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1.
Expert Opin Drug Metab Toxicol ; 15(8): 619-631, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31271537

RESUMO

Introduction: The comorbidity between obsessive-compulsive disorder (OCD) and bipolar disorders (BDs) is a frequent and severe condition characterized by a chronic course, high suicidal risk and tendency towards chronicity and treatment non-response. It represents a real challenge to psychiatrists, while requiring a careful and appropriate therapeutic management consisting in the combination of serotonergic antidepressants (ADs), such as serotonin reuptake inhibitors (SRIs), with mood stabilizers. This combination, like any other, raises the problems related to drug interactions that may lead to pharmacokinetic and pharmacodynamic changes, resulting in the modification of the pharmacologic effect and safety profile of a given compound. Areas covered: The aim of the present paper was to review the literature on the pharmacokinetic and pharmacodynamic changes resulting from the interactions of the different drugs prescribed in the OCD-BD comorbidity. Expert opinion: The literature data on pharmacokinetic and pharmacodynamic changes due to interactions of drugs commonly prescribed in the treatment of the OCD-BD comorbidity are extremely limited, and the information is inferred by findings gathered in psychiatric patients suffering from other disorders. This represents a gap in psychopharmacology that should be filled by specific studies on this important topic.


Assuntos
Transtorno Bipolar/tratamento farmacológico , Transtorno Obsessivo-Compulsivo/tratamento farmacológico , Antimaníacos/administração & dosagem , Antimaníacos/farmacocinética , Antimaníacos/farmacologia , Antipsicóticos/administração & dosagem , Antipsicóticos/farmacocinética , Antipsicóticos/farmacologia , Transtorno Bipolar/complicações , Interações de Medicamentos , Humanos , Transtorno Obsessivo-Compulsivo/complicações , Inibidores de Captação de Serotonina/administração & dosagem , Inibidores de Captação de Serotonina/farmacocinética , Inibidores de Captação de Serotonina/farmacologia
2.
Transl Psychiatry ; 9(1): 158, 2019 06 04.
Artigo em Inglês | MEDLINE | ID: mdl-31164628

RESUMO

A particular challenge in the development of a bipolar disorder (BD) model in animals is the complicated clinical course of the condition, characterized by manic, depressive and mixed mood episodes. Ouabain (OUA) is an inhibitor of Na+/K+-ATPase enzyme. Intracerebroventricular (ICV) injection of this drug in rats has been regarded a proper model to study BD by mimic specific manic symptoms, which are reversed by lithium (Li), an important mood stabilizer drug. However, further validation of this experimental approach is required to characterize it as an animal model of BD, including depressive-like behaviors. The present study aimed to assess manic- and depressive-like behaviors, potential alteration in the hypothalamic-pituitary-adrenal (HPA) system and oxidative stress parameters after a single OUA ICV administration in adult male Wistar rats. Moreover, we evaluated Li effects in this experimental setting. Data show that OUA ICV administration could constitute a suitable model for BD since the injection of the drug triggered manic- and depressive-like behaviors in the same animal. Additionally, the OUA model mimics significant physiological and neurochemical alterations detected in BD patients, including an increase in oxidative stress and change in HPA axis. Our findings suggest that decreased Na+/K+-ATPase activity detected in bipolar patients may be linked to increased secretion of glucocorticoid hormones and oxidative damage, leading to the marked behavioral swings. The Li administration mitigated these pathological changes in the rats. The proposed OUA model is regarded as suitable to simulate BD by complying with all validities required to a proper animal model of the psychiatric disorder.


Assuntos
Comportamento Animal/efeitos dos fármacos , Transtorno Bipolar/induzido quimicamente , Transtorno Bipolar/fisiopatologia , Modelos Animais de Doenças , Inibidores Enzimáticos/farmacologia , Sistema Hipotálamo-Hipofisário/efeitos dos fármacos , Ouabaína/farmacologia , Sistema Hipófise-Suprarrenal/efeitos dos fármacos , Animais , Antimaníacos/farmacologia , Transtorno Bipolar/tratamento farmacológico , Transtorno Bipolar/metabolismo , Sistema Hipotálamo-Hipofisário/metabolismo , Sistema Hipotálamo-Hipofisário/fisiopatologia , Injeções Intraventriculares , Compostos de Lítio/farmacologia , Masculino , Sistema Hipófise-Suprarrenal/metabolismo , Sistema Hipófise-Suprarrenal/fisiopatologia , Ratos Wistar
5.
Behav Brain Res ; 362: 109-113, 2019 04 19.
Artigo em Inglês | MEDLINE | ID: mdl-30630015

