Valproate and lithium: Old drugs for new pharmacological approaches in brain tumors?

Beyond its use as an antiepileptic drug, over time valproate has been increasingly used for several other therapeutic applications. Among these, the antineoplastic effects of valproate have been assessed in several in vitro and in vivo preclinical studies, suggesting that this agent significantly inhibits cancer cell proliferation by modulating multiple signaling pathways. During the last years various clinical trials have tried to find out if valproate co-administration could enhance the antineoplastic activity of chemotherapy in glioblastoma patients and in patients suffering from brain metastases, demonstrating that the inclusion of valproate in the therapeutic schedule causes an improved median overall survival in some studies, but not in others. Thus, the effects of the use of concomitant valproate in brain cancer patients are still controversial. Similarly, lithium has been tested as an anticancer drug in several preclinical studies mainly using the unregistered formulation of lithium chloride salts. Although, there are no data showing that the anticancer effects of lithium chloride are superimposable to the registered lithium carbonate, this formulation has shown preclinical activity in glioblastoma and hepatocellular cancers. However, few but interesting clinical trials have been performed with lithium carbonate on a very small number of cancer patients. Based on published data, valproate could represent a potential complementary therapeutic approach to enhance the anticancer activity of brain cancer standard chemotherapy. Same advantageous characteristics are less convincing for lithium carbonate. Therefore, the planning of specific phase III studies is necessary to validate the repositioning of these drugs in present and future oncological research.

Preventive Effects of Lithium Carbonate on Antidepressant-Induced Switch During Depressive Episodes: Chinese Data Analysis.

CONTEXT: Some patients experiencing depressive episodes can switch to mania or become mania during treatment with antidepressants. Avoiding a switch is an important part of any therapeutic plan, whether a patient suffers from unipolar or bipolar depression. One method of avoiding switching is use of a mood stabilizer, such as lithium carbonate. DESIGN: The research team performed a narrative review by searching Chinese electronic databases: the Chinese Biomedical Database (CBM), the China National Knowledge Infrastructure (CNKI), WANFANG, and the Chinese Social Sciences Citation Index (VIP). The search used the keywords depression-bipolar depression and depressive episode-and lithium carbonate. Results such as comments, letters, reviews, and case reports were excluded. SETTING: The study took place at Jinhua Second Hospital, China. RESULTS: A random effect model was used to account for the data, using Revman 5.2. The switch rate for the intervention groups was 8.28% or 29 out of 351 participants and of the control groups was 25.29% or 87 out of 344 participants (OR = 0.25, 95% CI: 0.16 to 0.39). Lithium carbonate reduced the switch rate by 67.25% [(25.29%-8.28%) /25.29%]. In the bipolar depression group, lithium carbonate reduced the switch rate by 68.11% [(25.84%-8.24%) /25.84%]. In the depression and unipolar depression groups, lithium carbonate reduced the switch rate by 67.07% [(25.29%-8.26%) /25.29%]. In the group of patients treated with selective serotonin reuptake inhibitors (SSRIs), lithium reduced the switch rate by 60.3% [(29.85%-11.85%) /29.85%]. In group of patients treated by tricyclic antidepressants (TCAs), lithium carbonate reduced the switch rate by 73.14% [(22.28%-6.01%) /22.28%]. CONCLUSIONS: As typical mood stabilizer, lithium carbonate can reduce the antidepressant-induced switch rates in patients with depressive episodes regardless of the type of antidepressant and the type of depressive episode. Further research should compare the effectiveness of lithium carbonate to that of other mood stabilizers in preventing switching associated with antidepressants.

Lithium treatment in the era of personalized medicine.

In 1949, an Australian psychiatrist, John Cade, reported on the antimanic efficacy of lithium carbonate, which is regarded as an introduction of lithium into contemporary psychiatry. Since the 1960s, lithium has been a precursor of mood stabilizers and has become first-choice drug for the prevention of affective episodes in mood disorders. For nearly four decades, lithium has also been used for the augmentation of antidepressant drugs in treatment-resistant depression. The knowledge of clinical and biological factors connected with the capability of long-term lithium treatment to prevent manic and depressive recurrences makes an important element of the personalized medicine of mood disorders. Excellent prophylactic lithium responders can be characterized by distinct mood episodes, with full remissions between them, the absence of other psychiatric morbidity, and the family history of bipolar illness. In recent years, many other clinical and biological factors connected with such a response have been identified, helping to select the best candidates for lithium prophylaxis. The antisuicidal effect of lithium during its long-term administration has been demonstrated and should also be taken into account as the element of personalized medicine for the pharmacological prophylaxis of patients with mood disorders. Several studies pertaining to personalized medicine were also dedicated to lithium treatment of acute mood episodes. Lithium still has a value in the treatment of mania and bipolar depression. However, it seems that the more important indication would be the augmentation of antidepressant drugs in treatment-resistant depression. The factors connected with the efficacy of lithium in these conditions are reviewed.

