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Introduction: Radioactive iodine (RAI) therapy is a critical component in the post-surgical management of thyroid cancer patients, as well as being a central therapeutic option in the treatment of hyperthyroidism. Previous work suggests that antithyroid drugs hinder the efficacy of RAI therapy in patients. However, the effects of other background medications on RAI treatment efficacy have not been evaluated. Therefore, we performed a systematic review and meta-analysis investigating the potential off-target effects of medication on RAI therapy in patients with thyroid cancer and hyperthyroidism. Methods: Systematic review and meta-analysis according to the 2020 PRISMA guidelines. Databases searched: MEDLINE, EMBASE and Cochrane Library for studies published between 2001 and 2021. Results: Sixty-nine unique studies were identified. After screening, 17 studies with 3313 participants were included. One study investigated thyroid cancer, with the rest targeted to hyperthyroidism. The majority of studies evaluated the effects of antithyroid drugs; the other drugs studied included lithium, prednisone and glycididazole sodium. Antithyroid drugs were associated with negative impacts on post-RAI outcomes (n = 5 studies, RR = 0.81, p = 0.02). However, meta-analysis found moderate heterogeneity between studies (I2 = 51%, t2 = 0.0199, p = 0.08). Interestingly, lithium (n = 3 studies), prednisone (n = 1 study) and glycididazole (n = 1 study) appeared to have positive impacts on post-RAI outcomes upon qualitative analysis. Conclusion: Our systematic review strengthens previous work on antithyroid medication effects on RAI, and highlights that this field remains under researched especially for background medications unrelated to thyroid disease, with very few papers on non-thyroid medications published. [ABSTRACT FROM AUTHOR]

Bipolar disorder is associated with a long range of medical comorbidities, including migraine, diabetes, and cardiovascular disease. Bipolar disorder has also been associated with an increased risk of bone fractures. Osteoporosis is a reduction in bone mineral density, which leads to an increased risk for fragility fractures. Currently there is limited research on the association between bipolar disorder and osteoporosis. We aimed to study the association between high and low bone mineral density in relation to disease and treatment history in a sample of bipolar patients. We found that bipolar patients with high bone mineral density were more often on lithium medication, had a more active lifestyle and expressed lower current disease burden. Low mineral density was not associated with any of the addressed aspects of disease and treatment history. In conclusion our results support that patients on lithium treatment have higher bone mineral density; further studies are needed to address if lithium medication causes an increase in bone mineral density, and lowers the risk of bone fractures in bipolar disorder. [ABSTRACT FROM AUTHOR]

Background: Lithium is a first-line pharmacotherapy for the treatment of bipolar disorder, but long-term use is associated with nephrotoxicity. However, as dialysis effectively eliminates lithium, it remains a pharmacotherapeutic option for patients on dialysis. This systematic review seeks to evaluate the dosing, safety, efficacy, and monitoring of lithium in patients receiving dialysis. Method: A PubMed database search performed May 5th, 2020, identified 535 article titles. After exclusion criteria were applied, a total of 15 articles were included in this systematic review. Results: In 18 patients receiving dialysis, lithium was primarily used for the treatment of mood disorders. The majority of patients received 300–900 mg lithium carbonate thrice-weekly following dialysis, but several alternative lithium salts and dosing strategies were utilized. The pharmacokinetic properties of lithium in dialysis are not well understood and can be complicated by a serum lithium "rebound effect" following dialysis, due to a two-compartment volume of distribution. Additionally, presence of residual diuresis in some patients may be reason to administer lithium more frequently than thrice-weekly following dialysis. Lithium was shown to be an effective pharmacotherapy in all patients, with many demonstrating rapid improvement after drug initiation. Five patients experienced an adverse event on lithium, but only one patient required lithium discontinuation. Conclusion: Lithium may be used in patients on dialysis, with close monitoring of pre-dialysis serum lithium concentrations for at least two weeks after treatment initiation, followed by a lower frequency after stabilization to ensure therapeutic concentrations and reduce toxicity risk. [ABSTRACT FROM AUTHOR]

Chronic lithium treatment for bipolar disease causes mainly side effects in the kidney. A subset of lithium users develops nephrogenic diabetes insipidus (NDI), a urinary concentrating disorder, and chronic kidney disease (CKD). Age, lithium dose, and duration of treatment are important risk factors, whereas genetic background might also play an important role. To investigate the role of genetics, female mice of 29 different inbred strains were treated for 1 year with control or lithium chow and urine, blood, and kidneys were analyzed. Chronic lithium treatment increased urine production and/or reduced urine osmolality in 21 strains. Renal histology showed that lithium increased interstitial fibrosis and/or tubular atrophy in eight strains, whereas in none of the strains glomerular injury was induced. Interestingly, lithium did not elevate urinary albumin-creatinine ratio (ACR) in any strain, whereas eight strains even demonstrated a lowered ACR. The protective effect on ACR coincided with a similar decrease in urinary IgG levels, a marker of glomerular function, whereas the adverse effect of lithium on interstitial fibrosis/tubular atrophy coincided with a severe increase in urinary β2-microglobulin (β2M) levels, an indicator of proximal tubule damage. Genetic background plays an important role in the development of lithium-induced NDI and chronic renal pathology in female mice. The strong correlation of renal pathology with urinary β2M levels indicates that β2M is a promising biomarker for chronic renal damage induced by lithium. [ABSTRACT FROM AUTHOR]

Background: Lithium is the most effective treatment in bipolar disorder. Its use is limited by concerns about risk of chronic kidney disease (CKD). We aimed to develop a model to predict risk of CKD following lithium treatment initiation, by identifying individuals with a high-risk trajectory of kidney function.Methods: We used United Kingdom Clinical Practice Research Datalink (CPRD) electronic health records (EHRs) from 2000 to 2018. CPRD Aurum for prediction model development and CPRD Gold for external validation. We used elastic net regularised regression to generate a prediction model from potential features. We performed discrimination and calibration assessments in an external validation data set. We included all patients aged ≥ 16 with bipolar disorder prescribed lithium. To be included patients had to have ≥ 1 year of follow-up before lithium initiation, ≥ 3 estimated glomerular filtration rate (eGFR) measures after lithium initiation (to be able to determine a trajectory) and a normal (≥ 60 mL/min/1.73 m2) eGFR at lithium initiation (baseline). In the Aurum development cohort, 1609 fulfilled these criteria. The Gold external validation cohort included 934 patients. We included 44 potential baseline features in the prediction model, including sociodemographic, mental and physical health and drug treatment characteristics. We compared a full model with the 3-variable 5-year kidney failure risk equation (KFRE) and a 3-variable elastic net model. We used group-based trajectory modelling to identify latent trajectory groups for eGFR. We were interested in the group with deteriorating kidney function (the high-risk group).Results: The high risk of deteriorating eGFR group included 191 (11.87%) of the Aurum cohort and 137 (14.67%) of the Gold cohort. Of these, 168 (87.96%) and 117 (85.40%) respectively developed CKD 3a or more severe during follow-up. The model, developed in Aurum, had a ROC area of 0.879 (95%CI 0.853-0.904) in the Gold external validation data set. At the empirical optimal cut-point defined in the development dataset, the model had a sensitivity of 0.91 (95%CI 0.84-0.97) and a specificity of 0.74 (95% CI 0.67-0.82). However, a 3-variable elastic net model (including only age, sex and baseline eGFR) performed similarly well (ROC area 0.888; 95%CI 0.864-0.912), as did the KFRE (ROC area 0.870; 95%CI 0.841-0.898).Conclusions: Individuals at high risk of a poor eGFR trajectory can be identified before initiation of lithium treatment by a simple equation including age, sex and baseline eGFR. Risk was increased in individuals who were younger at commencement of lithium, female and had a lower baseline eGFR. We did not identify strong predicters of eGFR decline specific to lithium-treated patients. Notably, lithium duration and toxicity were not associated with high-risk trajectory. [ABSTRACT FROM AUTHOR]

