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1.
Cells ; 10(2)2021 01 28.
Artigo em Inglês | MEDLINE | ID: mdl-33525562

RESUMO

Lithium salts have been in the therapeutic toolbox for better or worse since the 19th century, with purported benefit in gout, hangover, insomnia, and early suggestions that lithium improved psychiatric disorders. However, the remarkable effects of lithium reported by John Cade and subsequently by Mogens Schou revolutionized the treatment of bipolar disorder. The known molecular targets of lithium are surprisingly few and include the signaling kinase glycogen synthase kinase-3 (GSK-3), a group of structurally related phosphomonoesterases that includes inositol monophosphatases, and phosphoglucomutase. Here we present a brief history of the therapeutic uses of lithium and then focus on GSK-3 as a therapeutic target in diverse diseases, including bipolar disorder, cancer, and coronavirus infections.


Assuntos
Antimaníacos/uso terapêutico , Transtorno Bipolar/tratamento farmacológico , Compostos de Lítio/uso terapêutico , Neoplasias/tratamento farmacológico , Doenças Neurodegenerativas/tratamento farmacológico , Síndrome Respiratória Aguda Grave/tratamento farmacológico , Animais , Antimaníacos/farmacologia , Transtorno Bipolar/metabolismo , Coronavirus/efeitos dos fármacos , Quinase 3 da Glicogênio Sintase/metabolismo , Humanos , Compostos de Lítio/farmacologia , Neoplasias/metabolismo , Doenças Neurodegenerativas/metabolismo , Monoéster Fosfórico Hidrolases/metabolismo , Síndrome Respiratória Aguda Grave/metabolismo , Transdução de Sinais/efeitos dos fármacos
2.
Int J Mol Sci ; 22(3)2021 Jan 24.
Artigo em Inglês | MEDLINE | ID: mdl-33498969

RESUMO

Lithium has been the most important mood stabilizer used for the treatment of bipolar disorder and prophylaxis of manic and depressive episodes. Despite long use in clinical practice, the exact molecular mechanisms of lithium are still not well identified. Previous experimental studies produced inconsistent results due to different duration of lithium treatment and using animals without manic-like or depressive-like symptoms. Therefore, we aimed to analyze the gene expression profile in three brain regions (amygdala, frontal cortex and hippocampus) in the rat model of mania and depression during chronic lithium administration (2 and 4 weeks). Behavioral changes were verified by the forced swim test, open field test and elevated maze test. After the experiment, nucleic acid was extracted from the frontal cortex, hippocampus and amygdala. Gene expression profile was done using SurePrint G3 Rat Gene Expression whole transcriptome microarrays. Data were analyzed using Gene Spring 14.9 software. We found that chronic lithium treatment significantly influenced gene expression profile in both mania and depression models. In manic rats, chronic lithium treatment significantly influenced the expression of the genes enriched in olfactory and taste transduction pathway and long non-coding RNAs in all three brain regions. We report here for the first time that genes regulating olfactory and taste receptor pathways and long non-coding RNAs may be targeted by chronic lithium treatment in the animal model of mania.


Assuntos
Encéfalo/metabolismo , Depressão/tratamento farmacológico , Lítio/farmacologia , Transcriptoma , Animais , Antidepressivos/farmacologia , Antidepressivos/uso terapêutico , Antimaníacos/farmacologia , Antimaníacos/uso terapêutico , Depressão/genética , Modelos Animais de Doenças , Lítio/uso terapêutico , Masculino , Ratos , Ratos Wistar
3.
PLoS One ; 15(7): e0235033, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32639961

RESUMO

Lithium Chloride (LiCl) toxicity, mode of action and cellular responses have been the subject of active investigations over the past decades. In yeast, LiCl treatment is reported to reduce the activity and alters the expression of PGM2, a gene that encodes a phosphoglucomutase involved in sugar metabolism. Reduced activity of phosphoglucomutase in the presence of galactose causes an accumulation of intermediate metabolites of galactose metabolism leading to a number of phenotypes including growth defect. In the current study, we identify two understudied yeast genes, YTA6 and YPR096C that when deleted, cell sensitivity to LiCl is increased when galactose is used as a carbon source. The 5'-UTR of PGM2 mRNA is structured. Using this region, we show that YTA6 and YPR096C influence the translation of PGM2 mRNA.