RESUMO

Animal models are critical for the study of disease mechanisms and the screening of potential novel treatments. In the context of bipolar disorder, amphetamine-induced hyperactivity (AIH) is a frequently used screening model for antimanic effects. Yet, the utility of screening models depends on their predictive (or pharmacological) validity and it is expected that such models will respond to effective treatments. Lithium is the prototypic mood stabilizer but previous data regarding the effects of lithium in the AIH model are not clear and most data comes from studies using acute lithium administration that is not relevant to the therapeutic regimen in patients. To evaluate the pharmacological validity of AIH as a model for mania-like behavior we tested the interaction between chronic oral administration of lithium and amphetamine in ICR (CD-1®) mice and in black Swiss mice. We conducted 4 different experiments where chronic lithium was followed by an acute injection of amphetamine and one experiment where chronic amphetamine was combined with chronic lithium. The results show that amphetamine result in hyperactivity (experiments 1-4) and that lithium has no effects. Moreover, chronic amphetamine (experiment 5) result in sensitization that is not attenuated by lithium. The results clearly show that the predictive validity of the AIH model in ICR or black Swiss mice is problematic and possibly cast doubt on the utilization of the AIH as a screening model for novel mood stabilizers in other strains of mice.


Assuntos
Anfetamina/farmacologia , Comportamento Animal/efeitos dos fármacos , Atividade Motora/efeitos dos fármacos , Agitação Psicomotora/tratamento farmacológico , Animais , Anticonvulsivantes/farmacologia , Antimaníacos/farmacologia , Transtorno Bipolar/tratamento farmacológico , Estimulantes do Sistema Nervoso Central/farmacologia , Modelos Animais de Doenças , Masculino , Camundongos
6.
Pharmacol Biochem Behav ; 178: 51-55, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-29191711

RESUMO

BACKGROUND: One concern regarding animal models of psychopathology is unclear external validity. One way to establish external validity is to examine measures representing separate facets of the pathology with a battery of tests in the same cohort of animals. Additionally, utilizing the same animals in a battery of tests can help to reduce the number of animals in research. However, issues had been raised regarding the analysis of data coming from batteries and the standard practice is to analyze each test separately. This approach introduces two problems: (1) the analysis answers the question regarding separate tests but not regarding the general effect; (2) there is no correction for multiple comparisons. One way to overcome these challenges is to use transformations to Z-scores. We suggest an additional approach, analyzing test batteries with multivariate analysis of variance (MANOVA). METHODS: To compare the outcomes of Z-score analysis and MANOVA we re-analyzed two published studies where data were initially analyzed separately for each test. Additionally, we computed effect sizes. RESULTS: The first study tested interaction between sex and lithium in a battery of manic-like behaviors, the second study tested asenapine in a battery of anxiety-like behaviors. For the first study, the MANOVA analysis indicated no effects of sex and a significant antimanic-like effect of lithium and for the second study, the MANOVA indicated a significant anxiolytic effect of asenapine. Z-score analysis resulted in a significant general antimanic-like effect in the lithium study but failed to demonstrate the anxiolytic effects of asenapine in the second study. CONCLUSIONS: It is possible to suggest that MANOVA is an appropriate way to analyze data from test batteries and that its use, when appropriate, can increase the validity, predictability and reproducibility of results.


Assuntos
Análise de Variância , Modelos Animais de Doenças , Bateria Neuropsicológica de Luria-Nebraska , Análise Multivariada , Psicopatologia/métodos , Animais , Ansiolíticos/farmacologia , Ansiolíticos/uso terapêutico , Antimaníacos/farmacologia , Antimaníacos/uso terapêutico , Ansiedade/tratamento farmacológico , Escala de Avaliação Comportamental , Comportamento Animal/efeitos dos fármacos , Transtorno Bipolar/tratamento farmacológico , Feminino , Compostos Heterocíclicos de 4 ou mais Anéis/farmacologia , Compostos Heterocíclicos de 4 ou mais Anéis/uso terapêutico , Lítio/farmacologia , Lítio/uso terapêutico , Masculino , Camundongos , Reprodutibilidade dos Testes , Fatores Sexuais
7.
Genes Brain Behav ; 18(6): e12483, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-29667298

RESUMO

Monoamine oxidase-A (MAOA) metabolises monoamines and is implicated in the pathophysiology of psychiatric disorders. A polymorphic repetitive DNA domain, termed the uVNTR (upstream variable number tandem repeat), located at the promoter of the MAOA gene is a risk factor for many of these disorders. MAOA is on the X chromosome suggesting gender could play a role in regulation. We analysed MAOA regulation in the human female cell line, SH-SY5Y, which is polymorphic for the uVNTR. This heterozygosity allowed us to correlate allele-specific gene expression with allele-specific transcription factor binding and epigenetic marks for MAOA. Gene regulation was analysed under basal conditions and in response to the mood stabiliser sodium valproate. Both alleles were transcriptionally active under basal growth conditions; however, the alleles showed distinct transcription factor binding and epigenetic marks at their respective promoters. Exposure of the cells to sodium valproate resulted in differential allelic expression which correlated with allele-specific changes in distinct transcription factor binding and epigenetic marks at the region encompassing the uVNTR. Biochemically our model for MAOA promoter function has implications for gender differences in gene × environment responses in which the uVNTR has been implicated as a genetic risk.