Background: Bipolar disorder is a heritable disorder, and we aimed to assess the impact of family history of mental disorders in first-degree relatives on the severity and course of bipolar disorder.Methods: The Bipolar CHOICE (lithium versus quetiapine) and LiTMUS (optimized treatment with versus without lithium) comparative effectiveness studies were similar trials among bipolar disorder outpatients studying four different randomized treatment arms for 24 weeks. Patients self-reported on six severe mental disorders among first-degree relatives. We performed ANOVA and linear regression regarding disease severity measures, sociodemographic and cardiometabolic markers and mixed effects linear regression to evaluate treatment response.Results: Among 757 patients, 644 (85.1%) reported at least one first-degree relative with a severe mental disorder (mean=2.8; standard deviation=2.2; range=0-13). Depression (67.1%), alcohol abuse (51.0%) and bipolar disorder (47.0%) were the most frequently reported disorders. Familial psychiatric history correlated with several disease severity measures (hospitalizations, suicide attempts, and earlier onset) and sociodemographic markers (lower education and household income) but not with cardiometabolic markers (e.g. cholesterol or waist circumference) or cardiovascular risk scores, e.g. the Framingham risk score. Patients with familial psychiatric history tended to require more psychopharmacological treatment (p=0.054) but responded similarly (all p>0.1) to all four treatment arms.Conclusions: Our findings indicate that familial psychiatric history is common among outpatients with bipolar disorder and correlates with disease severity and sociodemographic measures. Patients with a greater familial psychiatric load required more intense treatment but achieved similar treatment responses compared to patients without familial psychiatric history. [ABSTRACT FROM AUTHOR]

Tay-Sachs disease is a rare lysosomal storage disorder (LSD) caused by a mutation in the HexA gene coding β-hexosaminidase A enzyme. The disruption of the HexA gene causes the accumulation of GM2 ganglioside resulting in progressive neurodegeneration in humans. Surprisingly, Hexa−/− mice did not show neurological phenotypes. Our group recently generated a murine model of Tay-Sachs disease exhibiting excessive GM2 accumulation and severe neuropathological abnormalities mimicking Tay-Sachs patients. Previously, we reported impaired autophagic flux in the brain of Hexa/-Neu3−/− mice. However, regulation of autophagic flux using inducers has not been clarified in Tay-Sachs disease cells. Here, we evaluated the effects of lithium treatment on dysfunctional autophagic flux using LC3 and p62 in the fibroblast and neuroglia of Hexa−/-Neu3−/− mice and Tay-Sachs patients. We discovered the clearance of accumulating autophagosomes, aggregate-prone metabolites, and GM2 ganglioside under lithium-induced conditions. Our data suggest that targeting autophagic flux with an autophagy inducer might be a rational therapeutic strategy for the treatment of Tay-Sachs disease. [ABSTRACT FROM AUTHOR]

• Lithium is effective for treatment-resistant depression rats. • Lithium enhanced the treatment effect of fluoxetine. • Lithium treatment caused side effects such as weight loss. • Lithium + fluoxetine treatment can be a standard to develop new treatment. Wistar Kyoto (WKY) rats are a useful animal model of treatment-resistant depression. Lithium is effective for treating recurrent mood disorders or treatment-resistant depression, and lithium augmentation treatment is also useful for treatment-resistant depression. However, the treatment effect of lithium on the depressive behavior of WKY rats remains poorly understood, and whether lithium augments the treatment effect of antidepressants in WKY rats is also unknown. In this study, we evaluated the treatment effect of lithium in WKY rats. We also sought to determine if lithium treatment augments the treatment effect of fluoxetine. Lithium was administered for 15 consecutive days and fluoxetine was administered 23.5, 5, and 1 h before the forced swim test (FST) day 2, based on previous studies. Lithium treatment counteracted depressive behavior in the FST and increased hippocampal neurogenesis. Additionally, co-administration of lithium and fluoxetine augmented the treatment effect observed in the FST and in hippocampal neurogenesis in WKY rats, although fluoxetine monotherapy showed no treatment effect. Lithium prevented an increase in body weight, similar to its effect in human patients. These results are consistent with those of lithium augmentation treatment for human patients with treatment-resistant depression. They suggest that WKY rats are a promising animal model for treatment-resistant depression. However, lithium treatment has various side effects. A new treatment with the same anti-depressive effect as fluoxetine + lithium treatment and fewer side effects compared with lithium would be desirable for patients with treatment-resistant depression. [ABSTRACT FROM AUTHOR]

• There are currently a number of positive findings in Lithium pharmacogenetics. • Candidate genes participating in monoaminergic neurotransmitter systems, the circadian system, neurotrophic mechanisms, or the inositol signalling pathway have been the most studied in the literature. • Genome wide association studies holds particular promise for future studies. • Clinical assessment for clinical use of pharmacogenetics testing needs more studies, involving larger sample sizes. Lithium is among the best proven treatments for patients diagnosed with Bipolar Disorder, however response to Lithium appears to be considerably variable among individuals and it has been suggested that this inconstancy in Lithium response could be genetically determined. Starting from this perspective, in the last few decades, a number of pharmacogenetic studies have attempted to identify genetic variants, which might be associated with response to Lithium in bipolar patients, in order to develop a pharmacogenetics test to tailor treatment on patients, identifying who will benefit the most from therapy with Lithium. Within this context, authors have critically reviewed pharmacogenetic studies of Lithium response in bipolar disorder, suggesting strategies for future work in this field. Computerized searches of PubMed and Embase databases, for studies published between 1998 and January 2018, was performed: 1162 studies were identified but only 37 relevant papers were selected for detailed review. Despite some interesting preliminary findings, the pharmacogenetics of Lithium and the development of a specific pharmacogenetics test in bipolar disorder appears to be a field still in its infancy, even though the advent of genome-wide association studies holds particular promise for future studies, which should include larger samples. [ABSTRACT FROM AUTHOR]

Objectives: Lithium is one of the most effective and specific treatments for bipolar disorder (BP), but the neural mechanisms by which lithium impacts symptoms remain unclear. Past research has been limited by a reliance on cross‐sectional designs, which does not allow for identification of within‐person changes due to lithium and has not examined communication between brain regions (ie, networks). In the present study, we prospectively investigated the lithium monotherapy associated effects in vivo on the brain connectome in medication‐free BP patients. In particular, we examined the within‐person impact of lithium treatment on connectome indices previously linked to mania and depression in bipolar disorder. Methods: Thirty‐nine medication‐free subjects – 26 BP (13 (hypo)manic and 13 depressed) and 13 closely matched healthy controls (HC) – were included. fMRI data were obtained at 3 timepoints: baseline, after 2 weeks, and after 8 weeks (total of 117 scans: 78 BP and 39 HC scans). BP subjects were clinically treated with lithium for 8 weeks while HC were scanned at the same time points but not treated. Graph theory metrics and repeated measures GLM were used to analyze lithium treatment associated effects. Results: Consistent with hypotheses, lithium treatment was associated with a normalizing effect on mania‐related connectome indices. Furthermore, shifts in both mania‐ and depression‐related connectome indices were proportional to symptom change. Finally, lithium treatment‐associated impact on amygdala function differed depending on baseline mood. Conclusions: Present findings provide deeper insight into the therapeutic neural mechanisms associated with lithium treatment. [ABSTRACT FROM AUTHOR]