Assuntos
Adenosina Trifosfatases/genética , Antimaníacos/farmacologia , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Cloreto de Lítio/farmacologia , RNA Mensageiro/genética , Proteínas de Saccharomyces cerevisiae/metabolismo , Saccharomyces cerevisiae/efeitos dos fármacos , Adenosina Trifosfatases/metabolismo , Regulação Fúngica da Expressão Gênica/efeitos dos fármacos , Peptídeos e Proteínas de Sinalização Intracelular/genética , Fosfoglucomutase/genética , Biossíntese de Proteínas/efeitos dos fármacos , Saccharomyces cerevisiae/enzimologia , Saccharomyces cerevisiae/genética , Proteínas de Saccharomyces cerevisiae/genética
4.
Neuron ; 106(5): 715-726, 2020 06 03.
Artigo em Inglês | MEDLINE | ID: mdl-32497508

RESUMO

Ketamine exerts rapid antidepressant action in depressed and treatment-resistant depressed patients within hours. At the same time, ketamine elicits a unique form of functional synaptic plasticity that shares several attributes and molecular mechanisms with well-characterized forms of homeostatic synaptic scaling. Lithium is a widely used mood stabilizer also proposed to act via synaptic scaling for its antimanic effects. Several studies to date have identified specific forms of homeostatic synaptic plasticity that are elicited by these drugs used to treat neuropsychiatric disorders. In the last two decades, extensive work on homeostatic synaptic plasticity mechanisms have shown that they diverge from classical synaptic plasticity mechanisms that process and store information and thus present a novel avenue for synaptic regulation with limited direct interference with cognitive processes. In this review, we discuss the intersection of the findings from neuropsychiatric treatments and homeostatic plasticity studies to highlight a potentially wider paradigm for treatment advance.


Assuntos
Antimaníacos/farmacologia , Transtorno Bipolar/tratamento farmacológico , Transtorno Depressivo Maior/tratamento farmacológico , Antagonistas de Aminoácidos Excitatórios/farmacologia , Homeostase/efeitos dos fármacos , Ketamina/farmacologia , Compostos de Lítio/farmacologia , Plasticidade Neuronal/efeitos dos fármacos , Animais , Antimaníacos/uso terapêutico , Transtorno Depressivo Resistente a Tratamento/tratamento farmacológico , Antagonistas de Aminoácidos Excitatórios/uso terapêutico , Humanos , Ketamina/uso terapêutico , Compostos de Lítio/uso terapêutico , Transtornos do Humor/tratamento farmacológico , Sinapses/efeitos dos fármacos
5.
Neuron ; 106(5): 769-777.e4, 2020 06 03.
Artigo em Inglês | MEDLINE | ID: mdl-32199104

RESUMO

Mutations in Shank3 are strongly associated with autism spectrum disorders and neural circuit changes in several brain areas, but the cellular mechanisms that underlie these defects are not understood. Homeostatic forms of plasticity allow central circuits to maintain stable function during experience-dependent development, leading us to ask whether loss of Shank3 might impair homeostatic plasticity and circuit-level compensation to perturbations. We found that Shank3 loss in vitro abolished synaptic scaling and intrinsic homeostatic plasticity, deficits that could be rescued by treatment with lithium. Further, Shank3 knockout severely compromised the in vivo ability of visual cortical circuits to recover from perturbations to sensory drive. Finally, lithium treatment ameliorated a repetitive self-grooming phenotype in Shank3 knockout mice. These findings demonstrate that Shank3 loss severely impairs the ability of central circuits to harness homeostatic mechanisms to compensate for perturbations in drive, which, in turn, may render them more vulnerable to such perturbations.


