bipolar disorder. Our working model of lithium action enables the development of targeted strategies to restore the balance of overactive networks, mimicking the therapeutic benefits of lithium but with reduced toxicity.

Immediate-release methylphenidate for attention deficit hyperactivity disorder (ADHD) in adults.

BACKGROUND: Attention deficit hyperactivity disorder (ADHD) is characterized by symptoms of inattention or impulsivity or both, and hyperactivity, which affect children, adolescents, and adults. In some countries, methylphenidate is the first option to treat adults with moderate or severe ADHD. However, evidence on the efficacy and adverse events of immediate-release (IR) methylphenidate in the treatment of ADHD in adults is limited and controversial. OBJECTIVES: To evaluate the efficacy and harms (adverse events) of IR methylphenidate for treating ADHD in adults. SEARCH METHODS: In January 2020, we searched CENTRAL, MEDLINE, Embase, eight additional databases and three trial registers. We also searched internal reports on the European Medicines Agency and the US Food and Drug Administration websites. We checked citations of included trials to identify additional trials not captured by the electronic searches. SELECTION CRITERIA: Randomized controlled trials (RCTs) comparing IR methylphenidate, at any dose, with placebo or other pharmacological interventions (including extended-release formulations of methylphenidate) for ADHD in adults. Primary outcomes comprised changes in the symptoms of ADHD (efficacy) and harms. Secondary outcomes included changes in the clinical impression of severity and improvement, level of functioning, depression, anxiety and quality of life. Outcomes could have been rated by investigators or participants. DATA COLLECTION AND ANALYSIS: Two review authors extracted data independently on the characteristics of the trials, participants, interventions; outcomes and financial conflict of interests. We resolved disagreements by discussion or consulting a third review author. We obtained additional, unpublished information from the authors of one included trial that had reported efficacy data in a graph. We calculated mean differences (MDs) or standardized MDs (SMDs) with 95% confidence intervals (CIs) for continuous data reported on the same or different scales, respectively. We summarized dichotomous variables as risk ratios (RRs) with 95% CI. MAIN RESULTS: We included 10 trials published between 2001 and 2016 involving 497 adults with ADHD. Three trials were conducted in Europe and one in Argentina; the remaining trials did not report their location. The RCTs compared IR methylphenidate with placebo, an osmotic-release oral system (OROS) of methylphenidate (an extended-release formulation), an extended-release formulation of bupropion, lithium, and Pycnogenol® (maritime pine bark extract). Participants comprised outpatients, inpatients in addiction treatment, and adults willing to attend an intensive outpatient program for cocaine dependence. The duration of the follow-up ranged from 6 to 18 weeks. IR methylphenidate versus placebo We found very low-certainty evidence that, compared with placebo, IR methylphenidate may reduce symptoms of ADHD when measured with investigator-rated scales (MD -20.70, 95% CI -23.97 to -17.43; 1 trial, 146 participants; end scores; Adult ADHD Investigator Symptom Report Scale (AISRS), scored from 0 to 54), but the evidence is uncertain. The effect of IR methylphenidate on ADHD symptoms when measured with participant-rated scales was moderate, but the certainty of the evidence is very low (SMD -0.59, 95% CI -1.25 to 0.06; I2 = 69%; 2 trials, 138 participants; end scores). There is very low-certainty evidence that, compared with placebo, IR methylphenidate may reduce the clinical impression of the severity of ADHD symptoms (MD -0.57, 95% CI -0.85 to -0.28; 2 trials, 139 participants; I2 = 0%; change and end scores; Clinical Global Impression (CGI)-Severity scale (scored from 1 (very much improved) to 7 (very much worse))). There is low-certainty evidence that, compared with placebo, IR methylphenidate may slightly impact the clinical impression of an improvement in symptoms of ADHD (MD -0.94, 95% CI -1.37 to -0.51; 1 trial, 49 participants; end scores; CGI-Improvement scale (scored from 1 (very much improved) to 7 (very much worse))). There is no clear evidence of an effect on anxiety (MD -0.20, 95% CI -4.84 to 4.44; 1 trial, 19 participants; change scores; Hamilton Anxiety Scale (HAM-A; scored from 0 to 56); very low-certainty evidence) or depression (MD 2.80, 95% CI -0.09 to 5.69; 1 trial, 19 participants; change scores; Hamilton Depression Scale (HAM-D; scored from 0 to 52); very low-certainty evidence) in analyses comparing IR methylphenidate with placebo. IR methylphenidate versus lithium Compared with lithium, it is uncertain whether IR methylphenidate increases or decreases symptoms of ADHD (MD 0.60, 95% CI -3.11 to 4.31; 1 trial, 46 participants; end scores; Conners' Adult ADHD Rating Scale (scored from 0 to 198); very low-certainty evidence); anxiety (MD -0.80, 95% CI -4.49 to 2.89; 1 trial, 46 participants; end scores; HAM-A; very low-certainty evidence); or depression (MD -1.20, 95% CI -3.81 to 1.41, 1 trial, 46 participants; end scores; HAM-D scale; very low-certainty evidence). None of the included trials assessed participant-rated changes in symptoms of ADHD, or clinical impression of severity or improvement in participants treated with IR methylphenidate compared with lithium. Adverse events were poorly assessed and reported. We rated all trials at high risk of bias due to selective outcome reporting of harms and masking of outcome assessors (failure to blind outcome assessor to measure adverse events). Overall, four trials with 203 participants who received IR methylphenidate and 141 participants who received placebo described the occurrence of harms. The use of IR methylphenidate in these trials increased the risk of gastrointestinal complications (RR 1.96, 95% CI 1.13 to 2.95) and loss of appetite (RR 1.77, 95% CI 1.06 to 2.96). Cardiovascular adverse events were reported inconsistently, preventing a comprehensive analysis. One trial comparing IR methylphenidate to lithium reported five and nine adverse events, respectively. We considered four trials to have notable concerns of vested interests influencing the evidence, and authors from two trials omitted information related to the sources of funding and conflicts of interest. AUTHORS' CONCLUSIONS: We found no certain evidence that IR methylphenidate compared with placebo or lithium can reduce symptoms of ADHD in adults (low- and very low-certainty evidence). Adults treated with IR methylphenidate are at increased risk of gastrointestinal and metabolic-related harms compared with placebo. Clinicians should consider whether it is appropriate to prescribe IR methylphenidate, given its limited efficacy and increased risk of harms. Future RCTs should explore the long-term efficacy and risks of IR methylphenidate, and the influence of conflicts of interest on reported effects.