Background: Metabolic dysfunctions in patients with bipolar disorder (BD) are critical factors that interfere with outcome, but only one study evaluated the influence of glucose dysmetabolism on the response to treatment with lithium. We aimed to investigate the potential impact of glucose metabolic status on clinical characteristics of BD patients and their response to treatment with different mood stabilizers in monotherapy or in combination.Methods: 45 BD patients with insulin resistance (IR) or type 2 diabetes mellitus (DM2) and 46 patients with normal glucose metabolism, treated with mood stabilizers for at least one year were assessed by diagnostic and rating instruments. Their clinical characteristics were compared and an ordinal logistic regression model was adopted to identify possible predictors of response to mood stabilizer treatments.Results: Compared to patients with normal glucose metabolism, BD patients with impaired glucose metabolism showed a worse clinical presentation of their psychiatric illness and a worse response to mood stabilizers. Ordinal logistic regression analysis evidenced that impaired glucose metabolism was the only predictor of poor response to mood stabilizers (OR 4.3; 95% CI: 1.7-11.1; p < 0.002).Limitations: Cross-sectional design and the relatively small sample size, are the main limitations of our study.Conclusions: Our findings expand literature data suggesting that BD patients with impaired glucose metabolism are at a greater risk of not responding to lithium as well as to different mood stabilizer treatments. [ABSTRACT FROM AUTHOR]

Clozapine is a second-generation antipsychotic drug, proven to be effective in treatment-resistant schizophrenia. Among patients using clozapine; the incidence of neutropenia is approximately 3% and the incidence of agranulocytosis is approximately 1%. This side effect is diminishing after 18 weeks of drug initiation. Here, we present a case of clozapine-induced neutropenia in a schizophrenic patient seen after 7 years of clozapine use and its treatment with lithium supplementation. [ABSTRACT FROM AUTHOR]

Micronutrients are indispensable for adequate metabolism, such as biochemical function and cell production. The production of blood cells is named haematopoiesis and this process is highly consuming due to the rapid turnover of the haematopoietic system and consequent demand for nutrients. It is well established that micronutrients are relevant to blood cell production, although some of the mechanisms of how micronutrients modulate haematopoiesis remain unknown. The aim of the present review is to summarise the effect of Fe, Mn, Ca, Mg, Na, K, Co, iodine, P, Se, Cu, Li and Zn on haematopoiesis. This review deals specifically with the physiological requirements of selected micronutrients to haematopoiesis, showing various studies related to the physiological requirements, deficiency or excess of these minerals on haematopoiesis. The literature selected includes studies in animal models and human subjects. In circumstances where these minerals have not been studied for a given condition, no information was used. All the selected minerals have an important role in haematopoiesis by influencing the quality and quantity of blood cell production. In addition, it is highly recommended that the established nutrition recommendations for these minerals be followed, because cases of excess or deficient mineral intake can affect the haematopoiesis process. [ABSTRACT FROM AUTHOR]

Background: Current intervention strategies have been slow in reducing suicide rates, particularly in mood disorders. Thus, for intervention and prevention, a new approach is necessary. Investigating the effects of a medication known for its anti-suicidal properties on neurobiological and neurocognitive substrates of suicidal thinking may provide a deeper and more meaningful understanding of suicide.Method: A literature search of recognised databases was conducted to examine the intersection of suicide, mood disorders, and the mechanisms of lithium.Results: This review synthesises the extant evidence of putative suicide biomarkers and endophenotypes and melds these with known actions of lithium to provide a comprehensive picture of processes underlying suicide. Specifically, the central importance of glycogen synthase kinase-3β (GSK3β) is discussed in detail because it modulates multiple systems that have been repeatedly implicated in suicide, and which lithium also exerts effects on.Limitations: Suicide also occurs outside of mood disorders but we limited our discussion to mood because of our focus on lithium and extending our existing model of suicidal thinking and behaviour that is contextualised within mood disorders.Conclusions: Focusing on the neurobiological mechanisms underpinning suicidal thinking and behaviours through a lithium lens identifies important targets for assessment and intervention. The use of objective measures is critical and using these within a framework that integrates findings from different perspectives and domains of research is likely to yield replicable and validated markers that can be employed both clinically and for further investigation of this complex phenomenon. [ABSTRACT FROM AUTHOR]

Objective: In the treatment of Bipolar disorder (BD), achieving euthymia is highly complex and usually requires a combination of mood stabilizers. The mechanism of action in stabilizing mood has not been fully elucidated, but alterations in N-Acetylaspartate (NAA), Myo-Inositol (mI) and Choline (Cho) have been implicated. Proton magnetic resonance spectroscopy (1H-MRS) is the gold standard technique for measuring brain NAA, Cho and mI in vivo. The objective of this study was to investigate the association of lithium use in BD type I and brain levels of NAA, mI and Cho in the (anterior cingulate cortex) ACC.Methods: 129 BD type I subjects and 79 healthy controls (HC) were submitted to a 3-Tesla brain magnetic resonance imaging scan (1H-MRS) using a PRESS ACC single voxel (8cm3) sequence.Results: BD patients exhibited higher NAA and Cho levels compared to HC. Lithium prescription was associated with lower mI (combination + monotherapy) and higher NAA levels (monotherapy).Conclusion: The results observed add to the knowledge about the mechanisms of action of mood stabilizers on brain metabolites during euthymia. Additionally, the observed decrease in mI levels associated with lithium monotherapy is an in vivo finding that supports the inositol-depletion hypothesis of lithium pharmacodynamics. [ABSTRACT FROM AUTHOR]

Lithium was discovered by the Swedish Arfvedson at the beginning of the 1800s and began to be used in psychiatry for the past 1950s. Lithium, as a mood stabilizer, is the gold standard and first choice treatment agent for the treatment of bipolar disorders in adults. However, it is mostly difficult in clinical practice to predict which patient would respond to the treatment with lithium well due to the huge variation in patients' characteristics. Clinicians seem to focus primarily on identifying a clinical phenotype to foresee lithium treatment response. In this article, researches on predictors of the lithium treatment response were reviewed and evaluated in four titles as clinical, biochemical, neuroimaging and genetic predictors. [ABSTRACT FROM AUTHOR]

Introduction Lithium is established as an effective treatment of mania, of depression in bipolar and unipolar disorder, and in maintenance treatment of these disorders. However, due to the necessity of monitoring and concerns about irreversible adverse effects, in particular renal impairment, after long-term use, lithium might be underutilized. Methods This study reviewed 6 large observational studies addressing the risk of impaired renal function associated with lithium treatment and methodological issues impacting interpretation of results. Results An increased risk of renal impairment associated with lithium treatment is suggested. This increased risk may, at least partly, be a result of surveillance bias. Additionally, the earliest studies pointed toward an increased risk of end-stage renal disease associated with lithium treatment, whereas the later and methodologically most sound studies do not. Discussion The improved renal outcome found in the more recent lithium studies may be a result of improved monitoring and focus on recommended serum levels (preferentially 0.6-0.8 mmol/L) as compared to poorer renal outcome in studies with patients treated in the 1960s to 1980s. [ABSTRACT FROM AUTHOR]

Evidence for a neuroprotective effect of lithium has accumulated over the last 2 decades, and this phenomenon has been regarded as an important mechanism of lithium action in mood disorders. It has been reflected by an increase in cerebral gray matter volume in lithium-treated subjects and by the favorable influence of lithium on cognitive functions. A neuroprotective effect of lithium also makes this ion a possible candidate for use as a therapeutic drug in neurology, especially in neurodegenerative disorders. In this paper, neurochemical mechanisms of neuroprotective action of lithium will be characterized. A possible association between the effect of lithium on brain structures reflected in neuroimaging studies, as well as on cognitive functions, and its neuroprotective action, will be considered. Data from experimental, epidemiological, and clinical studies have also pointed to an antidementia effect of lithium, bringing about some promise of using lithium in the treatment of mild cognitive impairment and Alzheimer's disease. The results of attempts of employing lithium in other neurodegenerative disorders will also be discussed. [ABSTRACT FROM AUTHOR]