Assuntos
Homeostase/genética , Proteínas do Tecido Nervoso/genética , Plasticidade Neuronal/genética , Neurônios/efeitos dos fármacos , Córtex Visual/efeitos dos fármacos , Animais , Antimaníacos/farmacologia , Transtorno Autístico/genética , Comportamento Animal/efeitos dos fármacos , Potenciais Pós-Sinápticos Excitadores/efeitos dos fármacos , Potenciais Pós-Sinápticos Excitadores/genética , Técnicas de Silenciamento de Genes , Quinase 3 da Glicogênio Sintase/antagonistas & inibidores , Asseio Animal/efeitos dos fármacos , Homeostase/efeitos dos fármacos , Compostos de Lítio/farmacologia , Camundongos , Camundongos Knockout , Proteínas dos Microfilamentos , Proteínas do Tecido Nervoso/efeitos dos fármacos , Vias Neurais , Plasticidade Neuronal/efeitos dos fármacos , Neurônios/metabolismo , Ratos , Bloqueadores dos Canais de Sódio/farmacologia , Tetrodotoxina/farmacologia , Córtex Visual/citologia , Córtex Visual/metabolismo
6.
Neuropsychobiology ; 79(1): 43-49, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31722343

RESUMO

The gut microbiome is a complex and dynamic community of commensal, symbiotic, and pathogenic microorganisms that exist in a bidirectional relationship with the host. Bacterial functions in the gut play a critical role in healthy host functioning, and its disruption can contribute to many medical conditions. The relationship between gut microbiota and the brain has gained attention in mental health due to the mounting evidence supporting the association of gut bacteria with mood and behavior. Patients with bipolar disorder exhibit an increased frequency of gastrointestinal illnesses such as inflammatory bowel disease, which mechanistically has been linked to microbial community function. While the heterogeneity in microbial communities between individuals might be associated with disease risk, it may also moderate the efficacy or adverse effects associated with the use of medication. The following review highlights published evidence linking the function of gut microbiota both to bipolar disorder risk and to the effect of medications that influence microbiota, inflammation, and mood symptoms.


Assuntos
Anticonvulsivantes/farmacologia , Antimaníacos/farmacologia , Antipsicóticos/farmacologia , Transtorno Bipolar/tratamento farmacológico , Transtorno Bipolar/microbiologia , Microbioma Gastrointestinal/efeitos dos fármacos , Inibidores de Captação de Serotonina/farmacologia , Animais , Humanos
7.
Handb Exp Pharmacol ; 261: 397-413, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31598836

RESUMO

Pharmacotherapy of psychiatric illnesses in children and adolescents has grown significantly over the last few decades. However, the body of research examining pharmacological treatments for psychiatric illnesses is much smaller in children and adolescents than it is in adults. As most treatments for psychiatric disorders are more effective if started early in the course of illness, treatment options for youth are especially important in order to ensure better treatment outcomes. This chapter discusses currently approved medications to treat psychiatric disorders in children and adolescents. Research on medications that may be effective treatments but are not yet FDA approved is also discussed. The medications are broken down into major categories used in youth with psychiatric disorders including antidepressants, mood stabilizers, ADHD medications, and antipsychotics.


Assuntos
Antipsicóticos , Transtornos Mentais , Adolescente , Adulto , Antidepressivos/farmacologia , Antimaníacos/farmacologia , Criança , Humanos
8.
Curr Drug Res Rev ; 11(2): 85-91, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31875781

