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.

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.

O tratamento farmacológico do transtorno bipolar: uma revisão sistemática e crítica dos aspectos metodológicos dos estudos clínicos modernos / The pharmacological treatment of bipolar disorder: a systematic and critical review of the methodological aspects of modern clinical trials

OBJETIVO: Revisar sistematicamente os principais estudos clínicos sobre o tratamento farmacológico do transtorno bipolar e fazer uma análise crítica de seus aspectos metodológicos. MÉTODO: Realizou-se uma busca nas bases de dados Medline, ISI e PsycINFO, utilizando-se os seguintes termos de busca: "bipolar", "randomized", "placebo" e "controlled". Foram selecionados estudos clínicos randomizados, duplo-cegos e controlados por placebo sobre o tratamento farmacológico do transtorno bipolar. Além disso, de acordo com os nossos critérios, as amostras deveriam ser de no mínimo 100 pacientes e a substância testada deveria ser usada como monoterapia. RESULTADOS: 34 artigos se adequaram aos critérios de seleção. Todas as substâncias atualmente indicadas para mania, depressão bipolar e para o tratamento de manutenção foram mais eficazes que o placebo em pelo menos um estudo. Todavia, esses estudos tiveram amostras altamente selecionadas, altas taxas de abandono e baixas taxas de resposta clínica. CONCLUSÃO: Os modernos estudos clínicos sobre o tratamento farmacológico do transtorno bipolar apresentam algumas importantes limitações metodológicas. Assim, seus resultados devem ser considerados com cautela.

OBJECTIVE: To review systematically the main clinical trials on the pharmacological treatment of bipolar disorder and to make a critical analysis of their methodological aspects. METHOD: A search in Medline, ISI and PsycINFO databases was conducted, using the following search terms: "bipolar", "randomized", "placebo" e "controlled". Randomized, double-blind, placebo-controlled clinical trials on the pharmacological treatment of bipolar disorder were selected. Besides, according to our criteria, samples had to consist of at least 100 patients and experimental drug had to be used as monotherapy. RESULTS: 34 articles met our selection criteria. All drugs currently indicated for mania, bipolar depression and maintenance treatment of bipolar disorder were more effective than placebo in at least one clinical trial. However, these studies had highly selected samples, high dropout rates and low response rates. CONCLUSION: Modern clinical trials on pharmacological treatment of bipolar disorder have important methodological limitations. So, their results should be taken with caution.

Health-related quality of life in Thai bipolar disorder.

BACKGROUND: Bipolar disorder (BPD) affects both patients 'functioning and well-being. Quality of life (QoL) has gained increasing attention as an important functional outcome in BPD. The present study was conducted to assess QoL of Thai BPD patients. MATERIAL AND METHOD: The authors obtained cross-sectional demographic, clinical, and functional ratings from 285 BPD outpatients. SF-36 and Thai Mania Rating Scale (TMRS) were used to assess QoL and severity of symptoms respectively. RESULTS: The mean TMRS was 4.42 +/- 5.87. Compared with the Thai general population, SF-36 scores of study population were significantly lower, except for bodily pain and social functioning domains. Sodium valproate treated group's SF-36 scores was better than lithium carbonate treated group' (p = 0.02). CONCLUSION: The present study is one of the pioneers in assessing the impact of co-morbidity on health-related QoL in Thai BPD patients. Even in the stable phase, patients were less functioning than the normal Thai population.

Tratamiento del trastorno afectivo bipolar en el embarazo / Treatment of bipolar disorder during pregnancy

A number offactors must be evaluated in order to determine the safety ofany medication that is being considered for use during pregnancy All psychotropic medications diffuse readily across the placenta. No psychotropic medication has been approved by the Food and Drug Administration (FDA) for use during the pregnancy and pregnant women have traditionally been excluded from pharmacologic research. Numerous studies have shown a high relapse rate in psychiatrk patient during the pregnancy whose medications were discontinued. When deciding whether or not to treat a psychiatrk patient during the pregnancy the guiding principie is to weigh the risks of fetal exposure to a psychotropic medication against the risks to both the mother and fetus of not treating a psychiatrk illness. Patients with bipolar disorder are at significant risk of relapse ifuntreated, particularly following abrupt discontinuation of lithium. Untreated bipolar illness with recurrence of mania may result in progression of the disorder. Another risk is disease chronkity and treatment resistance.