Objective: This study aimed to compare aripiprazole with lithium for the effectiveness of treating Iranian male patients with acute mania. Methods: A total of 30 male in-patients with bipolar I disorder who presented with relapse or new emergence of an episode of acute mania were equally randomised to receive 4 weeks of aripiprazole (5 mg uncoated tablets) or lithium carbonate (300 mg uncoated tablets) according to standard practice guidelines and titration protocols. The Manic State Rating Scale (MSRS) was used to determine the severity of manic symptoms at baseline (week 0) and up to week 4. The Bech-Rafaelsen Mania Scale (BRMS), Schedule for Assessment of Insight (SAI), and Clinical Global Impressions-Global Improvement scale (CGI-G) were used to determine the severity of manic symptoms, insight, and overall illness severity, respectively. All outcome measures were recorded by a single experienced psychiatrist. Results: The frequency and intensity of manic symptoms (MSRS score) in both groups decreased significantly from baseline to week 4. In the aripiprazole and lithium groups, the intensity of manic symptoms decreased by ≥25% in 5 and 7 patients and by >50% in 1 and 5 patients, respectively. Betweengroup analysis showed that lithium was more effective at weeks 3 and 4 in decreasing the frequency and intensity of manic symptoms. The lithium group achieved greater improvement in symptoms than the aripiprazole group in terms of BRMS score, SAI score, and CGI-G. Conclusion: Lithium is more effective than aripiprazole in improving manic symptoms. [ABSTRACT FROM AUTHOR]

Background: Although clozapine is the most effective medication for treatment refractory schizophrenia, only 40% of people will meet response criteria. We therefore undertook a systematic review and meta-analysis of global literature on clozapine augmentation strategies. Methods: We systematically reviewed PubMed, PsycInfo, Embase, Cochrane Database, Chinese Biomedical Literature Service System and China Knowledge Resource Integrated Database for randomised control trials of augmentation strategies for clozapine resistant schizophrenia. We undertook pairwise meta-analyses of within-class interventions and, where possible, frequentist mixed treatment comparisons to differentiate treatment effectiveness. Results: We identified 46 studies of 25 interventions. On pairwise meta-analyses, the most effective augmentation agents for total psychosis symptoms were aripiprazole (standardised mean difference: 0.48; 95% confidence interval: -0.89 to -0.07) fluoxetine (standardised mean difference: 0.73; 95% confidence interval: -0.97 to -0.50) and, sodium valproate (standardised mean difference: 2.36 95% confidence interval: -3.96 to -0.75). Memantine was effective for negative symptoms (standardised mean difference: -0.56 95% confidence interval: -0.93 to -0.20). However, many of these results included poor-quality studies. Single studies of certain antipsychotics (penfluridol), antidepressants (paroxetine, duloxetine), lithium and Ginkgo biloba showed potential, while electroconvulsive therapy was highly promising. Mixed treatment comparisons were only possible for antipsychotics, and these gave similar results to the pairwise metaanalyses. Conclusions: On the basis of the limited data available, the best evidence is for the use of aripiprazole, fluoxetine and sodium valproate as augmentation agents for total psychosis symptoms and memantine for negative symptoms. However, these conclusions are tempered by generally short follow-up periods and poor study quality. [ABSTRACT FROM AUTHOR]

Bipolar disorder (BD) is a common and disabling psychiatric condition with a severe socioeconomic impact. BD is treated with mood stabilizers, among which lithium represents the first-line treatment. Lithium alone or in combination is effective in 60% of chronically treated patients, but response remains heterogenous and a large number of patients require a change in therapy after several weeks or months. Many studies have so far tried to identify molecular and genetic markers that could help us to predict response to mood stabilizers or the risk for adverse drug reactions. Pharmacogenetic studies in BD have been for the most part focused on lithium, but the complexity and variability of the response phenotype, together with the unclear mechanism of action of lithium, limited the power of these studies to identify robust biomarkers. Recent pharmacogenomic studies on lithium response have provided promising findings, suggesting that the integration of genome-wide investigations with deep phenotyping, in silico analyses and machine learning could lead us closer to personalized treatments for BD. Nevertheless, to date none of the genes suggested by pharmacogenetic studies on mood stabilizers have been included in any of the genetic tests approved by the Food and Drug Administration (FDA) for drug efficacy. On the other hand, genetic information has been included in drug labels to test for the safety of carbamazepine and valproate. In this review, we will outline available studies investigating the pharmacogenetics and pharmacogenomics of lithium and other mood stabilizers, with a specific focus on the limitations of these studies and potential strategies to overcome them. We will also discuss FDA-approved pharmacogenetic tests for treatments commonly used in the management of BD. [ABSTRACT FROM AUTHOR]

Lithium has been an intriguing treatment option in psychiatry for over a century. While seemingly just a simple elemental compound, it has powerful treatment effects for both depression and bipolar disorder. The evidence base for treatment of pediatric bipolar disorder is relatively small, but, in recent years, additional clinical trial data have enabled lithium to re-emerge as a valuable and, in many cases, preferred treatment. Pharmacologically, lithium is complex, with varied effects at both intracellular and extracellular levels. As a treatment for bipolar disorder in pediatrics, lithium is challenging, given its narrow therapeutic window and myriad of potential side effects. However, the efficacy of lithium continues to match that of newer pharmacologic agents, and its tolerability has been shown to be comparable with more commonly prescribed medications. Lithium is still one of few drugs that have been proven to reduce the risk of suicidality, and it may have utility in illnesses beyond affective disorders. Practically, as a primary agent or as an adjunct, lithium continues to claim a rightful place in the treatment armamentarium of child psychiatry. New dosing paradigms have improved tolerability and reduced potential side effects. Recent evidence affirms that lithium is effective for pediatric bipolar disorder in multiple phases of the illness. [ABSTRACT FROM AUTHOR]

Lithium is an option for the long-term treatment for bipolar disorder, as it minimizes the risk of recurrences and improves inter-episodic symptomology. Antidepressants, antipsychotics, anticonvulsants and other drugs may be used concomitantly with, or instead of, lithium. As lithium has a narrow therapeutic index, careful drug monitoring and individualization of the treatment of bipolar disorder is crucial to improve effectiveness and reduce the risk of adverse events. [ABSTRACT FROM AUTHOR]

Lithium is used in the treatment for many psychiatric disorders, like bipolar disorder, schizoaffective disorder and depression. Lithium has a very narrow therapeutic range and there are many reasons that increase the blood levels of lithium. Combining lithium with other medications with the aim of reducing side effects or supporting the therapy may result in substantial elevations in lithium concentrations and may lead to signs of int oxication. This study presents increased blood lithium concentration after the initiation of the concomitant therapy of lithium and propranolol, which is a beta-blocker drug, due to the complaint of tremor causing functional impairment. [ABSTRACT FROM AUTHOR]