High lithium levels in tobacco may account for reduced incidences of both Parkinson's disease and melanoma in smokers through enhanced ß-catenin-mediated activity.

Parkinson's disease (PD) patients have higher rates of melanoma and vice versa, observations suggesting that the two conditions may share common pathogenic pathways. ß-Catenin is a transcriptional cofactor that, when concentrated in the nucleus, upregulates the expression of canonical Wnt target genes, such as Nurr1, many of which are important for neuronal survival. ß-Catenin-mediated activity is decreased in sporadic PD as well as in leucine-rich repeat kinase 2 (LRRK2) and ß-glucosidase (GBA) mutation cellular models of PD, which is the most common genetic cause of and risk for PD, respectively. In addition, ß-catenin expression is significantly decreased in more aggressive and metastatic melanoma. Multiple observational studies have shown smokers to have significantly lower rates of PD as well as melanoma implying that tobacco may contain one or more elements that protect against both conditions. In support, smoker's brains have significantly reduced levels of α-synuclein, a pathological intracellular protein found in PD brain and melanoma cells. Tobacco contains very high lithium levels compared to other plants. Lithium has a broad array of neuroprotective actions, including enhancing autophagy and reducing intracellular α-synuclein levels, and is effective in both neurotoxin and transgenic preclinical PD models. One of lithium's neuroprotective actions is enhancement of ß-catenin-mediated activity leading to increased Nurr1 expression through its ability to inhibit glycogen synthase kinase-3 ß (GSK-3ß). Lithium also has anti-proliferative effects on melanoma cells and the clinical use of lithium is associated with a reduced incidence of melanoma as well as reduced melanoma-associated mortality. This is the first known report hypothesizing that inhaled lithium from smoking may account for the associated reduced rates of both PD and melanoma and that this protection may be mediated, in part, through lithium-induced GSK-3ß inhibition and consequent enhanced ß-catenin-mediated activity. This hypothesis could be directly tested in clinical trials assessing lithium therapy's ability to affect ß-catenin-mediated activity and slow disease progression in patients with PD or melanoma.

Finding the best effective way of treatment for rapid I-131 turnover Graves' disease patients: A randomized clinical trial.

BACKGROUND: Rapid I-131 turnover Graves' disease patients have low cure rate. We aimed to compare cure percentage at 12 months among 3 treatment doses of I-131 with or without lithium carbonate (LiCO3) in rapid turnover Graves' disease patients. METHODS: Sixty Graves' disease patients referred for radioactive iodine treatment were randomised into three arms of treatment: Group A, 3.7 MBq I-131/g thyroid plus 600 mg/day LiCO3, Group B, 5.55 MBq I-131/g plus 600 mg/day LiCO3, and Group C, 7.4 MBq I-131/g without LiCO3. Data were collected at baseline, 3, 6, 9, and 12 months. The primary endpoint were cure rates (percentage of euthyroid or hypothyroid) at 12 months. Pairwise comparisons were made across 3 groups using an equality of proportions test. The secondary endpoint, the odds of cure over the total follow-up for group B and C versus group A, was analyzed using generalized estimating equation (GEE). Side effects of I-131 and LiCO3 treatment were evaluated at 1 to 2 weeks after treatment. RESULTS: The cure rate at 12 months was 45% (9/20) for group A, 60% (12/20) for group B and 80% (16/20) for group C. The mean difference in proportion cured at 12 months between group C and group A was 35 (7.0 to 66.8)%; P-value = .02. There was a statistically significant difference between cure rates over all follow-up of group C and A after adjustment for sex (adjusted OR = 3.09; 95%CI = 1.32-7.20; P-value = .009), but no significant difference was found between group B and A or C and B in the primary and/or secondary efficacy endpoints. Side effects from the treatment were found in 12% (7/60); 2 in group A, 4 in group B, and 1 in group C. Four of these were likely due to LiCO3 side effects. CONCLUSIONS: Treatment of rapid turnover Graves' disease patients with high dose I-131 (7.4 MBq/g) provides significantly higher cure rates at 12 months, and 3 times odds of cure than 3.7 MBq/g I-131 plus LiCO3 with lesser side effects. We thus recommend 7.4 MBq I-131/g for treatment in these patients.

