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.

Determination of lithium in human serum by isotope dilution atomic absorption spectrometry.

The therapeutic dose of lithium (Li) compounds, which are widely used for the treatment of psychiatric and hematologic disorders, is close to its toxic level; therefore, drug monitoring protocols are mandatory. Herein, we propose a fast, simple, and low-cost analytical procedure for the traceable determination of Li concentration in human serum, based on the monitoring of the Li isotope dilution through the partially resolved isotope shift in its electronic transition around 670.80 nm using a commercially available high-resolution continuum source graphite furnace atomic absorption spectrometer. With this technique, serum samples only require acidic digestion before analysis. The procedure requires three measurements-an enriched 6Li spike, a mixture of a certified standard solution and spike, and a mixture of the sample and spike with a nominal 7Li/6Li ratio of 0.82. Lanthanum has been used as an internal spectral standard for wavelength correction. The spectra are described as the linear superposition of the contributions of the respective isotopes, each consisting of a spin-orbit doublet, which can be expressed as Gaussian components with constant spectral position and width and different relative intensity, reflecting the isotope ratio in the sample. Both the spectral constants and the correlation between isotope ratio and relative band intensity have been experimentally obtained using commercially available materials enriched with Li isotopes. The Li characteristic mass (mc) obtained corresponds to 0.6 pg. The procedure has been validated using five human serum certified reference materials. The results are metrologically comparable and compatible to the certified values. The measurement uncertainties are comparable to those obtained by the more complex and expensive technique, isotope dilution mass spectrometry.

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.

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.

Compliance with the guidelines for laboratory monitoring of patients treated with lithium: A retrospective follow-up study among ambulatory patients in the Netherlands.

OBJECTIVES: Laboratory monitoring of patients using lithium is important to prevent harm and to increase effectiveness. The aim of this study is to determine compliance with the guidelines for laboratory monitoring of patients treated with lithium overall and within subgroups. METHODS: Patients having at least one lithium dispensing for 6 months or longer between January 2010 and December 2015 were identified retrospectively using data from the Dutch PHARMO Database Network. Laboratory monitoring was defined as being compliant with the Dutch Multidisciplinary Clinical Guideline Bipolar Disorders when lithium serum levels, creatinine and thyroid-stimulating hormone (TSH) had been measured at least every 6 months during lithium use. RESULTS: Data were analyzed from 1583 patients with a median duration of 7- to 6-months period of lithium use. Results indicated that patients had been monitored over 6-month period for lithium serum levels 65% of the time, for creatinine 73% of the time and for TSH 54% of the time. Just over one seventh (16%) of patients had been monitored in compliance with the guidelines for all three parameters during total follow-up. Especially males, patients aged below 65 years, patients receiving prescriptions solely from general practitioners, prevalent users of lithium, patients without interacting co-medication, and patients without other days with laboratory measurements had been monitored less frequently in compliance with the guidelines. CONCLUSIONS: A considerable proportion of patients had not been monitored in accordance with the guidelines. Further research is needed to understand the reasons for noncompliance and to implement strategies with the ultimate goal of optimizing safety and effectiveness for patients treated with lithium.

Differential Expression of Synapsin I and II upon Treatment by Lithium and Valproic Acid in Various Brain Regions.

Introduction: Due to the heterogeneity of psychiatric illnesses and overlapping mechanisms, patients with psychosis are differentially responsive to pharmaceutical drugs. In addition to having therapeutic effects for schizophrenia and bipolar disorder, antipsychotics and mood stabilizers have many clinical applications and are used unconventionally due to their direct and indirect effects on neurotransmitters. Synapsins, a family of neuronal phosphoproteins, play a key regulatory role in neurotransmitter release at synapses. In this study, we investigated the effects of mood stabilizers, lithium, and valproic acid on synapsin gene expression in the rat brain. Methods: Intraperitoneal injections of saline, lithium, and valproic acid were administered to male Sprague Dawley rats twice daily for 14 d, corresponding to their treatment group. Following decapitation and brain tissue isolation, mRNA was extracted from various brain regions including the hippocampus, striatum, prefrontal cortex, and frontal cortex. Results: Biochemical analysis revealed that lithium significantly increased gene expression of synapsin I in the striatum, synapsin IIa in the hippocampus and prefrontal cortex, and synapsin IIb in the hippocampus and striatum. Valproic acid significantly increased synapsin IIa in the hippocampus and prefrontal cortex, as well as synapsin IIb in the hippocampus and striatum. Conclusion: These significant changes in synapsin I and II expression may implicate a common transcription factor, early growth response 1, in its mechanistic pathway. Overall, these results elucidate mechanisms through which lithium and valproic acid act on downstream targets compared with antipsychotics and provide deeper insight on the involvement of synaptic proteins in treating neuropsychiatric illnesses.

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.