Una serie de factores deben ser evaluados a fin de determinar la seguridad de la medicación que se está considerando para su uso durante el embarazo. Todos los medicamentos psicotrópicos difunden fácilmente a través de la placenta. Ninguna medicación psicotrópica ha sido aprobada por la Food and Drug Administration (FDA) para su uso durante el embarazo, y las mujeres embarazadas han sido tradicionalmente excluidas de la investigación farmacológica. Numerosos estudios han demostrado una alta tasa de recaídas en pacientes psiquiátricos cuyos medicamentos fueron descontinuados. Al decidir si se debe o no tratar a una paciente psiquiátrica durante el embarazo, el principio rector es sopesar los riesgos de la exposición del feto a una medicación psicotrópica contra los riesgos para la madre y el feto de no tratar una enfermedad psiquiátrica. Los pacientes con trastorno bipolar se encuentran en gran riesgo de recaída si no se tratan, en particular después de la interrupción abrupta de litio. Si no se trata la enfermedad bipolar, con la recurrencia de la manía puede darse lugar a la progresión del trastorno. Otro riesgo es la cronicidad de la enfermedad y la resistencia al tratamiento.

Polypharmacy and suicide attempts in bipolar disorder

OBJECTIVE: The aim of this study was to assess the association between suicide attempts and the use of multiple drugs in patients with bipolar disorder. METHOD: One hundred sixty-nine bipolar disorder outpatients diagnosed using the DSM-IV Structured Clinical Interview were included. Demographic and socioeconomic data, number of medications currently in use, history of suicide attempts, number of years undiagnosed, age of onset and current psychiatric co-morbidities were assessed using a structured questionnaire and DSM-IV criteria. The main outcome measure was the number of psychotropic drugs currently in use. RESULTS: Approximately half of all patients (48.5 percent) presented a history of suicide attempt; 84 percent were using more than one medication, and 19 percent were using more than three drugs. The most frequent combinations of drugs used by these patients were: lithium + valproate (17 percent); lithium + antipsychotics (10 percent); lithium + valproate + antipsychotics (9 percent); and antidepressants + any drug (6 percent). The number of suicide attempts was associated with the use of multiple drugs. CONCLUSIONS: Our findings support the notion that the use of combination therapy in bipolar disorder may be related to severity of the BD, such as number of suicide attempts.

OBJETIVO: O objetivo deste trabalho foi verificar associação entre tentativas de suicídio e uso de múltiplas drogas em pacientes com transtorno do humor bipolar. MÉTODO: Cento e sessenta e nove pacientes ambulatoriais com transtorno do humor bipolar, diagnosticados pela entrevista clínica estruturada do DSM-IV, foram incluídos. Dados demográficos e socioeconômicos, número de medicações em uso, história de tentativas de suicídio, número de anos sem diagnóstico, idade de início e comorbidades psiquiátricas foram avaliados através de um questionário estruturado e pelos critérios do DSM-IV. A principal medida de desfecho foi o número de medicamentos psicotrópicos usados correntemente. RESULTADOS: Cerca de metade dos pacientes (48,5 por cento) apresentou uma história de tentativas de suicídio; 84 por cento estavam usando mais do que uma medicação e 19 por cento estavam usando mais do que três medicações. As combinações de fármacos mais utilizadas por estes pacientes foram: lítio + valproato (17 por cento); lítio + antipsicóticos (10 por cento); lítio + valproato + antipsicóticos (9 por cento); e antidepressivos + outros fármacos (6 por cento). O número de tentativas de suicídio mostrou-se associado ao uso de polifarmácia, na análise ajustada. CONCLUSÕES: Nossos resultados sugerem que a polifarmácia em pacientes bipolares pode estar relacionada a indicadores de gravidade, como número de tentativas de suicídio.