Lithium Augmentation Versus Citalopram Combination in Imipramine-Resistant Major Depression: A 10-Week Randomized Open-Label Study.

PURPOSE/BACKGROUND: According to available international clinical guides, tricyclic antidepressants are our first- or second-line treatment of choice for severe unipolar major depression. However, the therapeutic option after an unsuccessful response to a tricyclic antidepressant drug in unipolar major depression is still unclear. METHODS/PROCEDURES: This 10-week randomized open-label study assessed the effectiveness of add-on lithium (adjusted to plasma levels) compared with add-on citalopram (30 mg/d) in 104 severe unipolar major depressive patients after a 10-week unsuccessful imipramine (adjusted to plasma level). Efficacy analyses examined changes in the severity of depression symptoms from baseline visit to endpoint and the comparative remission rate between treatment subgroups. FINDINGS/RESULTS: The randomized sample consisted of 104 imipramine-resistant severe unipolar major depressed patients. Both, the percentage of remitters (40.4% vs 21.1%, P = 0.034) and the mean reduction of the Hamilton Depression Rating Scale score (58.8% vs 42.5%, P = 0.005) were significantly greater in the add-on citalopram subgroup at endpoint visit. IMPLICATIONS/CONCLUSIONS: Although we should be cautious about generalizing these results to patients with a less severe unipolar major episode, results from the present study suggest that add-on citalopram is a very effective treatment option in unipolar major depressive episodes after an unsuccessful imipramine regimen.