[Profile of lithium carbonate use in patients with bipolar disorder in Colombia].

INTRODUCTION: Lithium is the drug of choice for the treatment of bipolar affective disorder. OBJECTIVE: To define lithium therapeutic profile and adverse reactions to its use in patients with bipolar affective disorder in Colombia. MATERIALS AND METHODS: We conducted an observational retrospective cohort study between January 1 and December 31, 2013, which included patients with a diagnosis of bipolar disorder treated with lithium carbonate in 25 Colombian cities; we evaluated socio-demographic variables, lithium dose, co-medication, drug interactions and adverse reactions. A multivariate analysis was done using SPSS 22.0. RESULTS: The 331 patients had an average age of 44.5 ± 13.9 years; 59.2% were women. The mean dose of lithium was 898 ± 294 mg/day; 22% received doses lower than recommended, and patients had received lithium for 38.0 ± 39.5 months (range: 12-159 months). Lithium levels in blood had been measured only in 13.5% of patients; 71.3% of them had received adjuvant therapy for bipolar disorder with other drugs, especially clozapine (16.6%) and valproic acid (16.6%). The main comorbidities were hypothyroidism (18.1%) and hypertension (12.7%); 390 potentially toxic drug interactions were found, and adverse reactions were reported in 1.2% of patients. A statistically significant association was found between a lower risk of combination therapy and receiving treatment in the cities of Bogotá (OR=0.4, p=0.025), Cartagena (OR=0.3, p=0.015) and Ibagué (OR=0.3, p=0.025). CONCLUSION: Lithium was generally used at recommended doses and intervals, but a significant percentage of patients received lower doses than those recommended, and it was not possible to compare with lithium levels in blood. Adverse reactions and blood lithium levels reporting should be improved in patients with bipolar disorder in Colombia.

Perfil de utilización del carbonato de litio en pacientes con trastorno afectivo bipolar en 25 ciudades de Colombia / Profile of lithium carbonate use in patients with bipolar disorder in Colombia

Resumen Introducción. El litio es el medicamento de elección para el tratamiento del trastorno afectivo bipolar. Objetivo. Determinar el perfil de uso y las reacciones secundarias del litio en pacientes con trastorno afectivo bipolar en Colombia. Materiales y métodos. Se hizo un estudio observacional de cohorte retrospectiva entre el 1° de enero y el 31 de diciembre de 2013, en pacientes con diagnóstico de trastorno afectivo bipolar tratados con carbonato de litio en 25 ciudades colombianas. Se evaluaron las variables sociodemográficas, las dosis del litio, la medicación simultánea con otros fármacos, las interacciones medicamentosas y las reacciones adversas. Se hizo un análisis multivariado utilizando el programa SPSS 22.0®. Resultados. La edad promedio de los 331 pacientes fue de 44,5 ± 13,9 años, 59,2 % de ellos eran mujeres, la dosis promedio de litio fue de 898 ± 294 mg/día, y 22 % recibía dosis inferiores a las recomendadas; los participantes habían recibido el medicamento durante 38,0 ± 39,5 meses en promedio (rango: 12-159 meses), y solo a 13,5 % de ellos se les había hecho el análisis de litio en sangre. El 71,3 % recibía otros medicamentos como tratamiento coadyuvante para el trastorno afectivo bipolar, especialmente clozapina (16,6 %) y ácido valproico (16,6 %). Las principales enfermedades concomitantes fueron el hipotiroidismo (18,1 %) y la hipertensión arterial (12,7 %). Se encontraron 390 interacciones medicamentosas potencialmente tóxicas y se reportaron reacciones secundarias en 1,2 % de los casos. Se encontró una asociación estadísticamente significativa con un menor riesgo de recibir tratamiento combinado en pacientes tratados en las ciudades de Bogotá (odds ratio, OR=0,4; p=0,025), Cartagena (OR=0,3; p=0,015) e Ibagué (OR=0,3; p=0,025). Conclusiones. El litio se administraba en las dosis e intervalos recomendados, pero un porcentaje significativo recibía dosis inferiores a las recomendadas y no fue posible contrastar el efecto con los niveles de litio en suero. Se debe mejorar el reporte de reacciones adversas y la medición de los niveles de litio en suero en los pacientes con trastorno afectivo bipolar en Colombia.