Assuntos
Alelos , Cromatina/química , Monoaminoxidase/genética , Regiões Promotoras Genéticas , Antimaníacos/farmacologia , Linhagem Celular Tumoral , Cromatina/metabolismo , Epigênese Genética , Humanos , Monoaminoxidase/metabolismo , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Fatores de Transcrição/metabolismo , Ativação Transcricional , Ácido Valproico/farmacologia
8.
Osteoporos Int ; 30(2): 257-266, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30374598

RESUMO

This systematic review and meta-analysis summarized the results from nine eligible observational studies. Lithium use was significantly associated with a decrease risk of fractures. INTRODUCTION: The association between lithium use and risk of fracture is uncertain. To date, there have been no meta-analyses that have studied the association between the two. We conducted a systematic review and meta-analysis to examine the effect of lithium medication on the risk of fracture. METHODS: A comprehensive literature search was performed in PubMed, Embase, and MEDLINE to include eligible observational studies. Three reviewers conducted the literature search, study selection, study appraisal, and data abstraction independently. Random effects models were used to obtain the overall estimate for meta-analysis. Cochran's Q and Higgins' I2 were used to assess heterogeneity. A funnel plot and Egger's regression test were employed to assess publication bias. RESULTS: Of the 3819 studies that were identified by our search strategy, eight were eligible for the systematic review, while seven of them qualified for the meta-analysis. In studies that reported risk ratio (RR) of fracture as an outcome (five studies [n = 1,134,722]), lithium use was associated with a 20% decrease in risk of fracture (RR = 0.80; 95% CI, 0.73-0.87; p < 0.01). A decreased risk of fracture associated with lithium was also observed in studies that adjusted for previous fractures (RR = 0.81; 95% CI, 0.73-0.89; p < 0.01). The decreased risk of fracture associated with lithium use remained consistent in all the analyses with different inclusion criteria. Neither significant heterogeneity nor significant publication bias was observed. CONCLUSION: The present systematic review and meta-analysis demonstrated that lithium use was associated with a significant decreased risk of fracture.


Assuntos
Antimaníacos/uso terapêutico , Compostos de Lítio/uso terapêutico , Fraturas por Osteoporose/prevenção & controle , Antimaníacos/farmacologia , Densidade Óssea/efeitos dos fármacos , Humanos , Compostos de Lítio/farmacologia , Estudos Observacionais como Assunto , Medição de Risco/métodos , Fatores de Risco
9.
Neuropsychopharmacology ; 44(3): 620-628, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30487653

RESUMO

Bipolar disorder (BD) is a serious mood disorder associated with circadian rhythm abnormalities. Risk for BD is genetically encoded and overlaps with systems that maintain circadian rhythms. Lithium is an effective mood stabilizer treatment for BD, but only a minority of patients fully respond to monotherapy. Presently, we hypothesized that lithium-responsive BD patients (Li-R) would show characteristic differences in chronotype and cellular circadian rhythms compared to lithium non-responders (Li-NR). Selecting patients from a prospective, multi-center, clinical trial of lithium monotherapy, we examined morning vs. evening preference (chronotype) as a dimension of circadian rhythm function in 193 Li-R and Li-NR BD patients. From a subset of 59 patient donors, we measured circadian rhythms in skin fibroblasts longitudinally over 5 days using a bioluminescent reporter (Per2-luc). We then estimated circadian rhythm parameters (amplitude, period, phase) and the pharmacological effects of lithium on rhythms in cells from Li-R and Li-NR donors. Compared to Li-NRs, Li-Rs showed a difference in chronotype, with higher levels of morningness. Evening chronotype was associated with increased mood symptoms at baseline, including depression, mania, and insomnia. Cells from Li-Rs were more likely to exhibit a short circadian period, a linear relationship between period and phase, and period shortening effects of lithium. Common genetic variation in the IP3 signaling pathway may account for some of the individual differences in the effects of lithium on cellular rhythms. We conclude that circadian rhythms may influence response to lithium in maintenance treatment of BD.