Background: Lithium is widely used for the treatment of bipolar disorder. Owing to its narrow therapeutic index and side-effect profile, regular monitoring of serum levels, renal and thyroid function has been recommended by all major guidelines on lithium use.Objectives: We investigated whether lithium monitoring during maintenance phase treatment in clinical practice meets the latest recommendation by the National Institute for Health and Clinical excellence (i.e. lithium levels between 0.6 and 1.0 mmol/L and lithium level, thyroid and renal function tests every 6 months) in one of the largest mental health organizations in Europe, the South London and Maudsley (SLaM) NHS Foundation Trust.Methods: Retrospective data were extracted from SLaM's Clinical Record Interactive Search (CRIS) system. Adult patients with a psychiatric disorder who were on lithium at any point during the period January 2012-January 2016 and had at least one lithium level test result in the system were included in the analyses.Results: A total of 2639 lithium level tests results were retrieved for 412 patients. Overall, the serum level was within the recommended range in 50.7% of all tests, below the range in 42.4% and above in 6.9%. Lithium level, renal and thyroid function tests were performed at the recommended frequency of 6 months (or less) in 76.2%, 72.7% and 60.2% of patients, respectively.Conclusion: These data demonstrate that there is a gap between the NICE 2014 recommendation and lithium monitoring practice in secondary care, with a high number of lithium level results below the therapeutic minimum. Reminder strategies for secondary care practitioners, shared care agreements or a central registry for lithium users could improve monitoring performance. [ABSTRACT FROM AUTHOR]

Importance: Mood stabilizers and antipsychotics are the main maintenance treatments for bipolar disorder. Lithium is considered to be the most effective mood stabilizer, but very little is known about overall health outcomes associated with specific treatments and the comparative long-term effectiveness of specific psychotropics or routes of administration in the prevention of rehospitalizations.Objective: To study the comparative effectiveness of pharmacologic treatments in the prevention of rehospitalization in a nationwide cohort of patients with bipolar disorder.Design, Setting, and Participants: This cohort study examined the risk of psychiatric, cardiovascular, and all-cause hospitalization from January 1, 1987, to December 31, 2012, among all patients in Finland who had been hospitalized for bipolar disorder (N = 18 018; mean follow-up time, 7.2 years) using prospectively gathered nationwide databases for hospitalization and dispensed medications. The primary analysis was within-individual analysis, in which each individual was used as his or her own control to eliminate selection bias. The study adjusted for the effect of concomitant psychotropic medications, duration of illness, and the temporal orders of exposure and nonexposure periods. Statistical analysis was conducted from January 1, 1996, to December 31, 2012.Main Outcomes and Measures: Adjusted hazard ratios (HRs) for rehospitalization were calculated.Results: Among the cohort (9558 women and 8460 men; mean [SD] age, 46.6 [17.0] years), 9721 patients (54.0%) had at least 1 psychiatric rehospitalization. In comparison between use and no use among specific agents reaching nominal statistical significance, risperidone long-acting injection (HR, 0.58 [95% CI, 0.34-1.00]), gabapentin (HR, 0.58 [95% CI, 0.44-0.77]), perphenazine long-acting injection (HR, 0.60 [95% CI, 0.41-0.88]), and lithium carbonate (HR, 0.67 [95% CI, 0.60-0.73]) were associated with the lowest risk of psychiatric rehospitalization. Concerning all-cause hospitalization, lithium (HR, 0.71 [95% CI, 0.66-0.76]) was associated with the lowest risk. The most frequently used antipsychotic treatment, quetiapine fumarate, showed only modest effectiveness (risk of psychiatric rehospitalization: HR, 0.92 [95% CI, 0.85-0.98]; risk of all-cause hospitalization: HR, 0.93 [95% CI, 0.88-0.98]). Long-acting injections were associated with substantially better outcomes compared with identical oral antipsychotics (risk of psychiatric rehospitalization: HR, 0.70 [95% CI, 0.55-0.90]; risk of all-cause hospitalization: HR, 0.70 [95% CI, 0.57-0.86]). Results from sensitivity analyses showed consistent beneficial effects only for lithium and for long-acting injections compared with their oral counterparts.Conclusions and Relevance: Lithium was the most effective mood stabilizer, and long-acting injections the most effective antipsychotics, in preventing hospitalization due to mental or physical illness. [ABSTRACT FROM AUTHOR]

1H MRS is widely used in the research of mental disorders. It enables evaluation of concentration or ratios of several metabolites, which play important roles in brain metabolism: N-acetylaspartate (NAA), choline containing compounds, myo-inositol and glutamate, glutamine and GABA (together as Glx complex or separately). Specifically in bipolar disorder brain metabolite abnormalities include mostly NAA reduces and Glx increases in different brain regions. Bipolar disorder is associated with impairment in neurotrophic and cellular plasticity, resilience pathways and in neuroprotective processes. Lithium, which is commonly used in BD treatment, modulates neurotransmitter release, reduces oxidative stress and apoptosis, induces angiogenesis, neurogenesis and neurotrophic response. Thus brain metabolite abnormalities may elucidate the mechanisms of this processes. In the present article we systematically reviewed 26 studies - the majority of them investigated bipolar disorder ( 7 follow-up and all 11 cross-sectional studies). Moreover we dispute whether the influence of lithium on brain metabolites in bipolar disorder could explain the background of its potential neuroprotective action. The results of our literature review do not equivocally confirm Lithium's influence the metabolite changes in the brain. The majority of the follow-up studies do not support the initially assumed influence of Lithium on the increase of NAA level in various brain structures. The results of studies are inconclusive with regard to levels of Glx or Glu and Lithium intake, rather point a lack of relationship. The above results were reviewed according to the most recent theories in the field accounting for the impact of lithium (1)HMRS measures. [ABSTRACT FROM AUTHOR]

Mood stabilizers are a category of medications used in the management of mood disorders. The mood stabilizing properties of lithium were first reported in 1949 by John Cade, and since then it has been considered the first line treatment for bipolar disorder. Despite presenting more differences than similarities, mood stabilizers are all characterized by high variability in response in treated patients. This feature has stimulated a vast body of research on potential predictive markers of clinical response, with promising but often inconclusive findings. Pharmacogenetics of mood stabilizers has provided valuable hints toward the involvement of genes and pathways in modulating response. However, with the exception of lithium, the number of studies is still too sparse to draw definite conclusions. Moreover, the mechanism of action of these drugs has yet to be completely elucidated. A growing body of research has explored the effect of mood stabilizers on a family of molecular players responsible for the regulation of gene expression without interfering with the DNA sequence. These processes belong to the epigenetic machinery and represent the mechanisms through which our biological systems interact with environmental factors, including drug treatments. In this review we focused on findings from preclinical and clinical studies suggesting that mood stabilizers may interfere with epigenetic mechanisms, providing an intriguing perspective that may help us filling the gap between molecular functions and clinical efficacy of mood stabilizers. [ABSTRACT FROM AUTHOR]

Background: There is a paucity of treatment options for bipolar depression. The use of triiodothyronine (T3) has been suggested as adjunctive treatment.Methods: A search on Medline, Limo and ScienceDirect was performed using the search terms bipolar disorder, bipolar depression, treatment resistant, treatment refractory, thyroid hormones, triiodothyronine, T3, acceleration and augmentation.Results: We retrieved three open studies, one comparative study, two double blind and one retrospective chart review. The three open studies observed improvement in respectively 56%, 75% and 79% of patients, the retrospective chart review noted improvement in 89% of cases and the mirror design showed improvement in 66%. In the comparative study T3 performed significantly better than placebo. The only randomized double blind study could not prove any substantial difference between T3 and placebo.Limitations: Available studies are scarce and flawed. All have (very) low number of subjects: overall, only 353 subjects and only 194 of which in prospective trials. In only two of the prospective trials bipolar patients were analyzed separately. Comparing the studies is hampered by a high variability in assessment tools, baseline medication and degree of treatment-resistance.Conclusions: The few available studies are small and flawed. They do show promising results. We found many clues suggesting that T3 could augment and accelerate treatment response not only with antidepressants, but also with lithium and perhaps with other treatment options, that it might protect against rapid cycling bipolar disorder, as well as against relapse during the first few years of treatment. [ABSTRACT FROM AUTHOR]