Longitudinally Measured Changes in Somnolence Severity With a Visual Analog Scale in a Randomized Lithium Versus Quetiapine-IR Study in Bipolar Disorder.

OBJECTIVE: The aim of this study was to use a visual analog scale (VAS) longitudinally measuring somnolence severity in patients with bipolar disorder. METHODS: A data set of patients with bipolar spectrum disorders who were randomized to lithium or quetiapine-IR for 16 weeks was used. The somnolence severity was measured with a VAS from 0 to 100 (VAS based), and somnolence frequency was recorded according to incident report (incidence based) at each visit. The rates of VAS-based and incidence-based somnolence and changes in somnolence severity from baseline to the end of study were compared between the lithium and quetiapine groups. Longitudinal changes in somnolence severity were analyzed with linear regression analysis. RESULTS: Of 42 patients randomized, only 3 scored 0 on the VAS at baseline. The rates of incidence-based and VAS-based somnolence were similar in the lithium and quetiapine-IR groups. The VAS change scores from baseline to each visit varied in both groups with significant decreases at weeks 6 and 12 in the quetiapine-IR group only. The decrease at week 6 in the quetiapine-IR group was significantly different from that in the lithium group. Patterns of changes in somnolence severity were inconsistent in both groups. A significant interaction between time course and the decrease in VAS scores was observed in the quetiapine-IR group, but not in the lithium group. CONCLUSIONS: Baseline somnolence was highly prevalent in patients with bipolar disorder. The change in somnolence severity was different between lithium-treated and quetiapine-treated patients. Quantifying somnolence longitudinally is important in clinical trials and practice.

What is the optimal serum level for lithium in the maintenance treatment of bipolar disorder? A systematic review and recommendations from the ISBD/IGSLI Task Force on treatment with lithium.

AIMS: To systematically review the existing trials on optimal serum levels for lithium for maintenance treatment of bipolar disorder and to develop clinical recommendations. METHODS: Systematic literature search. Discussion of major characteristics, limitations, methodological quality, and results of selected trials. Delphi survey consisting of clinical questions and corresponding statements. For statements endorsed by at least 80% of the members, consensus was considered as having been achieved. RESULTS: With strict inclusion criteria no studies could be selected, making it difficult to formulate evidence-based recommendations. After loosening the inclusion criteria 7 trials were selected addressing our aims at least to some extent. Four of these studies suggest better efficacy being associated with lithium serum levels in a range above a lower threshold around 0.45/0.60 and up to 0.80/1.00 mmol/L. These findings support the outcome of the Delphi survey. CONCLUSIONS: For adults with bipolar disorder there was consensus that the standard lithium serum level should be 0.60-0.80 mmol/L with the option to reduce it to 0.40-0.60 mmol/L in case of good response but poor tolerance or to increase it to 0.80-1.00 mmol/L in case of insufficient response and good tolerance. For children and adolescents there was no consensus, but the majority of the members endorsed the same recommendation. For the elderly there was also no consensus, but the majority of the members endorsed a more conservative approach: usually 0.40-0.60 mmol/L, with the option to go to maximally 0.70 or 0.80 mmol/L at ages 65-79 years, and to maximally 0.70 mmol/L over age 80 years.

Predictive modeling for response to lithium and quetiapine in bipolar disorder.

