Conductas suicidas en adolescentes: factores de riesgo, fisiopatología y el uso de litio como terapia preventiva / SUICIDAL BEHAVIOURS IN ADOLESCENTS: RISK FACTORS, PATHOPHYSIOLOGY, AND THE USE OF LITHIUM AS A PREVENTIVE THERAPY

El suicidio en adolescentes representa una problemática de salud de suma importancia en la sociedad. El presente trabajo analiza los factores de riesgo asociados a la conducta suicida, sus correlaciones fisiopatológicas y su tratamiento con carbonato de litio. Los factores de riesgo asociados incluyen: el estrés, las crisis vitales propias de la población de estudio, y factores externos como el uso de pantallas y consumo de medios de comunicación. A su vez, las patologías psiquiátricas de base, en especial el trastorno depresivo mayor, se relacionan de manera positiva con conductas suicidas en adolescentes. Las conductas suicidas estarían vinculadas con cambios morfológicos y moleculares en el sistema nervioso. Los estados proinflamatorios mediados principalmente por la enzima glucógeno sintasa quinasa 3 beta (GSK3 ), se observarían con mayor frecuencia en sujetos con conductas suicidas. A su vez, la disminución de la expresión del factor neurotrófico derivado del cerebro (BDNF) a nivel central predispondría a mayor incidencia de suicidio. La alteración del tono serotoninérgico central sería otro factor de riesgo de suicidio en adolescentes. Las alteraciones serotoninérgicas se vincularían con conductas suicidas de tipo violentas, agresivas e impulsivas, con alta prevalencia en población adolescente. El presente trabajo muestra que el efecto anti-suicida del litio estaría mediado por la inhibición de la GSK3 , como así también por el aumento del tono serotoninérgico. De esta forma el litio disminuiría el estado proinflamatorio central, generaría un aumento de BDNF (con incremento de la supervivencia neuronal), con la subsecuente modulación de la respuesta serotoninérgica. Dada la alta prevalencia de suicidio en dicha población, es necesario contar con opciones terapéuticas eficaces y seguras, respaldados por ensayos clínicos que respalden su uso.

Suicide in adolescents represents a critical health problem in society. The present work analyzes the risk factors associated with suicidal behavior, their pathophysiological correlations, and their treatment with lithium carbonate. Associated risk factors include stress, vital crises typical of the study population, and external factors such as the use of screens and consumption of communication media. In turn, primary psychiatric pathologies, especially major depressive disorder, are positively related to suicidal behaviors in adolescents. Suicidal behaviors would be linked to morphological and molecular changes in the nervous system. Pro-inflammatory states mediated mainly by the enzyme glycogen synthase kinase 3 beta (GSK3 ) would be observed more frequently in subjects with suicidal behaviors. In turn, decreased expression of brain-derived neurotrophic factor (BDNF) at the central level would predispose to a higher incidence of suicide. The alteration of the central serotonergic tone would be another risk factor for suicide in adolescents. Serotonergic alterations would be associated with violent, aggressive and impulsive suicidal behaviors, with a high prevalence in the adolescent population.The anti-suicidal effect of lithium might be mediated by the inhibition of GSK3 , as well as the increase in serotonergic tone. In this way, lithium might decrease the central pro-inflammatory state, generate an increase in BDNF (with increased neuronal survival), and subsequently modify the serotonergic response. Given the high prevalence of suicide in this population, it is necessary to have effective and safe therapeutic options supported by clinical trials that support their use.

Optical coherence tomography findings in bipolar disorder: a preliminary receiver operating characteristic analysis on ganglion cell layer volume for diagnosis

Abstract Background Optical coherence tomography (OCT) has been recently used to investigate neuropsychiatric disorders. Objective The aim of this study was to compare the retinal nerve fiber layer thickness (RNFLT) and the ganglion cell layer (GCL) volume in patients with type 1 bipolar disorder (BPD1, diagnosed according to DSM 5) to the values in healthy controls. Methods Eighty consecutive outpatients with a diagnosis of euthymic BPD1 and 80 healthy controls were enrolled in the study. Following assessment with the Sociodemographic Data Form, Structured Clinical Interview for DSM-IV (SCID-I), Hamilton Depression Scale and Young Mania Evaluation Scale, both groups underwent Optical coherence tomography (OCT). Results The mean RNFL thickness and mean GCL volume were significantly lower in the BPD1 group than in the controls (p < 0.05). The GCL global value had a significant and independent effect in distinguishing the BPD1 patients from the controls. A cut-off value of 101 mm3 for global GCL volume was proposed to distinguish BPD1 patients from controls with a sensitivity of 87.5%. Discussion Lower values of GCL volume and RNFLT in patients suffering from BPD1 suggest that neurodegeneration may occur during the course of BPD and that this degeneration can be characterized in particular by a thinning of the GCL volume.