RESUMO

BACKGROUND: The effectiveness of lithium salts in neuropsychiatric disorders such as bipolar disorder, Alzheimer's disease, and treatment-resistant depression has been documented in an extensive scientific literature. Lithium inhibits inositol monophosphatase, inositol polyphosphate 1- phosphatase, and glycogen synthase kinase-3 and decreases expression level of tryptophan hydroxylase 2, conceivably underlying the mood stabilizing effects of lithium, as well as procognitive and neuroprotective effects. However, the exact molecular mechanisms of action of lithium on mood stabilizing and pro-cognitive effects in humans are still largely unknown. OBJECTIVE: On the basis of the known aspects of lithium pharmacology, this review will discuss the possible mechanisms underlying the therapeutic effects of lithium on positive symptoms of methamphetamine abuse and dependence. CONCLUSION: It is possible that lithium treatment reduces the amount of newly synthesized phosphatidylinositol, potentially preventing or reversing neuroadaptations contributing to behavioral sensitization induced by methamphetamine. In addition, it is suggested that exposure to repeated doses of methamphetamine induces hyperactivation of glycogen synthase kinase-3ß in the nucleus accumbens and in dorsal hippocampus, resulting in a long-term alterations in synaptic plasticity underlying behavioral sensitization as well as other behavioral deficits in memory-related behavior. Therefore it is clear that glycogen synthase kinase-3ß inhibitors can be considered as a potential candidate for the treatment of methamphetamine abuse and dependence.


Assuntos
Transtornos Relacionados ao Uso de Anfetaminas/tratamento farmacológico , Estimulantes do Sistema Nervoso Central , Compostos de Lítio/farmacologia , Compostos de Lítio/uso terapêutico , Metanfetamina , Animais , Antimaníacos/farmacologia , Antimaníacos/uso terapêutico , Quinase 3 da Glicogênio Sintase/antagonistas & inibidores , Humanos
9.
J Clin Psychopharmacol ; 39(6): 561-566, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31688390

RESUMO

BACKGROUND: The combination of olanzapine and valproic acid (VPA) is regularly prescribed in the treatment of bipolar or schizoaffective disorders. The VPA has been shown to reduce olanzapine concentration, but the mechanism behind this interaction remains unknown. We aimed to investigate the effect of VPA on olanzapine concentration during oral versus long-acting injectable (LAI) formulation in a real-life setting. METHODS: From a therapeutic drug monitoring service, prescribed doses and serum concentrations from 2791 olanzapine-treated patients (9433 measurements) were included. RESULTS: The number of patients on olanzapine-LAI treatment was 328, whereas 2463 were using oral olanzapine. The frequency of patients comedicated with VPA was 9.4% for olanzapine tablets and 5.8% for olanzapine-LAI. The VPA had no effect on olanzapine dose-adjusted concentrations in LAI users (1.6 vs 1.7 [ng/mL]/[mg/d]; P = 0.38), whereas in the oral group the dose-adjusted olanzapine concentration was lower in VPA users (2.2 vs 2.7 [ng/mL]/[mg/d]; P < 0.001). For smokers in the oral olanzapine group using VPA, 8.7% of the measurements were in the subtherapeutic range (<10 ng/mL) compared with 6.0% in nonusers (P = 0.003). IMPLICATIONS: These findings show that the VPA-olanzapine interaction involves a presystemic mechanism and is therefore restricted to oral olanzapine treatment. For oral treatment of olanzapine, comedication with VPA implies a risk of insufficient effect, which may be of clinical relevance in smokers in particular. Thus, it is important to be aware of the interaction potential with VPA during oral olanzapine use, whereas for LAI-treated patients fewer precautions are required from a pharmacokinetic point of view.


Assuntos
Antimaníacos/farmacologia , Antipsicóticos/administração & dosagem , Antipsicóticos/sangue , Transtorno Bipolar/tratamento farmacológico , Interações Medicamentosas , Olanzapina/administração & dosagem , Olanzapina/sangue , Transtornos Psicóticos/tratamento farmacológico , Fumar/sangue , Ácido Valproico/farmacologia , Administração Oral , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Preparações de Ação Retardada , Monitoramento de Medicamentos , Quimioterapia Combinada , Feminino , Humanos , Injeções , Masculino , Pessoa de Meia-Idade , Adulto Jovem
10.
Curr Mol Pharmacol ; 12(4): 301-310, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31677257