OBJECTIVES: Lithium and quetiapine are known to be effective treatments for bipolar disorder. However, little information is available to inform prediction of response to these medications. Machine-learning methods can identify predictors of response by examining variables simultaneously. Further evaluation of models on a test sample can estimate how well these models would generalize to other samples. METHODS: Data (N = 482) were drawn from a randomized clinical trial of outpatients with bipolar I or II disorder who received adjunctive personalized treatment plus either lithium or quetiapine. Elastic net regularization (ENR) was used to generate models for lithium and quetiapine; these models were evaluated on a test set. RESULTS: Predictions from the lithium model explained 17.4% of the variance in actual observed scores of patients who received lithium in the test set, while predictions from the quetiapine model explained 32.1% of the variance of patients that received quetiapine. Of the baseline variables selected, those with the largest parameter estimates were: severity of mania; attention-deficit/hyperactivity disorder (ADHD) comorbidity; nonsuicidal self-injurious behavior; employment; and comorbidity with each of two anxiety disorders (social phobia/society anxiety and agoraphobia). Predictive accuracy of the ENR model outperformed the simple and basic theoretical models. CONCLUSION: ENR is an effective approach for building optimal and generalizable models. Variables identified through this methodology can inform future research on predictors of response to lithium and quetiapine, as well as future modeling efforts of treatment choice in bipolar disorder.

No Connection between Long-Term Lithium Treatment and Antithyroid Antibodies.

INTRODUCTION: The studies on the effect of lithium treatment on antithyroid antibodies showed either a higher concentration of these antibodies in patients receiving lithium compared to those lithium-naive or no difference between these groups. In lithium-treated bipolar patients, some researchers pointed to an association between antithyroid antibodies and other features of thyroid dysfunction such as hypothyroidism and decrease of glomerular filtration rate. METHODS: We compared antithyroid antibodies in 98 patients (30 male, 68 female) with bipolar disorder, aged 62±13 years, who received lithium for 19±10 years to 39 patients (12 male, 27 female), aged 57±10 years, who were never treated with lithium. The antibodies against thyroid peroxidase (TPOAb), against thyroglobulin (TGAb), and thyroid-stimulating hormone (TSH) receptors (TSHRAb) were estimated. RESULTS: No difference in the percentages of antibodies occurrence was found between groups, although the concentrations of TGAb were higher in patients receiving lithium. In lithium-treated patients, the presence of TPOAb was associated with lower concentrations of free triiodothyronine and the presence of TGAb, with higher concentrations of TSH. In females, the levels of TGAb were associated with lower thyroid volume. The concentrations of TPOAb correlated positively with the duration of lithium therapy in males, and those of TPOAb and TGAb negatively, with such duration, in female patients. CONCLUSION: The results obtained showed no significant connection between long-term lithium treatment and antithyroid antibodies. In bipolar patients receiving lithium longitudinally, antithyroid antibodies can be associated with some indexes of thyroid function. However, they behave differently in male and female patients.

A case of skew deviation and downbeat Nystagmus induced by Lithium.

BACKGROUND: Lithium salts have been commonly used for prophylaxis and treatment of bipolar disorder and have numerous side effects. However, there has been no report of skew deviation and downbeat nystagmus associated with lithium. Herein, we report the first case of lithium-induced skew deviation and downbeat nystagmus. CASE PRESENTATION: A 39 years-old woman presented with intermittent vertical diplopia and dizziness within 1-2 months. Ophthalmologic examination revealed downbeat nystagmus and 6 prism diopters of right hypertropia. Funduscopic examination showed mild incyclotorsion on right eye. However, ductions and versions were within normal range. Other neurological examinations were also normal. She had a history of bipolar disorder treated with daily 600-900 mg of lithium for past 6 years, and 2 months before the first visit, daily dose of lithium was increased to 1200 mg. We referred the patients to psychiatrist. Although the serum level of lithium was within the normal therapeutic range, her daily dose of lithium was reduced to 600 mg and then stopped. 6 days after cessation of lithium, down beat nystagmus and right hypertropia were completely resolved and symptoms did not recur over a year. CONCLUSION: Even within a normal therapeutic range, downbeat nystagmus and skew deviation can occur as side effect of lithium. Dehydration may contribute to the neurotoxicity of lithium.

Therapeutic drug monitoring (TDM) during maintenance phase treatment at a community mental health centre.