The Biological Rhythms Interview of Assessment in Neuropsychiatry in patients with bipolar disorder: correlation with affective temperaments and schizotypy

Objective: To assess the relationship of biological rhythms, evaluated by the Biological Rhythms Interview of Assessment in Neuropsychiatry (BRIAN), with affective temperaments and schizotypy. Methods: The BRIAN assessment, along with the Temperament Evaluation of Memphis, Pisa, Paris, and San Diego-Autoquestionnaire (TEMPS-A) and the Oxford-Liverpool Inventory for Feelings and Experiences (O-LIFE), was administered to 54 patients with remitted bipolar disorder (BD) and 54 healthy control (HC) subjects. Results: The TEMPS-A cyclothymic temperament correlated positively and the hyperthymic temperament correlated negatively with BRIAN scores in both the BD and HC groups, although the correlation was stronger in BD subjects. Depressive temperament was associated with BRIAN scores in BD but not in HC; conversely, the irritable temperament was associated with BRIAN scores in HC, but not in BD. Several positive correlations between BRIAN scores and the schizotypal dimensions of the O-LIFE were observed in both BD and HC subjects, especially with cognitive disorganization and less so with unusual experiences and impulsive nonconformity. A correlation with introversion/anhedonia was found only in BD subjects. Conclusion: Cyclothymic and depressive temperaments predispose to disturbances of biological rhythms in BD, while a hyperthymic temperament can be protective. Similar predispositions were also found for all schizotypal dimensions, mostly for cognitive disorganization.

Correlation between Expression of Peripheral IL-17 Protein and Aggression of Bipolar Mania / 法医学杂志

OBJECTIVE@#To explore the correlation between the interleukin-17 (IL-17) level of peripheral blood and aggression of bipolar mania.@*METHODS@#Thirty-six patients of bipolar mania were selected as experimental group by DSM-IV-TR and received treatment with quetiapine and lithium. Thirty-six healthy volunteers with similar age and gender were selected as control group. The level of IL-17 at baseline in each group and the level of IL-17 in the experimental group after treatment for 2, 4 and 8 weeks were detected by ELISA.@*RESULTS@#The level of IL-17 in experimental group at baseline, after treatment for 2 and 4 weeks were all significantly higher than that in control group. After 8 weeks treatment, there was no significant difference between the two groups (P > 0.05). After 2, 4 and 8 weeks treatment, the total score and aggression score of Young Mania Rating Score (YMRS) were significantly lower than the baseline level (P < 0.05). In experimental group, the level of IL-17 was positively correlated with the two scores of YMRS at baseline (P < 0.05).@*CONCLUSION@#Bipolar mania may be related to the up-regulation of IL-17. The level of IL-17 is related to the severity of manic symptoms at baseline, especially aggression symptom.

Marrow hypoplasia: a rare complication of untreated Grave’s disease / Hipoplasia de medula óssea: uma rara complicação da doença de Graves não tratada

Atypical presentation forms of hyperthyroidism are always a challenge to the clinician. We present a female patient with the typical symptoms of thyrotoxicosis, without any thionamides treatment before, associated with pancytopenia, which recovered after euthyroidism state was achieved. Although the major cases of pancytopenia in Grave’s disease are seen as a complication of antithyroid drugs (thioamides), in this case report the alteration in blood tests was associated with untreated hyperthyroidism. In the literature review, we found 19 case reports between 1981 to 2012, but it has been related to a hypercellular bone marrow with periferic destruction. Our case, however, is about a hypocellular bone marrow without fibrosis or fat tissue replacement, which proceeded with a periferic improvement following thyroid treatment. Although rare, pancytopenia, when present, may develop as an unusual and severe manifestation in untreated subjects.

Formas atípicas de apresentação do hipertireoidismo são sempre um desafio para o clínico. Apresentamos uma paciente do sexo feminino, com sintomas típicos de tireotoxicose associado a um quadro de pancitopenia sem nenhum tratamento prévio com tionamidas. A melhora da alteração hematológica ocorreu após recuperação do eutireoidismo. Embora a maioria dos casos de pancitopenia na doença de Graves seja uma complicação das drogas antitireoidianas (tionamidas), neste caso a alteração hematológica foi associada ao quadro de hipertireoidismo não tratado. Após uma revisão na literatura, encontramos 19 relatos de caso descritos no período de 1981 a 2012, nos quais o quadro de pancitopenia estava relacionado à hipercelularidade medular com destruição periférica das células sanguíneas. Nosso caso, entretanto, trata-se de uma pancitopenia com medula óssea hipocelular, sem infiltração por tecido adiposo ou fibrose, que evoluiu com melhora dos elementos do sangue periférico após tratamento do hipertireoidismo. Embora rara, a pancitopenia, quando presente, pode se manifestar como uma severa manifestação se não tratada a condição desencadeadora.