Increased Brain Lactate During Depressive Episodes and Reversal Effects by Lithium Monotherapy in Drug-Naive Bipolar Disorder: A 3-T 1H-MRS Study.

OBJECTIVE: Mitochondrial dysfunction and energy metabolism impairment are key components in the pathophysiology of bipolar disorder (BD) and may involve a shift from aerobic to anaerobic metabolism. Measurement of brain lactate in vivo using proton magnetic resonance spectroscopy (H-MRS) represents an important tool to evaluate mitochondrial and metabolic dysfunction during mood episodes, as well as to monitor treatment response. To date, very few studies have quantified brain lactate in BD. In addition, no study has longitudinally evaluated lactate using H-MRS during depressive episodes or its association with mood stabilizer therapy. This study aimed to evaluate cingulate cortex (CC) lactate using 3-T H-MRS during acute depressive episodes in BD and the possible effects induced by lithium monotherapy. METHODS: Twenty medication-free outpatients with short length of BD (80% drug-naive) in a current major depressive episode were matched with control subjects. Patients were treated for 6 weeks with lithium monotherapy at therapeutic doses in an open-label trial (blood level, 0.48 ± 0.19 mmol/L). Cingulate cortex lactate was measured before (week 0) and after lithium therapy (week 6) using H-MRS. Antidepressant efficacy was assessed with the 21-item Hamilton Depression Rating Scale as the primary outcome. RESULTS: Subjects with BD depression showed a significantly higher CC lactate in comparison to control subjects. Furthermore, a significant decrease in CC lactate was observed after 6 weeks of lithium treatment compared with baseline (P = 0.002). CC Lactate levels was associated with family history of mood disorders and plasma lithium levels. CONCLUSIONS: This is the first report of increased CC lactate in patients with bipolar depression and lower levels after lithium monotherapy for 6 weeks. These findings indicate a shift to anaerobic metabolism and a role for lactate as a state marker during mood episodes. Energy and redox dysfunction may represent key targets for lithium's therapeutic actions.

A case of lithium-induced parkinsonism presenting with typical motor symptoms of Parkinson's disease in a bipolar patient.

Lithium is a mood stabilizer rarely associated with drug-induced parkinsonism (DIP). We present a case of an elderly woman with bipolar disorder who developed parkinsonian symptoms after chronic lithium administration despite therapeutic serum levels. Upon evaluation, classic parkinsonian signs of muscle rigidity, tremor, bradykinesia, freezing of gait, and cognitive decline were observed. Initially, she was diagnosed with Parkinson's disease (PD); however, DaTscan SPECT imaging clarified the diagnosis as DIP. As the daily lithium dosage was reduced, the patient's motor symptoms improved. This report emphasizes close monitoring of lithium levels in geriatric populations and the need to consider lithium-induced parkinsonism when PD symptoms appear in chronic lithium users.

Bimodal effect of lithium plasma levels on hippocampal glutamate concentrations in bipolar II depression: a pilot study.

BACKGROUND: The hippocampus has been highly implicated in the pathophysiology of bipolar disorder (BD). Nevertheless, no study has longitudinally evaluated hippocampal metabolite levels in bipolar depression under treatment with lithium. METHODS: Nineteen medication-free BD patients (78.9% treatment-naïve and 73.7% with BD type II) presenting an acute depressive episode and 17 healthy controls were studied. Patients were treated for 6 weeks with lithium in an open-label trial. N-acetyl aspartate (NAA), creatine, choline, myo-Inositol, and glutamate levels were assessed in the left hippocampus before (week 0) and after (week 6) lithium treatment using 3T proton magnetic resonance spectroscopy (1H-MRS). The metabolite concentrations were estimated using internal water as reference and voxel segmentation for partial volume correction. RESULTS: At baseline, acutely depressed BD patients and healthy controls exhibited similar hippocampal metabolites concentrations, with no changes after 6 weeks of lithium monotherapy. A significant correlation between antidepressant efficacy and increases in NAA concentration over time was observed. Also, there was a significant positive correlation between the changes in glutamate concentrations over follow-up and plasma lithium levels at endpoint. Mixed effects model analysis revealed a bimodal effect of lithium plasma levels in hippocampal glutamate concentrations: levels of 0.2 to 0.49 mmol/L (n=9) were associated with a decrease in glutamate concentrations, whereas the subgroup of BD subjects with "standard" lithium levels (≥ 0.50 mmol/L; n = 10) showed an overall increase in glutamate concentrations over time. CONCLUSIONS: These preliminary results suggest that lithium has a bimodal action in hippocampal glutamate concentration depending on the plasma levels.

Lithium tremor revisited: pathophysiology and treatment.