OBJECTIVE: To assess the extent to which therapeutic drug monitoring during maintenance phase treatment with lithium and clozapine was performed according to an agreed protocol and to identify strategies that may support monitoring. METHODS: Data concerning the prescribing and monitoring patterns of lithium for 31 patients and clozapine for 53 patients were collected retrospectively over a period of 2 years. RESULTS: Adherence to clozapine monitoring throughout the study period was 90.5%, while the monitoring of lithium was less likely at 58.1% (P < 0.001). While those prescribed lithium were less likely to adhere to prescribed dosing than those prescribed clozapine (P < 0.007), they were also more likely to have a change of medication (P < 0.005) and require admission to inpatient care (P < 0.002). CONCLUSIONS: Despite the initiatives established to improve adherence to monitoring, there was a significantly lower level of lithium monitoring compared to that of clozapine. Strategies that are likely to support monitoring include the use of labels to clarify tests required, the use of a database to keep track of those requiring pathology tests and allocation of time each week for a nurse to work with medical staff and case managers to support monitoring.

Lithium + Colchicine: A Potential Strategy to Reduce Pro-inflammatory Effects of Lithium Treatment.

PURPOSE: Rosenblat and McIntyre (Acta Psychiatr Scand. 2015;132: 180-191) propose that immune disorders are important mediators between bipolar disorders and medical comorbidities. Rosenblat et al (Bipolar Disord. 2016;18:89-101) present a meta-analysis showing that adjunctive anti-inflammatory agents could evoke moderate antidepressant responses in bipolar disorders. We propose using the anti-inflammatory drug colchicine to improve the long-term safety and efficacy of lithium treatment for bipolar disorders. METHODS: This report is based on searches of the PubMed and Web of Science databases. RESULTS: Bipolar disorders are associated with significant medical comorbidities such as hypertension, overweight/obesity, diabetes mellitus, metabolic syndrome, and arteriosclerosis, accompanied by enhanced release of pro-inflammatory markers during changes in mood state. During lithium therapy, granulocyte-colony stimulating factor, CD34+ hematopoietic stem/progenitor cells, and neutrophil elastase enter the circulation with activated neutrophils to promote the extravascular migration of activated neutrophils and enhance tissue inflammation. Concurrent treatment with lithium and low-dose colchicine could facilitate the responsiveness of bipolar patients to lithium by reducing leukocyte tissue emigration, the release of neutrophil elastase, and the release of leukocyte pro-inflammatory cytokines such as IL-1ß that are regulated by the NLRP3 inflammasome assembly complex. CONCLUSIONS: Concurrent therapy with lithium and low-dose colchicine could reduce complications involving leukocyte-mediated inflammatory states in bipolar patients and promote patient acceptance and responsiveness to lithium therapy.

Evaluation of clarity of presentation and applicability of monitoring instructions for patients using lithium in clinical practice guidelines for treatment of bipolar disorder.

OBJECTIVES: Clinical practice guidelines (CPGs) for treatment of bipolar disorder (BD) aim to provide guidance to health care professionals on monitoring of patients using lithium. The aim was to assess the clarity of presentation and applicability of monitoring instructions for patients using lithium in CPGs for treatment of BD. METHODS: CPGs for treatment of BD were selected from acknowledged professional organizations from multiple continents. CPGs were rated on the clarity of presentation and applicability of lithium monitoring instructions using the Appraisal of Guidelines Research and Evaluation (AGREE) II tool. The applicability of monitoring instructions was assessed according to the Systematic Information for Monitoring (SIM) score. Monitoring instructions were considered applicable when a SIM score of ≥3 was found. RESULTS: The clarity of presentation for six out of the nine CPGs was good (>70%) using the AGREE II tool. Only one CPG scored >70% on applicability. Descriptions of the resource implications and facilitators of and barriers to monitoring were most often missing. All CPGs contained instructions for monitoring of lithium serum levels and renal and thyroid function. Information provided in monitoring instructions (n = 247) was in general applicable to clinical practice (77%) based on the SIM score. Overall, a median SIM score of 3 (interquartile range 3-4) was found. CONCLUSIONS: Improvement of the applicability of CPGs is recommended, and can be achieved by describing the resource implications and facilitators of and barriers to monitoring. In addition, information on critical values and instructions on how to respond to aberrant monitoring parameters are needed. With such improvements, CPGs may better aid health care professionals to monitor patients using lithium.