Assuntos
Antimaníacos/farmacologia , Transtorno Bipolar/tratamento farmacológico , Transtorno Bipolar/fisiopatologia , Ritmo Circadiano , Fibroblastos , Compostos de Lítio/farmacologia , Adulto , Animais , Transtorno Bipolar/genética , Células Cultivadas , Ritmo Circadiano/efeitos dos fármacos , Ritmo Circadiano/fisiologia , Fibroblastos/efeitos dos fármacos , Fibroblastos/fisiologia , Técnicas de Genotipagem , Humanos , Receptores de Inositol 1,4,5-Trifosfato/genética , Medições Luminescentes , Camundongos , Células NIH 3T3 , Proteínas Circadianas Period , Polimorfismo de Nucleotídeo Único , Estudos Prospectivos
10.
Metab Brain Dis ; 34(2): 605-619, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30535659

RESUMO

Bipolar disorder is a psychiatric disease characterized by recurrent episodes of mania and depression. Blueberries contain bioactive compounds with important pharmacological effects such as neuroprotective and antioxidant actions. The aim of this study was to investigate the effects of blueberry extract and/or lithium on oxidative stress, and acetylcholinesterase (AChE) and Na+, K+-ATPase activity in an experimental ketamine-induced model of mania. Male Wistar rats were pretreated with vehicle, blueberry extract (200 mg/kg), and/or lithium (45 mg/kg or 22.5 mg/kg twice daily) for 14 days. Between the 8th and 14th days, the animals also received an injection of ketamine (25 mg/kg) or vehicle. On the 15th day the animals received a single injection of ketamine; after 30 min, the locomotor activity was evaluated in an open field test. Ketamine administration induced an increase in locomotor activity. In the cerebral cortex, hippocampus and striatum, ketamine also induced an increase in reactive oxygen species, lipid peroxidation and nitrite levels, as well a decrease in antioxidant enzyme activity. Pretreatment with blueberry extract or lithium was able to prevent this change. Ketamine increased the AChE and Na+, K+-ATPase activity in brain structures, while the blueberry extract partially prevented these alterations. In addition, our results showed that the neuroprotective effect was not potentiated when lithium and blueberry extract treatment were given together. In conclusion, our findings suggest that blueberry extract has a neuroprotective effect against an experimental model of mania. However, more studies should be performed to evaluate its effects as an adjuvant therapy.


Assuntos
Antimaníacos/farmacologia , Transtorno Bipolar/tratamento farmacológico , Mirtilos Azuis (Planta) , Lítio/farmacologia , Animais , Antioxidantes/farmacologia , Comportamento Animal/efeitos dos fármacos , Peroxidação de Lipídeos/efeitos dos fármacos , Locomoção/efeitos dos fármacos , Masculino , Modelos Teóricos , Fármacos Neuroprotetores/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Ratos Wistar , Substâncias Reativas com Ácido Tiobarbitúrico/farmacologia
11.
Psychiatry Res ; 272: 73-79, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30579185

RESUMO

Mania is accompanied with immune activation as indicated by increased pro-inflammatory cytokines, acute phase proteins; and carcinoembryonic antigen (CEA) is known to accompany signs of immune-inflammatory responses in bipolar disorder (BD) and medical disorders. In this study, it was aimed to compare high sensitivity C-reactive protein (hsCRP), CEA levels and white blood cells (WBCs) counts in the treatment-resistant BD (Group 3), the treatment-responsive BD patients (Group 2), and the healthy control group (Group 1). The sociodemographic data form, the Young Mania Rating Scale (YMRS), the Hamilton Depression Rating Scale (HDRS), and the Clinical Global Impression Severity of Illness (CGI-S) Scale were applied to the patients. In Group 3, the WBCs counts, and CEA levels were significantly higher than the other two groups. There was a positive correlation between WBCs counts and YMRS and CGI-S scores in all manic patients. There was a positive correlation between CEA levels and YMRS, HDRS and CGI-S in manic patients. This study shows that there is an activation of the immune-inflammatory response system in treatment resistant manic patients; and, WBCs counts and CEA levels are associated with severity of disease in manic patients.