Abstract Introduction: Lithium is the drug of choice for the treatment of bipolar affective disorder. Objective: To define lithium therapeutic profile and adverse reactions to its use in patients with bipolar affective disorder in Colombia. Materials and methods: We conducted an observational retrospective cohort study between January 1 and December 31, 2013, which included patients with a diagnosis of bipolar disorder treated with lithium carbonate in 25 Colombian cities; we evaluated socio-demographic variables, lithium dose, co-medication, drug interactions and adverse reactions. A multivariate analysis was done using SPSS 22.0. Results: The 331 patients had an average age of 44.5 ± 13.9 years; 59.2% were women. The mean dose of lithium was 898 ± 294 mg/day; 22% received doses lower than recommended, and patients had received lithium for 38.0 ± 39.5 months (range: 12-159 months). Lithium levels in blood had been measured only in 13.5% of patients; 71.3% of them had received adjuvant therapy for bipolar disorder with other drugs, especially clozapine (16.6%) and valproic acid (16.6%). The main comorbidities were hypothyroidism (18.1%) and hypertension (12.7%); 390 potentially toxic drug interactions were found, and adverse reactions were reported in 1.2% of patients. A statistically significant association was found between a lower risk of combination therapy and receiving treatment in the cities of Bogotá (OR=0.4, p=0.025), Cartagena (OR=0.3, p=0.015) and Ibagué (OR=0.3, p=0.025). Conclusion: Lithium was generally used at recommended doses and intervals, but a significant percentage of patients received lower doses than those recommended, and it was not possible to compare with lithium levels in blood. Adverse reactions and blood lithium levels reporting should be improved in patients with bipolar disorder in Colombia.

Omega-3 fatty acids and mood stabilizers alter behavioral and oxidative stress parameters in animals subjected to fenproporex administration.

Studies have shown that oxidative stress is involved in the pathophysiology of bipolar disorder (BD). It is suggested that omega-3 (ω3) fatty acids are fundamental to maintaining the functional integrity of the central nervous system. The animal model used in this study displayed fenproporex-induced hyperactivity, a symptom similar to manic BD. Our results showed that the administration of fenproporex, in the prevent treatment protocol, increased lipid peroxidation in the prefrontal cortex (143%), hippocampus (58%) and striatum (181%), and ω3 fatty acids alone prevented this change in the prefrontal cortex and hippocampus, whereas the co-administration of ω3 fatty acids with VPA prevented the lipoperoxidation in all analyzed brain areas, and the co-administration of ω3 fatty acids with Li prevented this increase only in the prefrontal cortex and striatum. Moreover, superoxide dismutase (SOD) activity was decreased in the striatum (54%) in the prevention treatment, and the administration of ω3 fatty acids alone or in combination with Li and VPA partially prevented this inhibition. On the other hand, in the reversal treatment protocol, the administration of fenproporex increased carbonyl content in the prefrontal cortex (25%), hippocampus (114%) and striatum (91%), and in prefrontal coxter the administration of ω3 fatty acids alone or in combination with Li and VPA reversed this change, whereas in the hippocampus and striatum only ω3 fatty acids alone or in combination with VPA reversed this effect. Additionally, the administration of fenproporex resulted in a marked increase of TBARS in the hippocampus and striatum, and ω3 fatty acids alone or in combination with Li and VPA reversed this change. Finally, fenproporex administration decreased SOD activity in the prefrontal cortex (85%), hippocampus (52%) and striatum (76%), and the ω3 fatty acids in combination with VPA reversed this change in the prefrontal cortex and striatum, while the co-administration of ω3 fatty acids with Li reversed this inhibition in the hippocampus and striatum. In conclusion, our results support other studies showing the importance of ω3 fatty acids in the brain and the potential for these fatty acids to aid in the treatment of BD.

[Cluster headache treatment]. / Traitements de l'algie vasculaire de la face.

UNLABELLED: Acute treatment: sumatriptan, oxygen inhalation. Prophylactic treatment: verapamil, lithium carbonate. Transitional treatment. SURGICAL TREATMENT: deep brain stimulation, occipital nerve stimulation, stimulation of the sphenopalatin ganglion.

The bipolarity of light and dark: A review on Bipolar Disorder and circadian cycles.