RESUMO

BACKGROUND: Breast cancer is the most common cancer among women. Radiation therapy is used for treating almost every stage of breast cancer. A strategy to reduce irradiation side effects and to decrease the recurrence of cancer is concurrent use of radiation and radiosensitizers. We studied the effect of the antimanic drug lithium on radiosensitivity of estrogen-receptor (ER)-positive MCF-7 and ER-negative, invasive, and radioresistant MDA-MB-231 breast cancer cell lines. METHODS: MCF-7 and MDA-MB-231 breast cancer cell lines were treated with 30 mM and 20 mM concentrations of lithium chloride (LiCl), respectively. These concentrations were determined by MTT viability assay. Growth curves were depicted and comet assay was performed for control and LiCl-treated cells after exposure to X-ray. Total and phosphorylated inactive levels of glycogen synthase kinase-3beta (GSK-3ß) protein were determined by ELISA assay for control and treated cells. RESULTS: Treatment with LiCl decreased cell proliferation after exposure to X-ray as indicated by growth curves of MCF-7 and MDA-MB-231 cell lines within six days following radiation. Such treatment increased the amount of DNA damages represented by percent DNA in Tails of comets at 0, 1, 4, and even 24 hours after radiation in both studied cell lines. The amount of active GSK-3ß was increased in LiCl-treated cells in ER-positive and ER-negative breast cancer cell lines. CONCLUSION: Treatment with LiCl that increased the active GSK-3ß protein, increased DNA damages and decreased survival independent of estrogen receptor status in breast cancer cells exposed to ionizing radiation.


Assuntos
Antimaníacos/farmacologia , Neoplasias da Mama/radioterapia , Cloreto de Lítio/farmacologia , Radiossensibilizantes/farmacologia , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos da radiação , Dano ao DNA/efeitos dos fármacos , Dano ao DNA/efeitos da radiação , Feminino , Glicogênio Sintase Quinase 3 beta/metabolismo , Humanos , Células MCF-7
11.
Turk Psikiyatri Derg ; 30(3): 163-171, 2019.
Artigo em Turco | MEDLINE | ID: mdl-31613975

RESUMO

OBJECTIVE: Despite lithium associated hyperparathyroidism (LAH) can lead to many complications, little notice has been paid to this sideeffect. The aim of this study was to investigate the effects of lithium on calcium and parathyroid hormone levels and the relation between lithium use and thyroid diseases. METHOD: This cross-sectional study was carried out with 87 lithiumtreated patients and 65 volunteers who had a similar age and gender distribution with the lithium group. Serum levels of corrected calcium, intact parathormone, phosphorus, magnesium, alkaline phosphatase, free thyroxine, thyroid stimulating hormone, thyroid autoantibodies and creatinine were assessed, and also, thyroid and parathyroid ultrasonography was conducted. Further detailed investigations were made depending on the elevation of the initially measured calcium and/ or parathormone levels. RESULTS: Median values of serum levels of the corrected calcium and the intact parathormone were significantly higher in the lithium group. Calcium levels had a mild correlation with the duration of lithium treatment. In the first assessment, while all control individuals had values within the normal reference range, 11 lithium-treated patients had corrected calcium and/or intact parathormone levels above the normal reference levels. All of the five patients, who were diagnosed with LAH after further investigation, were also diagnosed with a thyroid disorder. CONCLUSION: These results demonstrate that lithium treatment has a relationship with calcium and parathormone levels. The 5.7% prevalence of LAH and potential life-threatening conditions associated with LAH necessitates the use of available low-cost METHODS to monitor blood calcium levels of lithium-treated patients for early diagnosis.