OBJECTIVE: Tremor occurs frequently as a side-effect of lithium, and it is, however, easily overlooked in the clinical setting. In this article, we attempt to review the pathophysiology and the clinical approach of lithium tremor. METHOD: We searched the Pubmed and Cochrane Library for relevant articles up to the year 2012. Sixty-four articles including 10 review papers, 3 clinical trials, and 12 case reports were reviewed. RESULTS: Lithium tremor is classified as a postural tremor and subcategorized as an exaggerated physiologic tremor. Differential diagnosis includes metabolic abnormalities, benign essential tremor, Parkinson's disease, and lithium toxicity. Various methods of evaluating lithium tremor and treatment options are discussed. CONCLUSION: When lithium tremor has developed, thorough history taking, physical examination, and blood examination including serum lithium level are needed. Pharmacotherapy is indicated only in patients with disabling tremor.

Medication adherence in a comparative effectiveness trial for bipolar disorder.

OBJECTIVE: Psychopharmacology remains the foundation of treatment for bipolar disorder, but medication adherence in this population is low (range 20-64%). We examined medication adherence in a multisite, comparative effectiveness study of lithium. METHOD: The Lithium Moderate Dose Use Study (LiTMUS) was a 6-month, six-site, randomized effectiveness trial of adjunctive moderate dose lithium therapy compared with optimized treatment in adult out-patients with bipolar I or II disorder (N=283). Medication adherence was measured at each study visit with the Tablet Routine Questionnaire. RESULTS: We found that 4.50% of participants reported missing at least 30% of their medications in the past week at baseline and non-adherence remained low throughout the trial (<7%). Poor medication adherence was associated with more manic symptoms and side-effects as well as lower lithium serum levels at mid- and post-treatment, but not with poor quality of life, overall severity of illness, or depressive symptoms. CONCLUSION: Participants in LiTMUS were highly adherent with taking their medications. The lack of association with possible predictors of adherence, such as depression and quality of life, could be explained by the limited variance or other factors as well as by not using an objective measure of adherence.

The toxic trio: valproic acid, lithium, and carbamazepine.

Patients with altered mental status and seizure or psychiatric disease often present with an unclear medication history. Commonly prescribed medications include valproic acid (VPA), lithium (Li), or carbamazepine (CZN) of which the regional poison center (RPC) often recommends obtaining these serum concentrations. Regularly ruling out supratherapeutic concentrations without a known history of ingestion may help direct care. Cases from the RPC coded as VPA, Li, and CZN, from January 1, 2006 to December 31, 2008, were searched. All patients with supratherapeutic concentrations (VPA >100 µg/mL, Li >1.2 mEq/L, and CZN >12 µg/mL) were evaluated for the following criteria: (1) those with altered mental status and an unclear history of seizure or psychiatric disorder and (2) a mediation profile not including VPA, Li, or CZN. Twenty-six patients met the inclusion criteria: 8 patients in the VPA group (113-247 µg/mL; mean, 158), 9 patients in the Li group (1.9-5.2 mEq/L; mean, 2.9), and 9 patients in the CZN group (13.4-38.8 µg/mL; mean, 23.2). All patients survived and were treated with supportive care; however, 1 patient had a Li level of 5.2 mEq/L and received hemodialysis. In altered patients potentially being treated for seizure or psychiatric disorders and unknown ingestions or medication lists, obtaining concentrations of VPA, Li, and CZN may help direct care and provide clinically relevant information. The RPC detected 26 patients with supratherapeutic VPA, Li, or CZN concentrations in patients with potential indications for the agent but no available history of drug ingested or medication list. A prospective study is warranted to evaluate the usefulness of obtaining these concentrations in this patient population.

Is environmental temperature related to renal symptoms, serum lithium levels, and other laboratory test results in current lithium users?

OBJECTIVE: Lithium continues to be an important mood disorder treatment. Although patients exposed to higher environmental temperatures may have serum lithium level elevations due to dehydration, there is conflicting data in the literature. In addition, no study has assessed the association between temperature and other renal laboratory tests and symptoms in lithium users. METHODS: This is a cross-sectional analysis of 63 current lithium users who participated in the McGill Geriatric Lithium-induced Diabetes Insipidus Clinical Study. The relationship between mean daily temperature with diabetes insipidus symptoms, glomerular filtration rate, urine osmolality, serum sodium, lithium level, and lithium dose-level ratio was assessed. RESULTS: Although a higher temperature on the day of laboratory testing trended toward being independently associated with a lower lithium dose-level ratio (Beta = -0.17, p = 0.08), this was not found when using a dichotomous measure of temperature (T > 20°C). No association was observed between temperature and other renal parameters. CONCLUSIONS: The association of temperature with lithium levels, renal symptoms, and laboratory tests appears to be of relatively little clinical importance in lithium users in temperate climates. However, future research should re-examine patients living in climates with extreme temperatures (e.g., >40°C), who may theoretically be at higher risk.