BACKGROUND: Bipolar Disorder is characterized by episodes running the full mood spectrum, from mania to depression. Between mood episodes, residual symptoms remain, as sleep alterations, circadian cycle disturbances, emotional deregulation, cognitive impairment and increased risk for comorbidities. The present review intends to reflect about the most recent and relevant information concerning the biunivocal relation between bipolar disorder and circadian cycles. METHODS: It was conducted a literature search on PubMed database using the search terms "bipolar", "circadian", "melatonin", "cortisol", "body temperature", "Clock gene", "Bmal1 gene", "Per gene", "Cry gene", "GSK3ß", "chronotype", "light therapy", "dark therapy", "sleep deprivation", "lithum" and "agomelatine". Search results were manually reviewed, and pertinent studies were selected for inclusion as appropriate. RESULTS: Several studies support the relationship between bipolar disorder and circadian cycles, discussing alterations in melatonin, body temperature and cortisol rhythms; disruption of sleep/wake cycle; variations of clock genes; and chronotype. Some therapeutics for bipolar disorder directed to the circadian cycles disturbances are also discussed, including lithium carbonate, agomelatine, light therapy, dark therapy, sleep deprivation and interpersonal and social rhythm therapy. LIMITATIONS: This review provides a summary of an extensive research for the relevant literature on this theme, not a patient-wise meta-analysis. CONCLUSIONS: In the future, it is essential to achieve a better understanding of the relation between bipolar disorder and the circadian system. It is required to establish new treatment protocols, combining psychotherapy, therapies targeting the circadian rhythms and the latest drugs, in order to reduce the risk of relapse and improve affective behaviour.

Successful antidepressant chronotherapeutics enhance fronto-limbic neural responses and connectivity in bipolar depression.

The identification of antidepressant response predictors in bipolar disorder (BD) may provide new potential enhancements in treatment selection. Repeated total sleep deprivation combined with light therapy (TSD+LT) can acutely reverse depressive symptoms and has been proposed as a model antidepressant treatment. This study aims at investigating the effect of TSD+LT on effective connectivity and neural response in cortico-limbic circuitries during implicit processing of fearful and angry faces in patients with BD. fMRI and Dynamic Causal Modeling (DCM) were combined to study the effect of chronotherapeutics on neural responses in healthy controls (HC, n = 35) and BD patients either responder (RBD, n = 26) or non responder (nRBD, n = 11) to 3 consecutive TSD+LT sessions. Twenty-four DCMs exploring connectivity between anterior cingulate cortex (ACC), dorsolateral prefrontal cortex (DLPFC), Amygdala (Amy), fusiform gyrus and visual cortex were constructed. After treatment, patients significantly increased their neural responses in DLPFC, ACC and insula. nRBD showed lower baseline and endpoint neural responses than RBD. The increased activity in ACC and in medial prefrontal cortex, associated with antidepressant treatment, was positively associated with the improvement of depressive symptomatology. Only RBD patients increased intrinsic connectivity from DLPFC to ACC and reduced the modulatory effect of the task on Amy-DLPFC connection. A successful antidepressant treatment was associated with an increased functional activity and connectivity within cortico-limbic networks, suggesting the possible role of these measures in providing possible biomarkers for treatment efficacy.

Lithium carbonate in the management of cannabis withdrawal: a randomized placebo-controlled trial in an inpatient setting.

RATIONALE: Preclinical studies suggest that lithium carbonate (lithium) can reduce precipitated cannabinoid withdrawal in rats by stimulating release of the neuropeptide oxytocin, while two open-label studies indicate lithium may ameliorate cannabis withdrawal symptoms in humans. OBJECTIVES: This study was conducted to examine the efficacy and safety of lithium in the inpatient management of cannabis withdrawal and to determine whether lithium affects plasma oxytocin and the rate of elimination of plasma cannabinoids during abstinence. METHODS: Treatment-seeking cannabis-dependent adults (n = 38) were admitted for 8 days to an inpatient withdrawal unit and randomized to either oral lithium (500 mg) or placebo given twice a day under double-blind randomized controlled trial (RCT) conditions. Primary outcomes included withdrawal severity [cannabis withdrawal scale (CWS)], rates of detoxification completion, and adverse events. Plasma cannabinoids, plasma oxytocin and serum lithium levels were measured repeatedly over admission. Follow-up research interviews were conducted at 14, 30, and 90 days postdischarge. RESULTS: Lithium did not significantly affect total CWS scores relative to placebo, although it significantly reduced individual symptoms of "loss of appetite," "stomach aches," and "nightmares/strange dreams." No significant group differences were found in treatment retention or adverse events. Lithium did not increase plasma oxytocin levels nor influence the rate of elimination of cannabinoids. Both placebo- and lithium-treated participants showed reduced levels of cannabis use (verified by urinalysis) and improved health and psychosocial outcomes at 30- and 90-day follow-up relative to pretreatment baselines. CONCLUSIONS: Despite the strong rationale for the present study, the efficacy of lithium over placebo in the management of cannabis withdrawal was not demonstrated.

[The Kleine-Levin syndrome: new aspects of a rare disease]. / Das Kleine-Levin-Syndrom : Neues von einer seltenen Erkrankung.