Background: Hospitalization accounts for significant health care resource utilization for treatment-resistant Bipolar Disorder (BD), especially among frequent users of acute inpatient psychiatric units. Appraisal of the clinical features and predictive role of selected variables is therefore crucial in such population, representing the aim of the present research.Methods: A hundred and nineteen BD inpatients with an established history of pharmacological treatment resistance for either mania or bipolar depression were classified as long hospitalization cases (LOS+) and their controls and compared against each other for a number of demographic, clinical, and psychopathological features.Results: Overall, female sex, current second-generation atypical antipsychotic (SGA)/mood stabilizer other than lithium as well as antidepressant treatment at the admission occurred statistically more frequently among LOS+ cases, concordant with higher scores at the Hamilton scales for depression and anxiety. Lithium utilization at the time of hospitalization did not differ between cases and controls (LOS-, n = 81/119), as predominant affective temperament and other psychopathological rating did not. Overall, the time of admission, use of SGA, anticonvulsant (other than lithium), antidepressant, lifetime alcohol dependence, and BD Type (-I or -II), but not current mood polarity at the time of hospitalization, correctly predicted LOS+ grouping 68.2% of the times: Exp(B) = 3.151, p042.Limitations: Post-hoc, cross-sectional study, relatively small sample size, recall and selection bias on some diagnoses.Conclusions: Overall, LOS+ treatment-resistant BD inpatients characterize for higher severity and greater pharmaco-utilization use, which warrants replication studies to include additional predictors to shed further light on the matter. [ABSTRACT FROM AUTHOR]

Background: Clinicians treating a patient with bipolar disorder who is pregnant or breastfeeding may seek advice from bipolar management guidelines that provide recommendations for perinatal treatment. We examine the consistency of such recommendations across several evidence-based guidelines.Methods: A literature search in the National Guideline Clearinghouse, the Cochrane Database of Systematic Reviews, PsycInfo and PubMed was undertaken using the search terms "bipolar disorder" and "guidelines," which generated 11 sets of evidence-based guidelines published by professional organizations during the 2005-2015 period. Information relevant to management during the perinatal period was reviewed by two independent reviewers, with key themes qualitatively analysed.Results: There was a moderate level of agreement across guidelines regarding the potential teratogenic effects of lithium, sodium valproate and carbamazepine, with most highlighting caution in using these medications during the perinatal period. There was less agreement regarding the safety risks associated with lamotrigine, antipsychotics, and antidepressants, and little agreement regarding the risks and recommendations of medications during breastfeeding.Limitations: Some differences in recommendations are likely due to varying publication dates, with recent guidelines having more up-to-date evidence available to use when formulating recommendations. Further, due to ethical issues surrounding pregnancy and infant research, the evidence used to formulate perinatal recommendations is largely based on retrospective reports and/or case studies. It is therefore unrealistic to expect such recommendations to be entirely consistent and based on rigorous evidence.Conclusions: While there was some consistency across guidelines on key recommendations, there were also substantial inconsistencies, with the latter risking compromising clinical management. [ABSTRACT FROM AUTHOR]

Background: Anxiety symptoms are common in bipolar disorder. We explored the effect of anxiety on the outcome of acute and continuation pharmacotherapy of bipolar II depression.Methods: Data were derived from a randomized double-blind 12-week acute (N = 129) and 6-month continuation (N = 55) comparison of venlafaxine versus lithium monotherapy in bipolar II depression in adults. We distinguished between the items of the Hamilton Rating Scale for Depression (HRSD) that capture depression vs. anxiety (i.e., psychomotor agitation, psychic anxiety, somatic anxiety, hypochondriasis, and obsessive-compulsive concerns) and examined the effect of treatment on depression and anxiety. Additionally, we explored whether baseline anxiety or depression predicted changes over time in depression and anxiety ratings or moderated treatment outcomes. We also explored whether residual depressive and anxious symptoms predicted relapse during continuation therapy.Results: Venlafaxine was superior to lithium in reducing both depression and anxiety, though its effects on anxiety were more modest than those on depression. Baseline anxiety predicted change over time in anxiety, but not depression. By contrast, baseline depression did not predict change over time in depression or anxiety. Residual anxiety, specifically uncontrollable worry, was a stronger predictor of relapse than residual depression.Conclusion: Successful treatment of symptoms of anxiety in bipolar depression may protect against depressive relapse. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background: Electroconvulsive therapy (ECT) is effective in bipolar depression, but relapse is common. The aim of the study was (i) to identify prognostic factors (ii) and to determine the impact of pharmacological approaches on the risk for rehospitalization or suicide.Methods: This register study analyzed data from individuals treated with inpatient ECT for bipolar depression. Subjects were identified using the Swedish National Patient Register between 2011 and 2014 and the Swedish National Quality Register for ECT. Other national registers provided data on psychopharmacotherapy, socio-demographic factors, and causes of death. The endpoint was the composite of rehospitalization for any psychiatric disorder, suicide attempt or completed suicide (RoS). Cox regression was used to calculate hazard ratios in univariate and multivariate models.Results: Data from 1255 patients were analyzed. The mean period of follow-up was 346 days. A total of 29%, 41%, and 52% of patients reached RoS at 3, 6, and 12 months post-discharge. A history of multiple psychiatric admissions, lower age, and post-discharge treatment with antipsychotics or benzodiazepines was associated with RoS.Limitations: Indication bias may have affected the results.Conclusions: A history of multiple hospital admissions and lower age are key predictors of the composite of rehospitalization or suicide in patients treated with ECT for bipolar depression. Lithium might be effective. By contrast, antipsychotics and benzodiazepines were associated with increased risk, but possibly this finding was influenced by indication bias. [ABSTRACT FROM AUTHOR]

Background We investigated the effect of long-term lithium treatment on very-small embryonic-like stem cells (VSELs) and the mRNA expression of pluripotency and glial markers, in peripheral blood, in patients with bipolar disorder (BD). Methods Fifteen BD patients (aged 53 ± 7 years) not treated with lithium, with duration of illness > 10 years, 15 BD patients (aged 55 ± 6 years) treated with lithium for 8–40 years (mean 16 years) and 15 control subjects (aged 50 ± 5 years) were included. The number of VSELs was measured by flow cytometric analysis. Assessment of the mRNA levels of pluripotency markers (Oct-4, Sox 2 and Nanog) and glial markers (glial fibrillary acidic protein - GFAP, Olig1 and Olig2) was performed, using the Real-time quantitative reverse transcription PCR. Results In BD patients not taking lithium, the number of VSELs was significantly higher than in control subjects and correlated with the duration of illness. The expression of pluripotency markers was significantly higher than in the controls and correlated with the number of VSELs. The mRNA levels of the Olig1 and Olig 2 were higher than in the controls and those of the GFAP were higher than in patients receiving lithium. In lithium-treated BD patients the number of VSELs was similar to controls and correlated negatively with the duration of lithium treatment and serum lithium concentration. The mRNA levels of Oct-4, Sox-2, GFAP and Olig1 were not different from controls. The mRNA expression of Nanog was significantly higher and correlated with the number of VSELs. The mRNA expression of Olig 2 was higher than in the BD patients not taking lithium. Conclusion Long-term treatment with lithium may suppress the activation of regenerative processes by reducing the number of VSELs circulating in PB. These cells, in BD patients not treated with lithium, may provide a new potential biological marker of the illness and its clinical progress. The higher expression of peripheral mRNA markers in BD patients may involve ongoing inflammatory process, compensatory mechanisms and regenerative responses. Long-term lithium treatment may attenuate these mechanisms, especially in relation to the transcription factors Oct-4, Sox-2, GFAP and Olig1. [ABSTRACT FROM AUTHOR]