Erythrocyte phosphoglucomutase activity of bipolar I patients currently using lithium or carbamazepine

Lithium has been used for the last five decades to treat bipolar disorder, but the molecular basis of its therapeutic effect is unknown. Phosphoglucomutase is a key enzyme in the metabolism of glycogen. In yeast, rabbit and human HEK293 cells, it is inhibited by lithium in the therapeutic concentration range. We measured the phosphoglucomutase activity in erythrocytes and the inhibitor constant for lithium in a population of healthy subjects and compared them to those of bipolar patients treated with lithium or carbamazepine. The specific activity of phosphoglucomutase measured in vitro in erythrocytes from control subjects presented a normal distribution, with the difference between the lowest and the highest activity being approximately 2-fold (0.53-1.10 nmol mg Hb-1 min-1). Comparison of phosphoglucomutase activity in untreated bipolar patients and control subjects showed no significant difference, whereas comparison between bipolar patients treated with carbamazepine or lithium revealed significantly lower mean values in patients treated with carbamazepine (747.3 ± 27.6 vs 879.5 ± 35.9 pmol mg Hb-1 min-1, respectively). When we studied the concentration of lithium needed to inhibit phosphoglucomutase activity by 50 percent, a bimodal distribution among the population tested was obtained. The concentration of LiCl needed to inhibit phosphoglucomutase activity by 50 percent was 0.35 to 1.8 mM in one group of subjects and in the other it was 3 to 4 mM. These results suggest that phosphoglucomutase activity may be significant in patients with bipolar disorder treated with lithium and carbamazepine.

Mania associated with interferon alpha2b treatment.

Neuropsychiatric side effects are common with Interferon a 2b. Psychosis and depression have been reported. Several cases of mania have been reported but only few have been associated with treatment for hepatitis B. We report a case of mania with psychotic symptoms in a 21-year-old female diagnosed to have hepatitis-B infection, who was receiving interferon. The report supports the view that dose reductions or pauses during interferon treatment can cause mania. Family history of mood disorder could be a risk factor. Atypical presentations are common in interferon-induced mania. Mania induced by interferon responds well to antimanic drugs. Since the use of interferon is increasing in developing countries, the need for awareness of side effects and management issues are important and these are highlighted.

Hypomania as an aura in migraine.

We report a 19-year-old man presenting to the department of Psychiatry for the evaluation of prominent behavioral symptoms associated with episodic headaches, with normal inter-episodic periods. A diagnosis of classic migraine with hypomanic aura was made. Other possible co-morbid or causative illnesses were excluded and preventive therapy with valproate was started due to the prominent affective symptoms as a part of the migranous aura. With this the frequency of headaches gradually decreased over the next four months. He was followed up for 2 years when he was found to be symptom-free. Recent research into the mechanisms of migraine has identified that the cortical hyperexcitability and an imbalance between neuronal inhibition and excitement mediated by gamma-aminobutyric acid and excitatory amino acids respectively may be the underlying mechanism. The high rate of affective disorders in patients with migraine, association of migraine with an aura comprising of mood symptoms and good response to treatment with mood-stabilisers might give newer insights into the pathophysiology of mood disorder as well.

Gabapentin for overactive bladder and nocturia after anticholinergic failure

INTRODUCTION: We reviewed our experience with the use of gabapentin to treat symptoms of overactive bladder (OAB) and nocturia in patients who have failed conventional anticholinergic therapy. METHODS: Thirty-one patients referred to us with refractory (OAB) and/or nocturia were treated with oral gabapentin. All the patients had tried or remained on antimuscarinic drugs during treatment. Twenty-four of 31 complained of bothersome symptoms during day and night and the other seven had primary complaints of nocturia. Initial gabapentin doses ranged from 100-300 mg at bedtime. Dose was slowly titrated up to 3,000 mg based on patients' symptomatology and tolerability. RESULTS:The mean age was 51 years old (range 27-78). There were 13 men and 18 women. The median steady state dose chosen by the patient after initial titration was 600 mg/day. Fourteen of 31 patients reported subjective improvement of their frequency and 8 have been on the medication for over 12 months with persistent efficacy. For the 14 improved patients, mean frequency/24 hours decreased from 14.1 ± 2.2 to10.0 + 2.1. Three patients with primary nocturia reported improvement from a mean of 4.0 ± 1.3 to 1.0 ± 0.3 episodes/night. Six patients stopped taking the drug within one month due to side effects mostly described as drowsiness or lethargy. CONCLUSION: Fourteen of 31 patients with refractory (OAB) and nocturia improved with oral gabapentin. Gabapentin was generally well tolerated and can be considered in selective patients when conventional modalities have failed.