The Kleine-Levin syndrome (KLS) is a rare disease which can occur one to several times per year. The KLS belongs to the group of hypersomnia of central origin occurring mainly during the second decade of life after infections, sleep deprivation, alcohol consumption or minor trauma. Early manifestation combined with hypersexuality during symptomatic phases can be a predictor for a long course of the disease, which lasts a mean of 1-27 years. Due to the lack of biological markers diagnosis at first manifestation is difficult. The classical trias of hypersomnia, hyperphagia and hypersexuality can only be found in 45 % of patients. The dominant clinical symptoms are hypersomnia with changes in perception and behavior. Subtraction of perfusion studies performed during symptomatic and asymptomatic phases showed decreased perfusion of the left hypothalamus, thalamus, basal ganglia, medial and dorsolateral frontal and temporal regions. In the few patients who had lumbar punctures in both symptomatic and asymptomatic phases hypocretin-1 was moderately to slightly lowered during symptomatic phases. Meta-analyses showed good therapeutic effects of stimulants on the symptom sleepiness. Lithium reduces the frequency and duration of symptomatic phases. Assuming that KLS is underdiagnosed it should be considered as a differential diagnosis in young patients with recurrent hypersomnia.

Short TE (7) Li-MRS confirms Bi-exponential lithium T2 relaxation in humans and clearly delineates two patient subtypes.

PURPOSE: (i) To develop an MRS technique to measure (7) Li levels in human brain in a reasonable scan time, (ii) to develop a technique to quantify (7) Li T2 relaxation times as measured from human brain in patients taking lithium for the treatment of their bipolar disorder, and (iii) to confirm or refute the presence of bi-exponential (7) Li T2 relaxation in human brain. MATERIALS AND METHODS: We modified a spin-echo MRS pulse sequence to decrease its minimum echo time. With IRB approval, we performed lithium MRS with the modified pulse sequence on 13 euthymic bipolar patients stable on long-term lithium to treat their disease. RESULTS: We were able to achieve a total scan time per sample of 8:20; total scan time including imaging, calibration and MRS was approximately 1 h 15 min. We observed bi-exponential T2 relaxation in the majority of patients, with an average short decay time of 5.3 ± 1.4 ms and an average long decay time of 68.2 ± 10.2 ms. However, in two patients we observed strongly mono-exponential T2 relaxation with an average decay time of 47.4 ± 1.3 ms. CONCLUSION: (7) Li relaxation patterns may prove useful to distinguish between lithium-responsive and lithium nonresponsive bipolar patients.

Rationale for clinical interventions in prodromal psychosis. Are such interventions safe?

We compare the reported side effects of medication from the trials of prodromal psychosis treatment. We note that the side effects of antipsychotics are those described in the usual pharmacology of these substances and that the severity of side effects are dependent on dosage, with more side effects at higher doses. We report on the search for alternative compounds for the treatment of prodromal psychosis. Omega fatty acids and Cognitive Behavioural Therapy are certainly good adjuvant treatments for suspected prodromal psychosis. With further evidence they may be considered appropriate to use as monotherapy, particularly in the early prodrome. Treatment of prodromal psychosis continues to present a number of risks; therefore the decision to treat ultimately must depend on the symptoms presented by the individual.

Lithium as an adjuvant in the postoperative ablation of remnant tissue in low-risk thyroid carcinoma.

BACKGROUND: Thyroid remnant ablation (RA) with 30 mCi of radioactive iodine (131I) in patients thyroidectomized for treatment of low-risk differentiated thyroid carcinoma (DTC) has a success rate of 64% to 84%. Lithium increases the residence time of 131I in the thyroid tissue. The aim of this study was to determine if lithium treatment added to 30 mCi 131I would enhance the success rate of this treatment compared with 30 mCi 131I alone in patients who were thyroidectomized for treatment of low-risk DTC. METHODS: This was a randomized study with endpoint at one year. Sixty one consecutive patients were enrolled and randomized into two groups: group A (n=32) treated with 30 mCi 131I; group B (n=29) treated with 30 mCi 131I plus an oral dose of lithium 900 mg/day, for 7 days. All patients were evaluated by whole body scan (WBS) with 123I and had serum TSH, thyroglobulin (Tg), and anti-Tg antibodies (TgAb) determined when they were hypothyroid on no thyroid hormone. Patients were reevaluated after one year with serum TSH, Tg, and TgAb determinations and WBS with 123I. The criteria for defining a successful outcome was a negative WBS and a serum Tg of <1. RESULTS: Group A was composed of 28 women and four men (ages 25-71 years) with 2 having follicular thyroid carcinoma (FTC), 22 having papillary thyroid carcinoma (PTC) of 1-4.5 cm, and 8 having micro PTCs (mPTC) of 0.3-0.8 cm. Group B was composed of 26 women and 3 men (ages 20-63 years) with 3 having FTC, 15 having PTC of 1.2-3.5 cm, and 11 having mPTC of 0.2-0.8 cm. All patients had a history of a WBS after their post-therapeutic 131I dose that showed uptake in the cervical region. After one year, 22 patients from group A had a negative WBS (68.75%) and in group B, 27 patients had a negative WBS (93.1%). The successful rates for the follow-up WBS were significantly different (p=0.017). There were 19 patients in group A in whom the initial Tg was positive. Of these, 14 had a negative follow-up Tg (73.7%). Group B had 9 patients with a positive initial Tg and all of them had a negative follow-up Tg (100%). CONCLUSION: The addition of lithium to treatment with 30 mCi 131I in thyroidectomized patients with low-risk DTC improved the efficacy of thyroid RA and therefore might be a better alternative than using higher doses of 131I for remnant ablation in these patients.

