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1.
Am J Geriatr Psychiatry ; 30(5): 541-556, 2022 05.
Artigo em Inglês | MEDLINE | ID: mdl-34750057

RESUMO

BACKGROUND: Older, compared with younger, patients with treatment-resistant depression (TRD) typically have lower response and remission rates with poorer tolerability to antidepressant treatment. This post-hoc analysis compared outcomes following treatment with esketamine nasal spray (ESK) between younger (18-64 years) and older (≥65 years) patients with TRD. METHODS: SUSTAIN-2, an up to 1-year open-label safety and efficacy study of ESK plus an oral antidepressant, included patients with TRD either directly enrolled (≥18-year) or transferred from a phase 3 double-blind study, TRANSFORM-3 (≥65-year). Patients were treated in two phases: 4-week induction and 48-week optimization/maintenance. RESULTS: Younger (n = 624) and older (n = 178) patients had similar baseline characteristics except for hypertension history (21.5% versus 48.3%, respectively). Patients (younger versus older) had similar mean baseline Montgomery-Åsberg Depression Rating Scale (MADRS) total scores and mean (SD) reductions in MADRS total scores for induction (-18.0 [7.19] versus -18.1 [9.37]; p = 0.492 [t = 0.69, df = 701]) and optimization/maintenance (week 12) (-19.9 [7.03] versus -22.2 [9.50]; p = 0.265 [t = -1.12, df = 3470]) phases. Treatment-emergent adverse events (TEAEs) reported in younger versus older patients, respectively, were: induction, 86.1% versus 74.8%; optimization/maintenance, 86.8% versus 81.0%; serious TEAEs: induction, 2.2% versus 1.9%; optimization/maintenance, 6.7% versus 4.8%; TEAEs of increased blood pressure: induction, 6.9% versus 6.5%; optimization/maintenance, 7.1% versus 9.5%; and falls: induction, 0.3% versus 0.6%; optimization/maintenance, 0.2% versus 0.8%. Cognitive tests did not show clinically meaningful differences between the age groups. CONCLUSIONS: Although limited by the open-label design of SUSTAIN-2, this post-hoc analysis showed generally comparable improvement in depression between ESK-treated younger and older adult patients with TRD, with consistent safety outcomes.


Assuntos
Antidepressivos , Depressão , Ketamina , Administração Oral , Adolescente , Adulto , Idoso , Antidepressivos/administração & dosagem , Depressão/tratamento farmacológico , Método Duplo-Cego , Quimioterapia Combinada/efeitos adversos , Humanos , Ketamina/administração & dosagem , Pessoa de Meia-Idade , Sprays Nasais , Resultado do Tratamento , Adulto Jovem
2.
J Neurochem ; 158(2): 358-372, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-33025573

RESUMO

Molecular abnormalities within the Glucocorticoid Receptor (GR) stress signaling pathway involved in dysfunction of mitochondria and confer vulnerability to stress-related psychiatric disorders. Bcl-2 associated athanogene (Bag-1) is a target for the actions of mood stabilizers. Bag-1 interacts with GR, thereby regulating glucocorticoid function. In this study, we investigate the potential role of Bag-1 in regulating GR translocation into mitochondria. Corticosterone (CORT) treatment significantly enhanced Bag-1/GR complex formation and GR mitochondrial translocation in cultured rat cortical neurons after treatment for 30 min and 24 hr. By contrast, after stimulation with CORT for 3 days, localization of the Bag-1/GR complex and mitochondrial GR were reduced. Similar results were obtained in mice, in which administrated CORT in drinking water for 21 days significantly impaired the GR levels in the mitochondria, while Bag-1 over-expression rescued this reduction. Furthermore, chronic CORT exposure led to anhedonia-like and depression-like behaviors in the sucrose-consumption test and forced swimming test, and these behaviors were rescued by Bag-1 over-expression. These results suggest that Bag-1 mediates GR trafficking to mitochondria and regulates affective resilience in response to a CORT increase and provide potential insight into the mechanisms by which Bag-1 and GR could contribute to the physiology and pathogenesis of psychiatric disorders in response to the change of stress hormone.