Objective: The goal of this meta-analysis was to quantitatively summarize the evidence available on the differences in grey matter volume between lithium-treated and lithium-free bipolar patients.Methods: A systematic search was conducted in Cochrane Central, Embase, MEDLINE, and PsycINFO databases for original peer-reviewed journal articles that reported on global grey matter volume in lithium-medicated and lithium-free bipolar patients. Standard mean difference and Hedges' g were used to calculate effect size in a random-effects model. Risk of publication bias was assessed using Egger's test and quality of evidence was assessed using standard criteria.Results: There were 15 studies with a total of 854 patients (368 lithium-medicated, 486 lithium-free) included in the meta-analysis. Global grey matter volume was significantly larger in lithium-treated bipolar patients compared to lithium-free patients (SMD: 0.17, 95% CI: 0.01-0.33; z = 2.11, p = 0.035). Additionally, there was a difference in global grey matter volume between groups in studies that employed semi-automated segmentation methods (SMD: 0.66, 95% CI: 0.01-1.31; z = 1.99, p = 0.047), but no significant difference in studies that used fully-automated segmentation. No publication bias was detected (bias coefficient = - 0.65, p = 0.46).Limitations: Variability in imaging methods and lack of high-quality evidence limits the interpretation of the findings.Conclusions: Results suggest that lithium-treated patients have a greater global grey matter volume than those who were lithium-free. Further study of the relationship between lithium and grey matter volume may elucidate the therapeutic potential of lithium in conditions characterized by abnormal changes in brain structure. [ABSTRACT FROM AUTHOR]

Importance: Lithium is a first-line mood stabilizer for the treatment of bipolar affective disorder (BPAD). However, the efficacy of lithium varies widely, with a nonresponse rate of up to 30%. Biological response markers are lacking. Genetic factors are thought to mediate treatment response to lithium, and there is a previously reported genetic overlap between BPAD and schizophrenia (SCZ).Objectives: To test whether a polygenic score for SCZ is associated with treatment response to lithium in BPAD and to explore the potential molecular underpinnings of this association.Design, Setting, and Participants: A total of 2586 patients with BPAD who had undergone lithium treatment were genotyped and assessed for long-term response to treatment between 2008 and 2013. Weighted SCZ polygenic scores were computed at different P value thresholds using summary statistics from an international multicenter genome-wide association study (GWAS) of 36 989 individuals with SCZ and genotype data from patients with BPAD from the Consortium on Lithium Genetics. For functional exploration, a cross-trait meta-GWAS and pathway analysis was performed, combining GWAS summary statistics on SCZ and response to treatment with lithium. Data analysis was performed from September 2016 to February 2017.Main Outcomes and Measures: Treatment response to lithium was defined on both the categorical and continuous scales using the Retrospective Criteria of Long-Term Treatment Response in Research Subjects with Bipolar Disorder score. The effect measures include odds ratios and the proportion of variance explained.Results: Of the 2586 patients in the study (mean [SD] age, 47.2 [13.9] years), 1478 were women and 1108 were men. The polygenic score for SCZ was inversely associated with lithium treatment response in the categorical outcome, at a threshold P < 5 × 10-2. Patients with BPAD who had a low polygenic load for SCZ responded better to lithium, with odds ratios for lithium response ranging from 3.46 (95% CI, 1.42-8.41) at the first decile to 2.03 (95% CI, 0.86-4.81) at the ninth decile, compared with the patients in the 10th decile of SCZ risk. In the cross-trait meta-GWAS, 15 genetic loci that may have overlapping effects on lithium treatment response and susceptibility to SCZ were identified. Functional pathway and network analysis of these loci point to the HLA antigen complex and inflammatory cytokines.Conclusions and Relevance: This study provides evidence for a negative association between high genetic loading for SCZ and poor response to lithium in patients with BPAD. These results suggest the potential for translational research aimed at personalized prescribing of lithium. [ABSTRACT FROM AUTHOR]

Objective: To compare the long-term clinical outcomes of bipolar patients following lithium maintenance therapy between patients who received standard care plus pharmaceutical care service (lithium clinic group) and patients who received standard care alone (usual care group). Materials and Methods: This study was a single-center retrospective cohort study. Clinical outcomes were compared between the lithium clinic (n = 120) and usual care groups (n = 240) between January 2006 and December 2015. Results and Discussion: Average study observation time was 6.11 ± 3.14 years. Hospitalization rate due to any recurrence in lithium clinic group was significantly less than usual care group (2.61 cases per 100 patient-years [95% confidence interval (CI), 1.65-4.14]vs. 9.02 cases per 100 patient-years [95% CI, 7.34-11.04], P < 0.0001). Furthermore, hospitalization rate from manic recurrence and emergency room visit rate in lithium clinic group (2.60 cases per 100 patient-years [95% CI, 1.64-4.13]and 1.89 cases per 100 patientyears [95% CI, 1.10-3.26], respectively) was significantly lower than usual care group (7.40 cases per 100 patient-years [95% CI, 5.96-9.19]and 7.40 cases per 100 patient-years [95% CI, 5.95-9.20], respectively). Furthermore, lithium clinic group had risk of any recurrence (relative risk [RR]= 0.744, P = 0.02), manic recurrence (RR = 0.613, P = 0.001), and manic admission (RR = 0.439, P = 0.0001) significantly less than usual care group. Median time to manic recurrence was 4.44 (interquartile range [IQR]3.59-5.29) years for lithium clinic group, but 3.54 (IQR 3.08-3.99) years for usual care group. Median time to manic admission was 5.36 (IQR 4.81-5.92) and 3.98 (IQR 3.21-4.76) years for lithium clinic and usual care groups, respectively. Moreover, the median time to emergency room visit was 5.36 (IQR 4.93-5.80) years in lithium clinic and 4.09 (IQR 3.46-4.72) years in usual care groups. Conclusion: Lithium clinic group had better long-term clinical outcomes than usual care group. Therefore, pharmaceutical care in bipolar disorder patients is beneficial and should be implemented for other psychiatric hospitals. [ABSTRACT FROM AUTHOR]

Lithium has been used for the treatment of bipolar disorder (BD) for the last sixty or more years, and recent studies with more reliable designs and updated guidelines have recommended lithium to be the treatment of choice for acute manic, mixed and depressive episodes of BD, along with long-term prophylaxis. Lithium's specific mechanism of action in mood regulation is progressively being clarified, such as the direct inhibition on glycogen synthase kinase 3, and its various effects on neurotrophic factors, neurotransmitters, oxidative metabolism, apoptosis, second messenger systems, and biological systems are also being revealed. Furthermore, lithium has been proposed to exert its treatment effects through mechanisms associated with neuronal plasticity. In this review, we have overviewed the clinical aspects of lithium use for BD, and have focused on the neuroprotective and neurotrophic effects of lithium. [ABSTRACT FROM AUTHOR]