Assuntos
Antimaníacos/farmacologia , Transtorno Bipolar/tratamento farmacológico , Cálcio/sangue , Compostos de Lítio/farmacologia , Hormônio Paratireóideo/sangue , Adolescente , Adulto , Idoso , Antimaníacos/uso terapêutico , Transtorno Bipolar/sangue , Transtorno Bipolar/psicologia , Estudos de Casos e Controles , Estudos Transversais , Feminino , Humanos , Compostos de Lítio/uso terapêutico , Masculino , Pessoa de Meia-Idade , Adulto Jovem
12.
J Psychiatr Res ; 119: 76-83, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31574363

RESUMO

The present study aimed to evaluate the effects of treatment with lithium (Li) and valproate (VPA) on behaviors and brain BDNF, NGF, NT-3, NT-4 and GDNF levels in mice submitted to paradoxical sleep deprivation (PSD), which induces an animal model of mania. Male C57BL/6J mice received an intraperitoneal (i.p.) injection of saline solution (NaCl 0.09%, 1 ml/kg), Li (47.3 mg/kg, 1 ml/kg) or VPA (200 mg/kg, 1 ml/kg) once a day for seven days. Animals were randomly distributed into six groups (n = 10 per group): (1) Control + Sal; (2) Control + Li; (3) Control + VPA; (4) PSD + Sal; (5) PSD + Li; or (6) PSD + VPA. Animals were submitted to 36 h of PSD, and then, they were submitted to the open field test. The frontal cortex and hippocampus were dissected from the brain. The manic-like behaviors in the mice were analyzed. Treatment with Li and VPA reversed the behavioral alterations induced by PSD. PSD decreased BDNF, NGF, and GDNF levels in the frontal cortex and hippocampus of mice. The administration of Li and VPA protected the brain against the damage induced by PSD. However, PSD and the administration of Li and VPA did not affect the levels of NT-3 and NT-4 in either brain structure evaluated. In conclusion, the PSD protocol induced manic-like behavior in rats and induced alterations in neurotrophic factor levels. It seems that neurotrophic factors and sleep are essential targets to treat BD.


Assuntos
Antimaníacos/farmacologia , Comportamento Animal/efeitos dos fármacos , Transtorno Bipolar/tratamento farmacológico , Lobo Frontal/efeitos dos fármacos , Hipocampo/efeitos dos fármacos , Compostos de Lítio/farmacologia , Fatores de Crescimento Neural/efeitos dos fármacos , Privação do Sono/complicações , Ácido Valproico/farmacologia , Animais , Antimaníacos/administração & dosagem , Transtorno Bipolar/etiologia , Fator Neurotrófico Derivado do Encéfalo/efeitos dos fármacos , Modelos Animais de Doenças , Fator Neurotrófico Derivado de Linhagem de Célula Glial/efeitos dos fármacos , Compostos de Lítio/administração & dosagem , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Fator de Crescimento Neural/efeitos dos fármacos , Sono REM/fisiologia , Ácido Valproico/administração & dosagem
13.
Arch. Clin. Psychiatry (Impr.) ; 46(5): 125-131, Sept.-Oct. 2019. tab, graf
Artigo em Inglês | LILACS | ID: biblio-1054907

RESUMO

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.


Assuntos
Humanos , Masculino , Feminino , Adulto , Pessoa de Meia-Idade , Células Ganglionares da Retina/patologia , Transtorno Bipolar/diagnóstico por imagem , Tomografia de Coerência Óptica , Fibras Nervosas/patologia , Escalas de Graduação Psiquiátrica , Transtorno Bipolar/tratamento farmacológico , Inquéritos e Questionários , Análise de Regressão , Ácido Valproico/uso terapêutico , Ácido Valproico/farmacologia , Compostos de Lítio/uso terapêutico , Compostos de Lítio/farmacologia , Antimaníacos/uso terapêutico , Antimaníacos/farmacologia , Doenças Neurodegenerativas/prevenção & controle , Doenças Neurodegenerativas/diagnóstico por imagem , Entrevista Psicológica
14.
J Psychiatr Res ; 118: 66-72, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31494376

