[Dermatologic side effects with use of lithium]. / Efectos adversos dermatológicos con uso de litio.

Lithium is a mood stabilizer recommended by most clinical guidelines as the gold standard to prevent relapses in the treatment of Bipolar Affective Disorder. It is highly effective, but unfortunately, it causes adverse effects at several levels, including the skin. AIM: To review the frequency, presentation, evolution, and management of adverse dermatologic effects caused by this drug. METHODS: We performed a narrative review using Scielo, Web of Science (WoS), and Google Scholar search engines, using keywords in Spanish and English. RESULTS: The skin presentations that appear most frequently are the progression of previously existing or newly diagnosed psoriasis, alopecia, acne, follicular inflammation, and maculopapular eruptions. CONCLUSIONS: Lithium produces and/or exacerbates a series of dermatological conditions of different severity, even at therapeutic levels, which are not usually severe but, even so, should not be underestimated since it can affect adherence to the drug.

Ultra-long-term lithium therapy: all-important matters and a case of successful 50-year lithium treatment.

This paper discusses essential issues related to long-term lithium therapy and presents a case of successful 50-year lithium treatment. Lithium is currently regarded as the drug of choice for preventing manic and depressive recurrences in bipolar disorder. In 1/3 of patients with bipolar disorder, long-term monotherapy with lithium can completely prevent recurrences of abnormal mood. Numerous clinical and psychosocial factors associated with a good response to lithium have been described. Lithium is more efficacious than other mood stabilizers, and its long-term treatment significantly exceeds them. Lithium also exerts antisuicidal, immunomodulatory, and neuroprotective effects. The main problems associated with long-term lithium treatment include kidney, thyroid, and probably cognitive issues. In this paper, a case of successful continuous lithium treatment for 50 years in a 79-year-old female patient is presented. In this patient, apart from maintaining a euthymic state, long-term lithium treatment also exerted a favorable effect on general health, especially the elimination of viral and other respiratory infections. It is concluded that ultra-long term lithium therapy can enable good professional and psychosocial functioning for many patients, and the possible somatic side effects are manageable.

Diabetes insípida nefrogénica inducida por litio: reporte de 2 casos en niños con trastorno del ánimo / Lithium-induced Nephrogenic Diabetes Insipidus: Report of 2 Cases in Children with Mood Disorder

La diabetes insípida (DI) es un síndrome caracterizado por poliuria y polidipsia asociado a la producción crónica de grandes volúmenes de orina diluida, secundario a una disminución de la secreción o acción de la hormona antidiurética (ADH) [1]. El litio es el principal fármaco implicado en la inducción de esta patología cuando se presenta de forma secundaria. [2]. Se presentan 2 reportes de casos de niños de 10 y 12 años con uso de litio por diagnóstico de trastorno del ánimo. Palabras Clave: Diabetes Melitus, trastornos del ánimo, nefrogénica, litio, hormona antidiurética

Diabetes insipidus (DI) is a syndrome characterized by polyuria and polydipsia associated with the production of large volumes of diluted urine, secondary to a decrease in the secretion or action of antidiuretic hormone (ADH) [1]. Lithium is the main drug involved in the induction of this pathology when it appears with a preventable cause [2]. Two case reports of children 10 and 12 years old with mood disorder and lithium use are presented with the intention of being alert to clinical manifestations and observation by caregivers.Key words: Diabetes insipidus, mood disorders, nephogenic, lithium, antidiuretic hormone.

A randomized controlled trial comparing lithium plus valproic acid versus lithium plus carbamazepine in young patients with type 1 bipolar disorder: the LICAVAL study.