Microarray analysis of global gene expression in leukocytes following lithium treatment.

OBJECTIVES: To elucidate the molecular effects of lithium, we studied global gene expression changes induced by lithium in leukocytes from healthy subjects. METHODS: Eight healthy male subjects participated in this study. Lithium was prescribed for weeks to reach a therapeutic serum concentration. Leukocyte counts and serum lithium concentrations were determined at baseline (before medication), after 1 and 2 weeks of medication and at 2 weeks after stopping medication. Gene expression profiling was performed at each time point using Agilent G4112F Whole Human Genome arrays (The Agilent Technologies, Santa Clara, CA, USA). Expression of some candidate genes was also assessed by real-time polymerase chain reaction (PCR). RESULTS: Gene ontology analysis revealed that the cellular and immune responses to stimulus and stress indeed played a major role in the cellular response to lithium treatment. Pathway analysis revealed that the interleukin 6 pathway, the inhibitor of differentiation pathway, and the methane metabolism pathway were regulated by lithium. Using real-time PCR, we also confirmed that five candidate genes in these pathways were significantly changed, including suppressor of cytokine signaling 3 and myeloperoxidase. CONCLUSIONS: Our investigation suggests that the molecular action of lithium is mediated in part by its effects on the cellular and immune response to stimulus and stress followed by the interleukin 6, inhibitor of differentiation, and methane metabolism pathways.

Reformulation of current recommendations for target serum lithium concentration according to clinical indication, age and physical comorbidity.

BACKGROUND: There have been significant changes in the nature of psychiatric patient populations and patterns of drug prescribing in mood disorders since serum lithium monitoring was introduced. It seems opportune to review current guidelines for target lithium concentration given the decline in lithium monotherapy and increase in the numbers of older people and those with comorbid physical disease administered lithium. METHOD: A review was made of the literature of lithium monitoring and target serum concentration in mood disorders, older people, and comorbid physical illness. RESULTS: Current guidelines, which generally recommend a target serum concentration of 0.5/0.6 to 1.1/1.2 mmol/L, have a number of limitations. A target lithium level of > 0.8 mmol/L is inappropriate given poor tolerability, and adequate efficacy when combination lithium-antipsychotic therapy is used at this or lower levels. Guidelines have largely failed to match specific clinical indications to serum levels, and to consider comorbid physical illness factors known to be associated with lithium toxicity. CONCLUSION: For most patients, a target serum lithium concentration range of 0.5-0.8 mmol/L, varying according to clinical indication, age and concurrent physical status, seems most appropriate in enhancing efficacy and minimizing adverse effects. The lower end of this range (0.5-0.6 mmol/L) is recommended for patients 50 years and over; those with diabetes insipidus, renal impairment or thyroid dysfunction; those administered diuretics, angiotensin converting enzyme (ACE) inhibitors or non-steroidal anti-inflammatory drugs (NSAIDs)/COX-2 inhibitors; and in the prophylaxis of bipolar depression and management of acute unipolar depression. The higher end of this range (0.7-0.8 mmol/L) is recommended in the management of acute mania and prophylaxis of mania.

Acute lithium intoxication: properly directing an index of suspicion.

Lithium is known for its efficacy and toxicity. Toxic effects have been characterized even with therapeutic levels. Most physicians will at some point be faced with a patient with altered mental status and no records of his or her history. The differential diagnosis of altered mental status is long, and further lengthens in a patient with a psychiatric history. Since several life-threatening complications of psychotropic medications exist, physicians must be astute with their diagnoses. Lithium toxicity, neuroleptic malignant syndrome, and the serotonin syndrome can present similarly and require rapid recognition. We present a case of lithium toxicity in a patient who presented with altered mental status and a paucity of history information.

Application of Lithium Assay kit LS for quantification of lithium in whole blood and urine.

A commercially available kit for the quantitation of lithium, the Lithium Assay kit LS, was originally developed to measure lithium in serum or plasma using a conventional microplate reader. We investigated whether use of the kit could be extended to quantify lithium in whole blood and urine samples collected at autopsy. The calibration curve for whole blood showed good linearity ranging from 0.5 to 20 µg/mL with a coefficient of determination of 0.998 when samples were pretreated with methanol followed by acetonitrile. Moreover, for urine, we obtained excellent linearity with a coefficient of determination of 0.999 without any pretreatment. The accuracies and precisions were 106.3-174.7% and 1.9-18.1% for whole blood and 83.3-118.8% and 5.7-33.8% for urine. The values in the lower concentration range (0.5-1 µg/mL) were not satisfactory, whereas those in the higher range (2-20 µg/mL) were acceptable. The Lithium Assay kit LS was successfully applied to the measurement of lithium in whole blood and urine samples collected at autopsies. This method appears to be useful for forensic toxicological investigations because of its simplicity and speed.