RESUMO

BACKGROUND: Schizophrenia (SZ) is associated with cognitive impairment that contributes to disability, but the cognitive dysfunction is relatively refractory to pharmacologic intervention. Though Valproate augmentation is reported to improve psychopathology among patients with SZ, its effects on cognitive functions have not been investigated systematically. METHODS: Using a randomized double blind placebo controlled design, the effects of Valproate or placebo as adjuncts to risperidone (RISP) treatment were evaluated among patients with early course SZ (N = 109). Domains of cognitive function, estimated using the Arabic version of the Penn Computerized Neurocognitive Battery, were the prime outcomes. Clinical severity and social function were secondary outcomes. We also explored the effects of valproate treatment on serological responses to Toxoplama Gondii (TOXO), a putative risk factor for cognitive dysfunction in SZ. RESULTS: There were no significant differences between Valproate and placebo (PLA) treated groups with respect to changes in cognitive functions, positive or negative symptom scores or daily function scores at the beginning and end of the study. No significant Valproate/PLA differences were noted on TOXO serostatus or TOXO-related cognitive dysfunction. CONCLUSION: Valproate treatment may not be beneficial for cognitive dysfunction in SZ or for TOXO infection.


Assuntos
Antimaníacos/farmacologia , Antipsicóticos/farmacologia , Disfunção Cognitiva/tratamento farmacológico , Risperidona/farmacologia , Esquizofrenia/tratamento farmacológico , Toxoplasmose/tratamento farmacológico , Ácido Valproico/farmacologia , Adolescente , Adulto , Antimaníacos/administração & dosagem , Antipsicóticos/administração & dosagem , Disfunção Cognitiva/etiologia , Método Duplo-Cego , Sinergismo Farmacológico , Quimioterapia Combinada , Humanos , Pessoa de Meia-Idade , Risperidona/administração & dosagem , Esquizofrenia/complicações , Resultado do Tratamento , Ácido Valproico/administração & dosagem , Adulto Jovem
15.
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 Medicamentosas , Humanos , Transtorno Obsessivo-Compulsivo/complicações , Inibidores de Captação de Serotonina/administração & dosagem , Inibidores de Captação de Serotonina/farmacocinética , Inibidores de Captação de Serotonina/farmacologia
16.
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
17.
J Alzheimers Dis ; 69(3): 615-629, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31156173

RESUMO

Systems pharmacology is a novel framework for drug research that models traditional and innovative pharmacological parameters and provides the overall efficacy and safety profile of a drug across body systems and complex, non-linear, molecular interactions. Lithium chloride, a pharmacological compound approved for the therapy of psychiatric disorders, represents a poorly explored compound for the treatment of Alzheimer's disease (AD). Lithium has been shown to reduce downstream effects associated with the aberrant overactivation of certain molecular pathways, such as glycogen synthase kinase 3 subunit ß (GSK3-ß)-related pathways, involved in AD-related pathophysiology. It seems that overactivation and overexpression of GSK3-ß lead to an impairment of long-term potentiation and amyloid-ß induced neurotoxicity that can be normalized using lithium. Moreover, a growing body of evidence has demonstrated that lithium's GSK3-ß inhibitory effect prevents tau phosphorylation in mouse models of tauopathies. Clinical data have been inconclusive, partly due to methodological limitations. The lack of studies exploring the dynamics of protein misfolding in AD and investigating the specific tau-isoforms appearing prior to the accumulation of neurofibrillary tangles calls for new and optimized clinical trials. Advanced computer modeling based on a formal implementation of quantitative parameters and basic enzymatic insights into a mechanism-based model would present a good start to tackle these non-linear interactions. This innovative approach will pave the way for developing "molecularly" biomarker-guided targeted therapies, i.e., treatments specifically adapted ("tailored") to the individual, consistently with the primary objectives and key conceptual points of precision medicine and precision pharmacology.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Antimaníacos/farmacologia , Antimaníacos/uso terapêutico , Cloreto de Lítio/farmacologia , Cloreto de Lítio/uso terapêutico , Animais , Glicogênio Sintase Quinase 3 beta/metabolismo , Humanos , Redes e Vias Metabólicas/efeitos dos fármacos
18.
J Psychiatr Res ; 113: 181-189, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30981159