[Emotional hyper-reactivity and sleep disturbances in remitted patients with bipolar disorders]. / Perturbations de la réactivité émotionnelle et du sommeil dans les troubles bipolaires en période intercritique.

INTRODUCTION: Emotional reactivity and sleep constitute key dimensions of bipolar disorder. Emotional reactivity referred to emotion response intensity and emotion response threshold. Higher emotion reactivity is described during both mood episodes and periods of remission in bipolar disorder. As well, sleep disturbances are described during both acute episodes and euthymic periods in bipolar disorder. Links between sleep and emotion regulation start to be studied in general population. Interactions between sleep and emotion systems can rely on shared neuronal structures, which involve limbic system. Future research on sleep and emotion regulation relationships is required in bipolar disorder. METHODS: A systematic review of the scientific literature was conducted. Studies on emotional reactivity in bipolar disorder during periods of remission were presented. Sleep studies of bipolar disorder during inter-critical periods were discussed too. Researches on interactions between sleep and emotion regulation in general population were presented. Finally, therapeutic applications focusing on sleep and emotional regulation in bipolar disorder were described. RESULTS: Patients with bipolar disorder display disturbances of sleep and emotion reactivity even during periods of remission. Indeed, bipolar patients display more intense and more labile emotions assessed by self-questionnaires, increase positive attribution to neutral stimuli corroborated by startle reflex, functional changing on imagery studies. Sleep disturbances during inter-critical periods refer to clinical poor sleep quality and to increase time in bed, more frequent nocturnal awaking, more variable sleep-wake patterns assessed by actigraphy and polysomnography. In general population some studies have shown the impact of sleep restriction on emotion dysregulation. F-MRI studies show that healthy participants present increase activation of some structures such as amygdala involved in emotion processing. Deregulation of these areas has already been noticed in previous studies of euthymic bipolar patients without sleep restriction procedure. Considering sleep and emotion processes enhance our understanding of medication action mechanisms. Lithium and sodium valproate reduce melatonin light sensitivity and increased the activity period. It can be postulated that these effects on circadian system can impact sleep regulation. Furthermore, an f-MRI study shows that mood stabilizers can reduce amygdala activation of bipolar patients compared to untreated bipolar patients during an emotional task. Emotion and sleep regulation can be targeted by specific psychotherapy. Interpersonal and social rhythm therapy, cognitive behavioral therapy of insomnia and mindfulness applied to bipolar disorder are presented and discussed. DISCUSSION: Disturbances of sleep and emotional reactivity remain during periods of remission in bipolar disorder. Further research is required to better understand relationships between these two processes in bipolar disorder. Sleep and emotion dysgulations can be targeted by specific psychotherapy. More systematic assessment of sleep an emotional reactivity in remitted bipolar patients can lead to consider and treat this residual symptomatology that could reduce recurrences.

Pharmacologic treatments for pediatric bipolar disorder: a review and meta-analysis.