Assuntos
Antimaníacos/farmacologia , Transtorno Bipolar , Inflamação , Adulto , Biomarcadores , Transtorno Bipolar/sangue , Transtorno Bipolar/tratamento farmacológico , Transtorno Bipolar/imunologia , Transtorno Bipolar/fisiopatologia , Feminino , Humanos , Inflamação/sangue , Inflamação/imunologia , Masculino , Pessoa de Meia-Idade , Índice de Gravidade de Doença
12.
Curr Neuropharmacol ; 17(4): 318-341, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-29256353

RESUMO

BACKGROUND: Lithium is a first-line treatment for bipolar disorder in adults, but its mechanism of action is still far from clear. Furthermore, evidences of its use in pediatric populations are sparse, not only for bipolar disorders, but also for other possible indications. OBJECTIVES: To provide a synthesis of published data on the possible mechanisms of action of lithium, as well as on its use in pediatric samples, including pharmacokinetics, efficacy, and safety data. METHODS: Clinical trials in pediatric samples with at least one standardized measure of efficacy/ effectiveness were included in this review. We considered: i) randomized and open label trials, ii) combination studies iii) augmentation studies iv) case series including at least 5 patients. RESULTS: Different and non-alternative mechanisms of action can explain the clinical efficacy of lithium. Clinical studies in pediatric samples suggest that lithium is effective in managing manic symptoms/episodes of bipolar disorder, both in the acute phase and as maintenance strategy. Efficacy on depressive symptoms/phases of bipolar disorder is much less clear, while studies do not support its use in unipolar depression and severe mood dysregulation. Conversely, it may be effective on aggression in the context of conduct disorder. Other possible indications, with limited published evidence, are the acute attacks in Kleine-Levin syndrome, behavioral symptoms of X-fragile syndrome, and the management of clozapine- or chemotherapy- induced neutropenia. Generally, lithium resulted relatively safe. CONCLUSIONS: Lithium seems an effective and well-tolerated medication in pediatric bipolar disorder and aggression, while further evidences are needed for other clinical indications.


Assuntos
Transtorno Bipolar/tratamento farmacológico , Transtorno Depressivo Maior/tratamento farmacológico , Compostos de Lítio/administração & dosagem , Adolescente , Fatores Etários , Antidepressivos/administração & dosagem , Antidepressivos/efeitos adversos , Antidepressivos/farmacocinética , Antidepressivos/farmacologia , Antimaníacos/administração & dosagem , Antimaníacos/efeitos adversos , Antimaníacos/farmacocinética , Antimaníacos/farmacologia , Transtorno Bipolar/metabolismo , Criança , Ensaios Clínicos como Assunto , Transtorno Depressivo Maior/metabolismo , Humanos , Compostos de Lítio/efeitos adversos , Compostos de Lítio/farmacocinética , Compostos de Lítio/farmacologia , Ensaios Clínicos Controlados Aleatórios como Assunto
13.
Hum Psychopharmacol ; 33(6): e2676, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30311959

RESUMO

OBJECTIVE: This study aims to describe the prescription patterns of the mood stabilizers most commonly used for the treatment of bipolar I and II disorders (lithium, valproate, and carbamazepine) and to analyze the treatment outcomes. METHODS: Two hundred and thirty-four outpatients with bipolar disorders receiving prophylactic treatment with lithium, valproate, carbamazepine, or their combination were followed up for at least 18 months in two Italian psychiatric centers specialized in mood disorders. RESULTS: The combination of lithium and valproate or carbamazepine was the most common prophylactic treatment (54.3%), followed by valproate or carbamazepine (24%) and lithium monotherapy (22%). Polytherapy was prescribed mainly to patients with bipolar I disorder, a high number of previous episodes and lifetime psychotic symptoms, whereas valproate or carbamazepine monotherapy was prescribed to patients with anxiety comorbidity. The annual frequency of recurrences decreased significantly after entering the study in the overall sample, and the reduction was significantly higher in patients on lithium plus valproate or carbamazepine compared with the valproate or carbamazepine group, but not with the lithium monotherapy group. The number of mixed recurrences during the follow-up was significantly higher in patients on lithium plus valproate or carbamazepine. CONCLUSIONS: Our findings may help clinicians to personalize long-term treatment to prevent relapses of bipolar disorder according to clinical presentation.


Assuntos
Antimaníacos/farmacologia , Transtorno Bipolar/tratamento farmacológico , Carbamazepina/farmacologia , Compostos de Lítio/farmacologia , Ácido Valproico/farmacologia , Adulto , Prescrições de Medicamentos , Quimioterapia Combinada , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Pacientes Ambulatoriais , Estudos Prospectivos
14.
Curr Psychiatry Rep ; 20(11): 104, 2018 09 24.
Artigo em Inglês | MEDLINE | ID: mdl-30246221

RESUMO

PURPOSE OF REVIEW: Psychotropics are prescribed to youth at rapidly growing rates and may negatively impact bone health. Little awareness exists of this association among prescribing providers. Childhood and adolescence are critical times for bone development. Understanding these effects and their management is important to informed psychotropic use. RECENT FINDINGS: Through a variety of mechanisms, antidepressants, benzodiazepines, mood stabilizers, neuroleptics, and stimulants may all negatively impact pediatric bone health. This confers added risk of osteoporosis in a population already at high risk for suboptimal bone health. Awareness of psychotropic-mediated effects on pediatric bone development is clinically relevant to the use and monitoring of these agents. Clinicians can manage these effects through informed consent, vitamin D supplementation, lifestyle modifications, and reducing polypharmacy. For mood stabilizers, vitamin D level monitoring and secondary prevention is indicated. Future longitudinal studies and development of monitoring guidelines regarding psychotropic impact on bone health are necessary.