BACKGROUND: Treatment of bipolar disorder (BD) usually requires drug combinations. Combinations of lithium plus valproic acid (Li/VPA) and lithium plus carbamazepine (Li/CBZ) are used in clinical practice but were not previously compared in a head-to-head trial. OBJECTIVE: The objective of this trial was to compare the efficacy and tolerability of Li/VPA versus Li/CBZ in treating type 1 BD in any phase of illness in young individuals. METHODS: LICAVAL was a randomized, unicenter, open-label, parallel-group trial that was conducted from January 2009 to December 2012 in a tertiary hospital in São Paulo, Brazil. Participants were between 18 and 35 years old and were followed up for 2 years. Our primary outcome was the number of participants achieving/maintaining response and remission during the acute and maintenance phases of BD treatment, respectively. Other outcomes assessed were symptom severity and adverse events throughout the study. In the analysis of the primary outcome, we compared groups by using a two-way repeated measures analysis of variance and estimated effect sizes by using Cohen's d. RESULTS: Of our 64 participants, 36 were allocated to Li/VPA and 28 to Li/CBZ. Our sample was composed predominantly of females (66.6%) and the average age was 27.8 years. A total of 27 (45.0%) participants had depression, 17 (28.3%) had mania/hypomania, and 16 (26.7%) had a mixed state. We found no between-group differences in CGI-BP (Clinical Global Impression Scale modified for use in bipolar disorder) scores (P = 0.326) or in any other outcome. Side effects differed significantly between groups only in the first week of treatment (P = 0.021), and there were more side effects in the Li/VPA group. Also, the Li/VPA group gained weight (+2.1 kg) whereas the Li/CBZ group presented slight weight loss (-0.2 kg). CONCLUSION: Our study suggests that Li/VPA and Li/CBZ have similar efficacy and tolerability in BD but that Li/CBZ might have metabolic advantages in the long term. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT00976794 . Registered on September 9, 2009.

Complicaciones endocrinológicas de psicofármacos en psiquiatría infantil / Endocrinological complications of psychoactive drugs in childhood psychiatry

El uso de psicofármacos en el ejercicio de la psiquiatría infantil es cada vez mayor en los últimos años. Su correcto uso requiere que el psiquiatra desarrolle a partir del diagnóstico, un tratamiento que incluya una monitorización adecuada en el caso de uso de psicofármacos, ya que esto nos permitirá tener los mejores resultados con menores efectos adversos, como también la mejor adhesión al tratamiento que se haya propuesto (1). En esta revisión encontraremos varios fármacos de uso común en el ejercicio de la profesión, asociado a efectos adversos endocrinológicos que se han descrito en la literatura, seguido de recomendaciones de manejo y seguimiento.

The use of psychotropic drugs in child psychiatry has increased in recent years. Its correct use requires that the psychiatrist develops from starting point of a diagnosis, a treatment that includes an appropriate monitoring of the use of psychotropic drug, since this will allow the patient to have the best results with fewest adverse effects, as well as the better adherence to the treatment (1). In this review we will discuss several drugs commonly used in the practice of the profession, associated with adverse endocrine effects that have been described in the literature, followed by recommendations for management and monitoring.

[Chronic kidney disease and renal failure due to lithium treatment]. / Enfermedad renal crónica y falla renal por tratamiento con litio.

Lithium has been approved for the treatment of bipolar disorder since the 1970s and even today it is considered a first-line drug for the treatment of this disease. As bipolar disorder often begins between 15-35 years of age and requires long-term treatment, the assessment of the adverse effects of the drugs used is critical. Recently, there has been renewed interest on the risk of chronic kidney disease and kidney failure induced by lithium, with findings suggesting that both complications could be more frequent than previously considered. These data have led to question traditional measures of monitoring renal function such as levels of urea and creatinine, which show signifcant increases only after an important reduction of the glomerular filtration rate. Preliminary data have suggested that certain biomarkers of kidney injury, such as neutrophil gelatinase-associated lipocalin, may be more sensitive indicators of renal damage. The use of new biomarkers that allow early detection of kidney damage could be useful for the monitoring of patients treated with lithium.

Lithium toxicity and PRES: a novel association.

We report two cases of posterior reversible encephalopathy syndrome (PRES) occurring in association with supra-therapeutic serum lithium levels. Although the neurologic manifestations of lithium toxicity are well known, this is, to our knowledge, the first report describing a link between lithium toxicity and PRES. We discuss the current understanding of the pathogenesis of PRES and suggest mechanisms by which lithium may play a role in its development.