OBJECTIVE: A growing body of literature has documented pediatric bipolar disorder to be a severely impairing form of psychopathology. However, concerns remain as to the inadequacy of the extant literature on its pharmacotherapy. Furthermore, treatment studies have not been systematically reviewed for treatment effects on core and associated symptoms. Thus, a systematic evaluation and synthesis of the available literature on the efficacy of antimanic pharmacotherapy for pediatric bipolar disorder on symptoms of mania, depression, and attention-deficit/hyperactivity disorder was undertaken. METHOD: A systematic search was conducted through PubMed from 1989 through 2010 for open-label and randomized controlled trials published in English on the pharmacotherapy of pediatric mania. RESULTS: There have been 46 open-label (n = 29) and randomized (n = 17) clinical trials of antimanic agents in pediatric bipolar disorder encompassing 2,666 subjects that evaluated a range of therapeutic agents, including traditional mood stabilizers, other anticonvulsants, second-generation antipsychotics, and naturopathic compounds. This literature has documented that the available armamentarium has different levels of efficacy in the treatment of pediatric mania. Because all psychotropic classes are associated with important adverse effects, a careful risk-benefit analysis is warranted when initiating pharmacologic treatment with any of these compounds. In the limited data available, the effects of antimanic agents on depression and symptoms of attention-deficit/hyperactivity disorder have been, in general, modest. Few studies have evaluated the effects of antimanic agents in children younger than 10 years. CONCLUSIONS: A substantial body of scientific literature has evaluated the safety and efficacy of various medicines and drug classes in the treatment of mania in pediatric bipolar disorder. More work is needed to assess the safety and efficacy of psychotropic drugs in children younger than 10 years, to further evaluate the efficacy of naturopathic compounds, and to further evaluate the effects of antimanic treatments for the management of depression and attention-deficit/hyperactivity disorder.

Cluster headache--acute and prophylactic therapy.

Cluster headache (CH) pain is the most severe of the primary headache syndromes. It is characterized by periodic attacks of strictly unilateral pain associated with ipsilateral cranial autonomic symptoms. The majority of patients have episodic CH, with cluster periods that typically occur in a circannual rhythm, while 10% suffer from the chronic form, with no significant remissions between cluster periods. Sumatriptan injection or oxygen inhalation is the first-line therapy for acute CH attacks, with the majority of patients responding to either treatment. The calcium channel blocker verapamil is the drug of choice for CH prevention. Other drugs that may be used for this purpose include lithium carbonate, topiramate, valproic acid, gabapentin, and baclofen. Transitional prophylaxis, most commonly using corticosteroids, helps to control the attacks at the beginning of a cluster period. Peripheral neural blockade is effective for short-term pain control. Recently, the therapeutic options for refractory CH patients have expanded with the emergence of both peripheral (mostly occipital nerve) and central (hypothalamic) neurostimulation. With the emergence of these novel treatments, the role of ablative surgery in CH has declined.

[Management of patients with acute manic or mixed episodes and outcome at three months]. / Modalités de prise en charge de l'accès maniaque ou mixte aigu et évolution à trois mois.

METHODS: EMBLEM is a prospective, multicenter observational study on the management of patients with a manic or mixed episode in routine clinical practice (total of 3566 subjects included in 14 European countries). The study consisted of a 12-week acute phase and a 24-month maintenance phase. Subjects were included if they initiated or changed oral medication, according to the decision of the treating psychiatrist, with antipsychotics, anticonvulsants and / or lithium, for the treatment of a manic or mixed episode. The present report describes the acute phase outcomes of the French subgroup. RESULTS: Between December 2002 and June 2004, 126 investigators included a total of 795 subjects as in- or outpatients (450 women, 320 men, mean age: 45.6 years). The episode was most often recurrent (74.7 %) and patients were suffering from either a manic (65.8 %) or a mixed episode (34.2 % vs. EMBLEM Europe, 24 %). The intensity of manic symptoms was elevated (YMRS mean total score: 26.6) and functional impairment of the individuals was high, with 41.9 % experiencing moderate to severe work impairment and 23.6 % being unable to work. The prevalence of suicide attempts was 35.8 % (lifelong), close to the prevalence in the other French cohort EPIMAN (32 %). Abuse / dependence on alcohol and cannabis were present in 10.2 % and 11.1 % of subjects, respectively. At entry, 37.4 % were receiving monotherapy while 27.3 % received a combined therapy. All patients received treatment for their manic / mixed episode, either in combination (59.2 %) or in monotherapy (40.8 %). Atypical antipsychotics were more often prescribed in association (34.0 % of subjects) than in monotherapy (21.1 %). In patients treated in monotherapy, atypical antipsychotics were the most often prescribed drug (51.9 %). Results showed an improvement within both monotherapy and combination therapy in effectiveness measures at week 12. After 12 weeks, 31.3 % were considered recovered and 67.9 % did not relapse. These results confirm current data on co-morbidities and give information on treatment for bipolar patients at three months of follow-up. The long-term evaluation of the French EMBLEM cohort - 12, 24 months and up to five years - is presently ongoing.