Assuntos
Densidade Óssea/efeitos dos fármacos , Psicotrópicos/farmacologia , Psicotrópicos/uso terapêutico , Adolescente , Anticonvulsivantes/farmacologia , Anticonvulsivantes/uso terapêutico , Antidepressivos/farmacologia , Antidepressivos/uso terapêutico , Antimaníacos/farmacologia , Antimaníacos/uso terapêutico , Antipsicóticos/farmacologia , Antipsicóticos/uso terapêutico , Benzodiazepinas/farmacologia , Benzodiazepinas/uso terapêutico , Estimulantes do Sistema Nervoso Central/farmacologia , Estimulantes do Sistema Nervoso Central/uso terapêutico , Criança , Humanos , Polimedicação
15.
Bipolar Disord ; 20(7): 583-593, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30221434

RESUMO

OBJECTIVES: To assess the efficacy and tolerability of lithium for the treatment of acute mania in children and adolescent diagnosed with bipolar disorder. METHODS: A systematic literature search up to August 2017 was conducted for clinical trials that included lithium in males and females up to 18 years of age with a diagnosis of bipolar disorder and experiencing a manic or mixed episode according to standardized diagnostic criteria. The protocol was registered in PROSPERO (CRD42017055675). RESULTS: Four independent studies described in seven manuscripts met the inclusion criteria. Overall, 176 patients were treated with lithium either as a monotherapy or adjunct to risperidone. Efficacy results suggest that lithium may be superior to placebo (standardized mean difference [SMD] -0.42, 95% confidence interval [CI] -0.88 to 0.04), comparable to sodium divalproex (SMD -0.07, 95% CI: -0.31 to 0.18), but significantly less effective than risperidone for treating protracted manic/mixed episodes and comorbid attention-deficit hyperactivity disorder (ADHD) in prepubertal children (SMD 0.85, 95% CI: 0.54 to 1.15). Lithium was not associated with serious adverse events, and was generally well tolerated with common side effects similar to those reported in adults. CONCLUSIONS: Limited data suggests that lithium may be an effective and tolerable treatment for some forms of paediatric mania. However, lithium is clearly inferior in efficacy to risperidone in prepubertal patients diagnosed with protracted manic/mixed episodes and comorbid ADHD. There is a lack of data concerning the efficacy and tolerability of lithium as an acute treatment for classical mania in adolescents and important clinical issues remain unaddressed.


Assuntos
Transtorno Bipolar/tratamento farmacológico , Compostos de Lítio/farmacologia , Adolescente , Antimaníacos/farmacologia , Criança , Feminino , Humanos , Masculino , Resultado do Tratamento
16.
J Affect Disord ; 241: 192-199, 2018 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-30130684

RESUMO

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


Assuntos
Antimaníacos/farmacologia , Transtorno Bipolar/tratamento farmacológico , Transtorno Ciclotímico/tratamento farmacológico , Compostos de Lítio/farmacologia , Espectroscopia de Prótons por Ressonância Magnética/métodos , Adulto , Ácido Aspártico/análogos & derivados , Ácido Aspártico/análise , Transtorno Bipolar/diagnóstico por imagem , Encéfalo/enzimologia , Química Encefálica , Colina/análise , Transtorno Ciclotímico/diagnóstico por imagem , Feminino , Giro do Cíngulo/diagnóstico por imagem , Giro do Cíngulo/efeitos dos fármacos , Giro do Cíngulo/metabolismo , Humanos , Inositol/análise , Masculino , Pessoa de Meia-Idade , Resultado do Tratamento
17.
Neurochem Res ; 43(8): 1692-1701, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-29968232

RESUMO

Here we present the data indicating that chronic treatment with three antibipolar drugs, lithium, carbamazepine and valproic acid regulates Cav-1/PTEN/PI3K/AKT/GSK-3ß signalling pathway and glycogen content in primary cultured astrocytes. All three drugs down-regulate gene expression of Caveoline 1 (Cav-1), decrease membrane content of phosphatase and tensin homolog (PTEN), increase activity of phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K) and serine-threonine kinase (AKT), and elevate glycogen synthase kinase 3ß (GSK-3ß) phosphorylation thus suppressing its activity. As expected, treatment with any of these three drugs increases glycogen content in astrocytes. Our findings indicate that regulation of glycogen content via Cav-1/PTEN/AKT/GSK-3ß pathway by the three anti-bipoar drugs may be responsible for therapeutic effects of these drugs, and Cav-1 is an important signal element that may contribute to pathogenesis of various CNS diseases and regulation of its gene expression may be one of the underlying mechanisms of drug action for antibipolar drugs and antidepressants currently in clinical use.