Tiroiditis no-autoinmunes / Non-autoimmune thyroiditis

El término tiroiditis comprende un grupo de enfermedades de la glándula tiroides caracterizado por la presencia de inflamación, abarcando entidades autoinmunes y no-autoinmunes. Pueden manifestarse como enfermedades agudas con dolor tiroideo severo (tiroiditis subaguda y tiroiditis infecciosas), y condiciones en las cuales la inflamación no es clínicamente evidente, cursando sin dolor y presentando disfunción tiroidea y/o bocio (tiroiditis inducida por fármacos y tiroiditis de Riedel). El objetivo de esta revisión es aportar un enfoque actualizado sobre las tiroiditis no-autoinmunes cubriendo sus aspectos clínicos, diagnósticos y terapéuticos.

The term thyroiditis comprises a group of thyroid diseases characterized by the presence of inflammation, including autoimmune and non-autoimmune entities. It may manifest as an acute illness with severe thyroid pain (subacute thyroiditis and infectious thyroiditis), and conditions in which the inflammation is not clinically evident evolving without pain and presenting primarily thyroid dysfunction and/or goiter (drug-induced thyroiditis and Riedel thyroiditis). The aim of this review is to provide an updated approach on non-autoimmune thyroiditis and its clinical, diagnostic and therapeutic aspects.

[Non-autoimmune thyroiditis]. / Tiroiditis no-autoinmunes.

The term thyroiditis comprises a group of thyroid diseases characterized by the presence of inflammation, including autoimmune and non-autoimmune entities. It may manifest as an acute illness with severe thyroid pain (subacute thyroiditis and infectious thyroiditis), and conditions in which the inflammation is not clinically evident evolving without pain and presenting primarily thyroid dysfunction and/or goiter (drug-induced thyroiditis and Riedel thyroiditis). The aim of this review is to provide an updated approach on non-autoimmune thyroiditis and its clinical, diagnostic and therapeutic aspects.

Endocrine disturbances related to the use of lithium.

Despite recent advances in pharmacological treatment of psychiatric disorders, lithium salts remain frequently used, as they are effective and inexpensive alternatives, especially in the treatment of bipolar disorders. Their use is commonly associated with various endocrine disorders, mainly in thyroid and parathyroid function, and in mineral metabolism. This article aims at reviewing these potential endocrinopathies related to the use of lithium to make health care professionals aware and familiar with these possible complications when they follow up patients using this drug, and to make them able to monitor, identify and institute early and appropriate treatment.

[Lithium and its relation with the epithelial sodium channel and aquaporin-2]. / El litio y su relación con la acuaporina-2 y el canal de sodio ENaC.

For more than 40 years lithium has been used to treat bipolar disorder and recent trials suggest a potential efficacy also in the treatment of the amnestic mild cognitive impairment. Lithium is filtered by the glomerulus and 65% - 75% of the filtered amount is reabsorbed along the proximal tubule and in the thick ascending limb of Henle's loop by the Na+, K+, 2Cl- transporter and via paracellular. A small fraction of lithium is reabsorbed in the collecting duct's principal cells through the epithelial Na channel (ENaC) located on the apical side of the cells. Polyuria, renal tubular acidosis and chronic renal failure are the most frequent adverse effects of lithium after 10-20 years of treatment and these alterations can reach to a vasopressin nonresponding form of diabetes insipidus entity called nephrogenic diabetes insipidus. It is believed that the molecular mechanisms of these renal changes are related to a reduction in the number of aquaporin-2 inserted in the apical membrane of the cells. The causes of this are complex. Lithium is a powerful inhibitor of the enzyme glycogen synthase kinase 3ß and this is associated with a lower activity of adenylate cyclase with a reduction in the cAMP levels inside of the cells. The latter may interfere with the synthesis of aquaporin-2 and also with the traffic of these molecules from the subapical site to membrane promoting the impairment of water reabsorption in the distal part of the kidney.