Background: Lithium is the mainstay of treatment for bipolar disorder, mania and an augmentation therapy in patients with treatment resistant depression. It has a narrow therapeutic index, with recognized adverse multi-system and endocrine side effects. Aim: To assess the impact of lithium therapy, in particular lithium toxicity, on the development of endocrine and renal disorders in a cohort of patients in a single tertiary referral centre in Ireland. Study design: A retrospective analysis was performed of the prevalence of lithium toxicity and renal, thyroid and parathyroid dysfunction in our study population. Methods: We collected laboratory data from the Clinical Chemistry department of the Adelaide and Meath Hospital incorporating the National Children's Hospital (AMNCH), Dublin, Ireland. Our study population included all patients who had at least one serum lithium measurement from January 1st 2000 to December 31st 2014 inclusive. Results: A total of 580 patients were included in the study. Among our study group, 70 patients (12.1%) had 1 toxic lithium measurement (lithium level >1.2 mmol/l). 27.8% (n>161) of patients developed stage 3 Chronic kidney Disease (CKD) or higher, which was commoner in those patients who developed toxic lithium levels (P<0.0001) and in those who developed hypernatraemia (P>0.0001). 16.2% of patients (n>94) had one serum sodium >145 mmol/l during follow up. 60 patients (10.3%) had a TSH >10 mU/l, while complete suppression of TSH (<0.05 mU/l) was observed in 22 patients (3.8%) during follow-up. 4% (n>37) of the study population had ≥1 serum corrected calcium level > 2.55 mmol/l, and 4 patients had biochemical confirmation of primary hyperparathyroidism but PTH levels were only performed in 2.8% (n>16) of the study population. Conclusion: Stage 3 CKD is common in patients receiving lithium therapy. Lithium toxicity is associated with CKD and hypernatraemia. Thyroid dysfunction and hypercalcaemia are common in patients receiving lithium therapy. Patients receiving lithium therapy require surveillance of renal, thyroid and bone biochemistry. [ABSTRACT FROM AUTHOR]

Lithium (Li) is a chemical element used for treating and preventing bipolar disorder (BD) and exerts positive effects such as anti-inflammatory effects as well as undesirable side effects. These effects of Li can be influenced by interaction with some nutritional elements. Therefore, we investigated the potential effects of xanthine (caffeine and theobromine) and catechin molecules present in some food beverages broadly consumed worldwide, such as coffee and tea, on Li-induced anti-inflammatory effects. In the present study, we concomitantly exposed RAW 264.7 macrophages to Li, isolated xanthine and catechin molecules, and a xanthine-catechin mixture (XC mixture). We evaluated the effects of these treatments on cell proliferation, cell cycle progression, oxidative and antioxidant marker expression, cytokine levels, gene expression, and GSK-3β enzyme expression. Treatment with the XC mixture potentialized Li-induced anti-inflammatory effects by intensification of the following: GSK-3β inhibitory action, lowering effect on proinflammatory cytokines (IL-1β, IL-6, and TNFα), and increase in the levels of IL-10 that is an anti-inflammatory cytokine. Despite the controversial nature of caffeine consumption by BD patients, these results suggested that consumption of caffeine, in low concentrations, mixed with other bioactive molecules along with Li may be safe. [ABSTRACT FROM AUTHOR]

Objective: Clinicians treating older patients with bipolar disorder with mood stabilizers need evidence from age-specific randomized controlled trials. The authors describe findings from a first such study of late-life mania.Method: The authors compared the tolerability and efficacy of lithium carbonate and divalproex in 224 inpatients and outpatients age 60 or older with bipolar I disorder who presented with a manic, hypomanic, or mixed episode. Participants were randomly assigned, under double-blind conditions, to treatment with lithium (target serum concentration, 0.80-0.99 mEq/L) or divalproex (target serum valproate concentration, 80-99 μg/mL) for 9 weeks. Participants with an inadequate response after 3 weeks received open adjunctive risperidone. The authors hypothesized that divalproex would be better tolerated and more efficacious than lithium. Tolerability was assessed based on a measure of sedation and on the proportions of participants achieving target concentrations. Efficacy was assessed with the Young Mania Rating Scale (YMRS).Results: Attrition rates were similar for lithium and divalproex (14% and 18% at week 3 and 51% and 44% at week 9, respectively). The groups did not differ significantly in sedation. Participants in the lithium group tended to experience more tremor. Similar proportions of participants in the lithium and divalproex groups achieved target concentrations (57% and 56%, respectively). A longitudinal mixed model of improvement (change from baseline in YMRS score) favored lithium (change in score, 3.90; 97.5% CI=1.71, 6.09). Nine-week response rates did not differ significantly between the lithium and divalproex groups (79% and 73%, respectively). The need for adjunctive risperidone was low and similar between groups (17% and 14%, respectively).Conclusions: Both lithium and divalproex were adequately tolerated and efficacious; lithium was associated with a greater reduction in mania scores over 9 weeks. [ABSTRACT FROM AUTHOR]

Pragmatic studies indicate that a substantial number of depressed patients do not remit with current first-line antidepressant treatments and after two failed treatment steps the chance of remission with subsequent therapies is around 15%. This paper focuses on current evidence for pharmacological treatments in resistant depression as well as possible future developments. For patients who have failed to respond to two antidepressant trials, augmentation with atypical antipsychotic drugs, specifically quetiapine and aripiprazole, has the best evidence for efficacy, though older treatments such as lithium and triiodothyronine still have utility. The striking antidepressant effect of ketamine in resistant depression has stimulated research into glutamatergic compounds; however, capturing the efficacy of ketamine with drugs suitable for continuous use has proved challenging. Growing knowledge of the pathophysiological role of inflammation in depression offers great opportunities for future treatment in terms of repurposing anti-inflammatory agents from general medicine and pre-treatment stratification of those depressed patients in whom such interventions are likely to be beneficial. Finally an older drug, the dopamine receptor agonist pramipexole, if used carefully may well improve the prospects of depressed patients who are refractory to current approaches. [ABSTRACT FROM AUTHOR]

Background: Despite lithium being a highly effective drug, it is commonly associated with inducing nephrogenic diabetes insipidus (NDI) in a high number of patients. In this case report we describe the successful use of amiloride as an effective means to manage and minimise NDI occurring in patients while they are on lithium therapy. Clinical details: The patient had been taking lithium for management of her bipolar disorder for approximately 5 years. While on this medication the patient suffered from acute kidney impairment, hypernatraemia, reduced urine osmolality, increased plasma osmolality, polyuria, polydipsia and severe dehydration. These clinical results were consistent with an adverse reaction known as NDI acquired from long-term lithium use and fluid restriction. Outcomes: Lithium was ceased on day two of admission. Intravenous fluid replacements were provided until the patient' s renal function and sodium levels returned to normal. Once the patient was symptomatically stable, lithium was reintroduced at initiating dosage levels concomitantly with amiloride with aims of reversing the concentrating defect and preventing this side effect from occurring again. The patient was discharged 15 days later. Conclusion: In most cases NDI is reversible with the cessation of lithium. However, a subset of the mental health population is resistant to other forms of therapy, leaving lithium as their only option to successfully manage their mood disorder. For patients who suffer from mental health disorders, the literature has found that amiloride can be an effective means to restore a patient' s impaired urine concentrating ability. [ABSTRACT FROM AUTHOR]

Lithium (Li) is a mood-stabilizing drug used in the treatment of bipolar disorder (BD). Recently, preclinical studies have demonstrated the potential of tamoxifen (TMX) in the treatment of acute episodes of BD. However, the prolonged use of TMX for mood disorders treatment is controversial. In this study, we evaluated the effects of TMX or Li on cognitive behavior, as well as the levels of neurotrophic factors in the brain of male and female rats. Male and female Wistar rats received administrations of water (control group), TMX or Li via gavage for a period of 28 days; the rats were then subjected to the open-field test (to evaluate spontaneous locomotion), and the novel object recognition and step-down inhibitory avoidance tests (to evaluate cognition). The levels of NGF, BDNF and GDNF were evaluated in the hippocampus and frontal cortex of the subject rats. No significant differences were observed in the open-field and inhibitory avoidance tests after drug administration in either the male or female rats. The administration of TMX, but not Li, decreased the recognition index of both the male and female rats in the object recognition test. The chronic administration of TMX decreased, whereas Li increased the levels of BDNF in the hippocampus of both the male and female rats. Tamoxifen decreased the levels of NGF in the hippocampus of female rats. In conclusion, it can be suggested that long-term treatments with TMX can lead to significant cognitive impairments by reducing the levels of neurotrophic factors in the brain of rats. [ABSTRACT FROM AUTHOR]