Assuntos
Antimaníacos/farmacologia , Astrócitos/metabolismo , Caveolina 1/metabolismo , Glicogênio Sintase Quinase 3 beta/metabolismo , Glicogênio/metabolismo , PTEN Fosfo-Hidrolase/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Animais , Animais Recém-Nascidos , Antimaníacos/uso terapêutico , Astrócitos/efeitos dos fármacos , Transtorno Bipolar/tratamento farmacológico , Transtorno Bipolar/metabolismo , Carbamazepina/farmacologia , Carbamazepina/uso terapêutico , Células Cultivadas , Relação Dose-Resposta a Droga , Lítio/farmacologia , Lítio/uso terapêutico , Camundongos , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologia , Ácido Valproico/farmacologia , Ácido Valproico/uso terapêutico
18.
Int J Neuropsychopharmacol ; 21(10): 938-948, 2018 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-29860313

RESUMO

Background: Several currently available animal models reproduce select behavioral facets of human mania as well as the abnormal glutamatergic neurotransmission and dysregulation of glycogen synthase kinase 3ß that accompanies this disease. Methods: In this study, we addressed the therapeutic potential of ligands of sigma receptor type 1 (σ1R) in 2 putative models of mania: the "manic" Black Swiss outbred mice from Taconic farms (BStac) and mice with the 129 genetic background and histidine triad nucleotide-binding protein 1 (HINT1) deletion (HINT1-/- mice) that exhibit bipolar-like behaviors. Results: The activity of control mice, which do not exhibit manic-like behaviors in the forced swim test, was significantly enhanced by MK801, an inhibitor of glutamate N-methyl-D-aspartate receptor activity, an effect that was not or barely observed in manic-like mice. Typical mood stabilizers, such as glycogen synthase kinase 3ß inhibitors, but not σ1R ligands, reduced the N-methyl-D-aspartate receptor-mediated behaviors in control mice. Notably, σ1R antagonists S1RA, PD144418, BD1047, and BD1063, but not σ1R agonists PRE084 and PPCC, attenuated the manic-like behaviors of BStac and HINT1-/- mice by increasing antiactivity behaviors. The antimanic effects of a single administration of σ1R antagonists persisted for at least 24 hours, and these drugs did not alter the behavior of the "bipolar" HINT1-/- mice during pro-depressive episodes. Conclusions: σ1R antagonists exhibit a selective normalizing effect on specific behavioral domains of mania without altering control (normal) or depressive-like behaviors.


Assuntos
Antimaníacos/farmacologia , Camundongos Knockout/psicologia , Proteínas do Tecido Nervoso/genética , Receptores sigma/antagonistas & inibidores , Animais , Animais não Endogâmicos/psicologia , Ciclopropanos/farmacologia , Maleato de Dizocilpina/farmacologia , Interações de Medicamentos , Glicogênio Sintase Quinase 3 beta/efeitos dos fármacos , Camundongos , Morfolinas/farmacologia , Atividade Motora/efeitos dos fármacos , Atividade Motora/genética , Piperidinas/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Receptores sigma/agonistas
19.
Mol Pharm ; 15(7): 2528-2538, 2018 07 02.
Artigo em Inglês | MEDLINE | ID: mdl-29874916