El litio y su relación con la acuaporina-2 y el canal de sodio ENaC / Lithium and its relation with the epithelial sodium channel and aquaporin-2

Desde hace más de cuarenta años que el litio es usado para el tratamiento de la enfermedad bipolar; recientes estudios sugieren también su utilidad en el trastorno cognitivo mínimo tipo amnésico. El litio es filtrado en el glomérulo y un 65-75% del mismo es reabsorbido en el túbulo contorneado proximal y en el asa ascendente de Henle por el transportador Na+, K+, 2Cl- y vía paracelular. Una pequeña fracción del litio entra en las células principales del túbulo colector por medio del canal epitelial de sodio sensible al amiloride (ENaC) localizado en la membrana apical de la célula. Luego de 10- 20 años de tratamiento con litio los enfermos pueden desarrollar poliuria, acidosis tubular e insuficiencia renal crónica que puede terminar en una forma de diabetes que no responde a la arginina vasopresina llamada diabetes insípida nefrogénica. Se cree que estas fallas renales son consecuencias de una reducción en el número de moléculas de acuaporina 2 en la membrana apical. Las causas para esto son complejas. El litio es un poderoso inhibidor de la isoforma beta de la enzima glicógeno sintetasa quinasa y esto está asociado a una menor actividad de la adenilato ciclasa que lleva a una disminución en la concentración intracelular de cAMP. Esto finalmente interferiría con la síntesis de nuevas moléculas de acuaporina 2 y con el tráfico de ellas desde la zona subapical de la célula hacia la membrana celular, causando la disminución en la reabsorción de agua en la parte distal del nefrón.

For more than 40 years lithium has been used to treat bipolar disorder and recent trials suggest a potential efficacy also in the treatment of the amnestic mild cognitive impairment. Lithium is filtered by the glomerulus and 65% - 75% of the filtered amount is reabsorbed along the proximal tubule and in the thick ascending limb of Henle's loop by the Na+, K+, 2Cl- transporter and via paracellular. A small fraction of lithium is reabsorbed in the collecting duct's principal cells through the epithelial Na channel (ENaC) located on the apical side of the cells. Polyuria, renal tubular acidosis and chronic renal failure are the most frequent adverse effects of lithium after 10-20 years of treatment and these alterations can reach to a vasopressin nonresponding form of diabetes insipidus entity called nephrogenic diabetes insipidus. It is believed that the molecular mechanisms of these renal changes are related to a reduction in the number of aquaporin-2 inserted in the apical membrane of the cells. The causes of this are complex. Lithium is a powerful inhibitor of the enzyme glycogen synthase kinase 3β and this is associated with a lower activity of adenylate cyclase with a reduction in the cAMP levels inside of the cells. The latter may interfere with the synthesis of aquaporin-2 and also with the traffic of these molecules from the subapical site to membrane promoting the impairment of water reabsorption in the distal part of the kidney.

Endocrine disturbances related to the use of lithium / Distúrbios endocrinológicos relacionados ao uso de lítio

Despite recent advances in pharmacological treatment of psychiatric disorders, lithium salts remain frequently used, as they are effective and inexpensive alternatives, especially in the treatment of bipolar disorders. Their use is commonly associated with various endocrine disorders, mainly in thyroid and parathyroid function, and in mineral metabolism. This article aims at reviewing these potential endocrinopathies related to the use of lithium to make health care professionals aware and familiar with these possible complications when they follow up patients using this drug, and to make them able to monitor, identify and institute early and appropriate treatment.

Apesar dos recentes avanços farmacológicos no tratamento dos transtornos psiquiátricos, os sais de lítio permanecem como uma alternativa eficaz e de menor custo, sendo usados com frequência principalmente no tratamento dos transtornos bipolares. O seu uso é comumente relacionado com diversas alterações endocrinológicas, principalmente nas funções tiroidiana, paratiroidiana e do metabolismo iônico. Este artigo tem por objetivo fazer uma revisão dessas potenciais endocrinopatias relacionadas ao uso do lítio, para que, no seguimento de pacientes em uso dessa medicação, os profissionais de saúde estejam atentos e familiarizados com essas possíveis complicações, conseguindo identificar e instituir tratamento precocemente.