Evaluation of parathyroid function and mineral metabolism in psychiatric patients using lithium salts / Avaliação da função paratireoidiana e metabolismo mineral em pacientes psiquiátricos usuários de sais de lítio

Objective: To evaluate parathyroid function and mineral metabolism in psychiatric patients users of lithium salts. Materials and methods: We measured the serum levels of calcium, ionized calcium, inorganic phosphorus, alkaline phosphatase, albumin, parathyroid hormone (PTH), urea, creatinine, 25-hydroxy-vitamin D and lithium of 35 patients diagnosed with bipolar disorder in use of lithium carbonate (LC) for at least one year (Lithium Group – LG) and 35 healthy subjects (Control Group – CG). Results: The LG and CG were matched by sex and age. There was only statistic difference in relation to the levels of PTH and ionized calcium, with p < 0.004 and p < 0.03, respectively. Secondary form of hyperparathyroidism (HPT) was found in eight (22.8%) LG patients and in none of the CG. There was no correlation between lithemia, usage time and dosage of LC. Conclusion: Our data demonstrate that lithium may create an imbalance in the parathyroid axis, characterized by elevated levels of PTH. .

Objetivo: Avaliar a função paratireoidiana e o metabolismo mineral em pacientes psiquiátricos usuários de sais de lítio. Materiais e métodos: Foram avaliados os níveis séricos de cálcio total, cálcio iônico, fósforo inorgânico, fosfatase alcalina, albumina, paratormônio (PTH), ureia, creatinina, 25-hidroxivitamina D e lítio de 35 pacientes diagnosticados com transtorno afetivo bipolar usuários de carbonato de lítio (CL) há pelo menos um ano (Grupo Lítio – GL) e 35 indivíduos saudáveis (Grupo Controle – GC). Resultados: O GL e o GC foram pareados por sexo e idade. Somente se observou diferença estatística em relação aos níveis de PTH e cálcio iônico, com p < 0,004 e p < 0,03, respectivamente. Hiperparatireoidismo secundário foi encontrado em oito (22.8%) pacientes do GL e em nenhum do GC. No GL, não houve correlação entre litemia, tempo de uso e posologia do CL. Conclusão: Nossos dados demonstram que o lítio pode suscitar um desequilíbrio no eixo paratireoideano, caracterizado por níveis elevados de PTH. .

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.

Lithium-induced sinus node dysfunction at therapeutic serum levels.

Lithium-induced cardiotoxicity, though rare at therapeutic levels, has been reported frequently in overdoses. We report a patient who developed sinus bradycardia while being treated with lithium carbonate even though the serum lithium levels were within the therapeutic range. It reversed following withdrawal of lithium and did not reappear with subsequent treatment with valproate.

Kleine-Levin syndrome: interface between neurology and psychiatry

We report the first episode of Kleine-Levin (KLS) syndrome in a 17-year-old male. The illness onset, clinical features, neuropsychological evaluation and polysomnographic recording are described. Typical symptoms hypersomnia, hyperphagia and sexual disinhibition were observed besides behavioral disturbances, polysonographic and neuropsychological alterations. Behavioral disturbances similar to a manic episode including psychotic symptoms were relevant. The pharmacologic treatment included lithium, methylphenidate and risperidone. The introduction of risperidone aimed the control of psychotic symptoms and the persistent manifestations of hypersexuality after sleepness control and to the best of our knowledge there are no other report regarding risperidone use for KLS in the literature.

Relatamos o primeiro episódio de síndrome de Kleine-Levin (SKL) num adolescente de 17 anos. São descritos o modo de aparecimento da doença, achados clínicos, avaliação neuropsicológica e polissonografia. Foram observados sintomas típicos como hipersonolência, hiperfagia e desinibição sexual, e outras alterações comportamentais, polissonográficas e neuropsicológicas. As alterações comportamentais assemelhadas a um episódio de mania, incluindo sintomas psicóticos, foram relevantes. O tratamento farmacológico incluiu lítio, metilfenidato e risperidona. A introdução de risperidona teve por objetivo o controle dos sintomas psicóticos e das persistentes manifestações da hipersexualidade, que permaneceram após diminuição da sonolência; não temos conhecimento de relatos anteriores, na literatura, de seu uso no tratamento da SKL.