RESUMO

Variability in drug response to lithium (Li+) is poorly understood and significant, as only 40% of patients with bipolar disorder highly respond to Li+. Li+ can be transported by sodium (Na+) transporters in kidney tubules or red blood cells, but its transport has not been investigated at the blood-brain barrier (BBB). Inhibition and/or transcriptomic strategies for Na+ transporters such as NHE (SLC9), NBC (SLC4), and NKCC (SLC12) were used to assess their role on Li+ transport in human brain endothelial cells. Na+-free buffer was also used to examine Na+/Li+ countertransport (NLCT) activity. The BBB permeability of Li+ evaluated in the rat was 2% that of diazepam, a high passive diffusion lipophilic compound. Gene expression of several Na+ transporters was determined in hCMEC/D3 cells, human hematopoietic stem-cell-derived BBB models (HBLEC), and human primary brain microvascular endothelial cells (hPBMECs) and showed the following rank order with close expression profile: NHE1 > NKCC1 > NHE5 > NBCn1, while NHE2-4, NBCn2, and NBCe1-2 were barely detected. Li+ influx in hCMEC/D3 cells was increased in Na+-free buffer by 3.3-fold, while depletion of chloride or bicarbonate had no effect. DMA (NHE inhibitor), DIDS (anionic carriers inhibitor), and bumetanide (NKCC inhibitor) decreased Li+ uptake significantly in hCMEC/D3 by 52, 51, and 47%, respectively, while S0859 (NBC inhibitor) increased Li+ influx 2.3-fold. Zoniporide (NHE1 inhibitor) and siRNA against NHE1 had no effect on Li+ influx in hCMEC/D3 cells. Our study shows that NHE1 and/or NHE5, NBCn1, and NKCC1 may play a significant role in the transport of Li+ through the plasma membrane of brain endothelial cells.


Assuntos
Antimaníacos/farmacologia , Barreira Hematoencefálica/metabolismo , Células Endoteliais/metabolismo , Compostos de Lítio/farmacologia , Proteínas Carreadoras de Solutos/metabolismo , Animais , Antimaníacos/uso terapêutico , Transtorno Bipolar/tratamento farmacológico , Barreira Hematoencefálica/citologia , Barreira Hematoencefálica/efeitos dos fármacos , Permeabilidade Capilar/efeitos dos fármacos , Membrana Celular/efeitos dos fármacos , Membrana Celular/metabolismo , Células Endoteliais/efeitos dos fármacos , Células HEK293 , Humanos , Compostos de Lítio/uso terapêutico , Masculino , Microvasos/citologia , Microvasos/efeitos dos fármacos , Microvasos/metabolismo , Cultura Primária de Células , Ratos , Ratos Sprague-Dawley , Sódio/metabolismo , Proteínas Carreadoras de Solutos/antagonistas & inibidores
20.
Artigo em Inglês | MEDLINE | ID: mdl-29789269

RESUMO

BACKGROUND: Bipolar disorder is a chronic and recurrent illness characterized by depressive and manic episodes. Proton magnetic resonance spectroscopy (1H-MRS) studies have demonstrated glutamate (Glu) system abnormalities in BD, but it is unclear how Glu varies among mood states and how medications modulate it. The objective of this study was to investigate the influence of mood stabilizers on anterior cingulate cortex Glu levels using 1H-MRS during euthymia. METHODS: One hundred twenty-eight bipolar I disorder (BDI) euthymic subjects and 80 healthy control subjects underwent 3T brain 1H-MRS imaging examination including acquisition of an anterior cingulate cortex single voxel (8 cm3) 1H-MRS, based on a point resolved spectroscopy (PRESS) sequence with an echo time of 80 ms and a repetition time of 1500 ms (BIPUSP MRS study). The Glu system was described by measuring Glu and the sum of Glu and glutamine (Glx) using creatine (Cre) as a reference. RESULTS: Euthymic BDI subjects presented with higher ratios of Glu/Cre and Glx/Cre compared to healthy control subjects. Glu/Cre ratios were lower among patients using anticonvulsants, while Glx/Cre did not differ between the two groups. Lithium, antipsychotics, and antidepressants did not influence Glu/Cre or Glx/Cre. CONCLUSIONS: We reported Glu/Cre and Glx abnormalities in the largest sample of euthymic BDI patients studied by 1H-MRS to date. Our data indicate that both Glu/Cre and Glx/Cre are elevated in BDI during euthymia regardless of medication effects, reinforcing the hypothesis of glutamatergic abnormalities in BD. Furthermore, we found an effect of anticonvulsants on Glu/Cre during euthymia, which might indicate a mechanism of mood stabilization in BD.


Assuntos
Afeto/efeitos dos fármacos , Transtorno Bipolar/tratamento farmacológico , Ácido Glutâmico/metabolismo , Espectroscopia de Prótons por Ressonância Magnética , Adolescente , Adulto , Anticonvulsivantes/metabolismo , Anticonvulsivantes/farmacologia , Antidepressivos/metabolismo , Antidepressivos/farmacologia , Antimaníacos/metabolismo , Antimaníacos/farmacologia , Antipsicóticos/metabolismo , Transtorno Bipolar/diagnóstico , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Transtorno Ciclotímico/tratamento farmacológico , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Espectroscopia de Prótons por Ressonância Magnética/métodos , Adulto Jovem
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