Trace lithium and mental health.

Lithium therapy is generally accepted as a first-line treatment for bipolar disorder, and it is also identified as one of the best augmenting options for treatment-resistant depression. Furthermore, lithium has been investigated in association with suicide, dementia and aggressiveness. In this review, we examined articles about the effects of very small amounts of lithium in treating suicide, dementia, bipolar disorder and temperament, to assess the present state of trace lithium's effect on mental state. The results indicate that trace lithium may be effective for suicide prevention but randomized, placebo-controlled trials are required to draw a definite conclusion. Indications for using trace lithium in treating such conditions as dementia, bipolar disorder and temperament are supported by very limited evidence and such effects are yet to be determined.

Lithium dosing strategies during pregnancy and the postpartum period.

BackgroundLithium is challenging to dose during pregnancy.AimsTo provide guidance for dosing lithium during pregnancy.MethodRetrospective observational cohort study. Data on lithium blood level measurements (n = 1101), the daily lithium dose, dosing alterations/frequency and creatinine blood levels were obtained from 113 pregnancies of women receiving lithium treatment during pregnancy and the postpartum period.ResultsLithium blood levels decreased in the first trimester (-24%, 95% CI -15 to -35), reached a nadir in the second trimester (-36%, 95% CI -27 to -47), increased in the third trimester (-21%, 95% CI -13 to -30) and were still slightly increased postpartum (+9%, 95% CI +2 to +15). Delivery itself was not associated with an acute change in lithium and creatinine blood levels.ConclusionsWe recommend close monitoring of lithium blood levels until 34 weeks of pregnancy, then weekly until delivery and twice weekly for the first 2 weeks postpartum. We suggest creatinine blood levels are measured to monitor renal clearance.

Comparison of the Effects of Quetiapine XR and Lithium Monotherapy on Actigraphy-Measured Circadian Parameters in Patients With Bipolar II Depression.

PURPOSE/BACKGROUND: The aim of this study was to evaluate the effects of quetiapine XR and lithium on actigraphy-measured circadian parameters in patients with bipolar II depression. METHODS/PROCEDURES: This was an 8-week, open-label, prospective, randomized comparative study. The assessments included the 17-item Hamilton Depression Rating Scale score and actigraphic measures concerning the previous 7 days, collected at each visit (weeks 0 [baseline], 1, 2, 4, 6, and 8); the actigraphic data were analyzed with a cosinor analysis. FINDINGS/RESULTS: Medication, time, and the interaction between medication and time were significantly associated with acrophase for the entire group (Ps = 0.003, 0.020, and 0.042, respectively). More specifically, acrophase was significantly delayed at weeks 1 and 6 (Ps = 0.004 and 0.039, respectively) in the quetiapine XR group. The F statistics significantly increased over time for the entire group (P < 0.001), and there was a significant increase in F statistics on weeks 4 and 6 in the quetiapine XR group (Ps = 0.016 and 0.020, respectively) and on weeks 4 and 8 in the lithium group (Ps = 0.001 and 0.016, respectively). In addition, scores on the 17-item Hamilton Depression Rating Scale were significantly associated with the F statistics during 8 weeks for the entire group (P = 0.008). IMPLICATIONS/CONCLUSIONS: Both quetiapine XR and lithium affected several circadian parameters, including peak activity time and robustness of circadian rhythm, but exerted different effects on acrophase in patients with bipolar II depression. In particular, clinical depressive symptoms were associated with robustness of circadian rhythm during the course of the 8-week treatment.