RESUMO

Studies have suggested the involvement of oxidative stress in the physiopathology of bipolar disorder. Preclinical data have shown that PKC inhibitors may act as mood-stabilizing agents and protect the brain in animal models of mania. The present study aimed to evaluate the effects of Lithium (Li) or tamoxifen (TMX) on behavioral changes and oxidative stress parameters in an animal model of mania induced by ouabain (OUA). Wistar rats received a single intracerebroventricular (ICV) injection of OUA or artificial cerebrospinal fluid (ACSF). From the day following ICV injection, the rats were treated for seven days with intraperitoneal injections of saline, Li or TMX twice a day. On the 7th day after OUA injection, locomotor activity was measured using the open-field test, and the oxidative stress parameters were evaluated in the hippocampus and frontal cortex of rats. The results showed that OUA induced hyperactivity in rats, which is considered a manic-like behavior. Also, OUA increased lipid peroxidation and oxidative damage to proteins, as well as causing alterations to antioxidant enzymes in the frontal cortex and hippocampus of rats. The Li or TMX treatment reversed the manic-like behavior induced by OUA. Besides, Li, but not TMX, reversed the oxidative damage caused by OUA. These results suggest that the manic-like effects induced by OUA and the antimanic effects of TMX seem not to be related to the oxidative stress.


Assuntos
Antimaníacos/farmacologia , Transtorno Bipolar/tratamento farmacológico , Encéfalo/efeitos dos fármacos , Encéfalo/fisiopatologia , Estresse Oxidativo , Tamoxifeno/farmacologia , Animais , Transtorno Bipolar/fisiopatologia , Modelos Animais de Doenças , Masculino , Ouabaína/administração & dosagem , Ratos , Ratos Wistar , Moduladores Seletivos de Receptor Estrogênico/farmacologia
20.
Metab Brain Dis ; 34(3): 941-950, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30919245

RESUMO

The present study aimed to evaluate the effects of resveratrol on behavior and oxidative stress parameters in the brain of rats submitted to the animal model of mania induced by m-AMPH. In the first model (reversal treatment), rats received intraperitoneal (i.p.) injection of saline or m-AMPH (1 mg/kg body weight) once a day for 14 days, and from the 8th to the 14th day, they were orally treated with water or resveratrol (15 mg/kg), once a day. In the second model (maintenance treatment), rats were orally pretreated with water or resveratrol (15 mg/kg) once a day, and from the 8th to the 14th day, they received saline or m-AMPH i.p., once a day. Locomotor and exploratory activities were assessed in the open-field test. Oxidative and nitrosative damage parameters to lipid and proteins were evaluated by TBARS, 4-HNE, carbonyl, and 3-nitrotyrosine in the brain submitted to the experimental models. m-AMPH administration increased the locomotor and exploratory activities; resveratrol was not able to reverse or prevent these manic-like behaviors. Additionally, m-AMPH increased the lipid and protein oxidation and nitrosylation in the frontal cortex, hippocampus, and striatum of rats. However, resveratrol prevented and reversed the oxidative and nitrosative damage to proteins and lipids in all cerebral areas assessed. Since oxidative stress plays an important role in BD pathophysiology, supplementation of resveratrol in BD patients could be regarded as a possible adjunctive treatment with mood stabilizers.


Assuntos
Transtorno Bipolar/tratamento farmacológico , Encéfalo/efeitos dos fármacos , Atividade Motora/efeitos dos fármacos , Resveratrol/farmacologia , Animais , Antimaníacos/farmacologia , Encéfalo/metabolismo , Estimulantes do Sistema Nervoso Central/farmacologia , Modelos Animais de Doenças , Masculino , Estresse Oxidativo/efeitos dos fármacos , Substâncias Protetoras/uso terapêutico , Ratos Wistar
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