Sildenafil reduces polyuria in rats with lithium-induced NDI.

Lithium (Li)-treated patients often develop urinary concentrating defect and polyuria, a condition known as nephrogenic diabetes insipidus (NDI). In a rat model of Li-induced NDI, we studied the effect that sildenafil (Sil), a phosphodiesterase 5 (PDE5) inhibitor, has on renal expression of aquaporin-2 (AQP2), urea transporter UT-A1, Na(+)/H(+) exchanger 3 (NHE3), Na(+)-K(+)-2Cl(-) cotransporter (NKCC2), epithelial Na channel (ENaC; α-, ß-, and γ-subunits), endothelial nitric oxide synthase (eNOS), and inducible nitric oxide synthase. We also evaluated cGMP levels in medullary collecting duct cells in suspension. For 4 wk, Wistar rats received Li (40 mmol/kg food) or no treatment (control), some receiving, in weeks 2-4, Sil (200 mg/kg food) or Li and Sil (Li+Sil). In Li+Sil rats, urine output and free water clearance were markedly lower, whereas urinary osmolality was higher, than in Li rats. The cGMP levels in the suspensions of medullary collecting duct cells were markedly higher in the Li+Sil and Sil groups than in the control and Li groups. Semiquantitative immunoblotting revealed the following: in Li+Sil rats, AQP2 expression was partially normalized, whereas that of UT-A1, γ-ENaC, and eNOS was completely normalized; and expression of NKCC2 and NHE3 was significantly higher in Li rats than in controls. Inulin clearance was normal in all groups. Mean arterial pressure and plasma arginine vasopressin did not differ among the groups. Sil completely reversed the Li-induced increase in renal vascular resistance. We conclude that, in experimental Li-induced NDI, Sil reduces polyuria, increases urinary osmolality, and decreases free water clearance via upregulation of renal AQP2 and UT-A1.

The Syndrome of Irreversible Lithium-Effectuated Neurotoxicity (SILENT): one-year follow-up of a single case.

In this article, we report the case history of a 44-year-old female patient with bipolar disorder who developed the so-called Syndrome of Irreversible Lithium-Effectuated Neurotoxicity (SILENT). A detailed description of our patient's neurologic status is provided at baseline (i.e. during lithium intoxication) and after one year of follow-up, confirming the persistency of cerebellar signs and symptoms. Although rare, our report - which shows a severe and disabling form of SILENT - underscores the need to perform a strict control of the putative risk factors argued to be associated with the development of this syndrome. In our case, the presence of fever and the administration of multiple doses of antipsychotics may have contributed to the poor outcome exhibited by the patient.

Comparison of carbamazepine and lithium in treatment of bipolar disorder: a systematic review of randomized controlled trials.

OBJECTIVES: To review data from randomized controlled trials (RCTs) assessing the comparative efficacy of carbamazepine and lithium in treatment of acute manic and maintenance phase of bipolar disorder (BD). DESIGN: RCTs were identified through a search strategy that included: electronic databases, reference cross-checking, hand search of non-indexed publications, and book chapters on the treatment of BD comparing carbamazepine with lithium. Outcomes investigated were antimanic effect, trial withdrawal, relapse, hospitalization, need for rescue medication, and presence of adverse effects. Selection of studies and data analysis were performed independently by authors. Whenever possible, data from trials were combined through meta-analyses. Relative risks (RR) were estimated for dichotomous data. RESULTS: In acute mania, carbamazepine was similar to lithium on the following outcomes: trial withdrawal due to adverse effects, number of participants with at least one adverse effect, improvement in the Clinical Global Impression (CGI). In acute mania, carbamazepine was associated with fewer trial withdrawals. In maintenance treatment, carbamazepine was similar to lithium in relapses and hospitalization, but there were fewer trial withdrawals due to adverse effects on lithium. CONCLUSION: This review suggests that carbamazepine might be comparable to lithium in terms of efficacy and safety, and therefore a valuable option in the treatment of both manic and maintenance phases.