Assuntos
Afeto/efeitos dos fármacos , Corticosterona/farmacologia , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Mitocôndrias/metabolismo , Receptores de Glucocorticoides/metabolismo , Resiliência Psicológica/efeitos dos fármacos , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Anedonia , Animais , Depressão/psicologia , Relação Dose-Resposta a Droga , Feminino , Masculino , Neurônios/efeitos dos fármacos , Gravidez , Cultura Primária de Células , Transporte Proteico , Ratos , Ratos Sprague-Dawley , Estimulação Química , Natação/psicologia
3.
Int J Neuropsychopharmacol ; 24(1): 22-31, 2021 01 20.
Artigo em Inglês | MEDLINE | ID: mdl-32861217

RESUMO

BACKGROUND: Patients with major depressive disorder (MDD) having active suicidal ideation with intent require immediate treatment. METHODS: This double-blind study (ASPIRE II) randomized adults (aged 18-64 years) with MDD having active suicidal ideation with intent to esketamine 84 mg or placebo nasal spray twice weekly for 4 weeks, given with comprehensive standard of care (hospitalization ≥5 days and newly initiated or optimized oral antidepressant[s]). Change from baseline to 24 hours post-first dose in Montgomery-Asberg Depression Rating Scale total score (primary efficacy endpoint) was analyzed using ANCOVA. Clinical Global Impression-Severity of Suicidality-revised (key secondary endpoint) was analyzed using ANCOVA on ranks of change. RESULTS: Of 230 patients who were randomized (115 per arm), 227 received study drug and were included in efficacy/safety analyses; 184 (80.0%) completed double-blind treatment. Greater improvement in Montgomery-Asberg Depression Rating Scale total score was observed with esketamine (mean [SD]: -15.7 [11.56]) vs placebo (-12.4 [10.43]), each with standard of care, at 24 hours (least-squares mean difference [SE]: -3.9 [1.39], 95% CI: -6.60, -1.11; 2-sided P = .006). This was also noted at the earlier (4-hour) timepoint (least-squares mean difference -4.2, 95% CI: -6.38, -1.94). Patients in both treatment groups experienced rapid reduction in Clinical Global Impression-Severity of Suicidality-revised score; the between-group difference was not statistically significant. The most common adverse events among esketamine-treated patients were dizziness, dissociation, nausea, dysgeusia, somnolence, headache, and paresthesia. CONCLUSION: This study confirmed rapid and robust reduction of depressive symptoms with esketamine nasal spray in severely ill patients with MDD who have active suicidal ideation with intent. Trial Registration: Clinical Trials.gov identifier: NCT03097133.


Assuntos
Antidepressivos/farmacologia , Transtorno Depressivo Maior/tratamento farmacológico , Ketamina/farmacologia , Ideação Suicida , Administração Intranasal , Adolescente , Adulto , Antidepressivos/administração & dosagem , Método Duplo-Cego , Feminino , Humanos , Ketamina/administração & dosagem , Masculino , Pessoa de Meia-Idade , Sprays Nasais , Avaliação de Resultados em Cuidados de Saúde , Gravidade do Paciente , Adulto Jovem
4.
Am J Geriatr Psychiatry ; 28(2): 121-141, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31734084

RESUMO

BACKGROUND: Elderly patients with major depression have a poorer prognosis, are less responsive to treatment, and show greater functional decline compared with younger patients, highlighting the need for effective treatment. METHODS: This phase 3 double-blind study randomized patients with treatment-resistant depression (TRD) ≥65 years (1:1) to flexibly dosed esketamine nasal spray and new oral antidepressant (esketamine/antidepressant) or new oral antidepressant and placebo nasal spray (antidepressant/placebo). The primary endpoint was change in the Montgomery-Åsberg Depression Rating Scale (MADRS) from baseline to day 28. Analyses included a preplanned analysis by age (65-74 versus ≥75 years) and post-hoc analyses including age at depression onset. RESULTS: For the primary endpoint, the median-unbiased estimate of the treatment difference (95% CI) was -3.6 (-7.20, 0.07); weighted combination test using MMRM analyses z = 1.89, two-sided p = 0.059. Adjusted mean (95% CI) difference for change in MADRS score between treatment groups was -4.9 (-8.96, -0.89; t = -2.4, df = 127; two-sided nominal p = 0.017) for patients 65 to 74 years versus -0.4 (-10.38, 9.50; t = -0.09, two-sided nominal p = 0.930) for those ≥75 years, and -6.1 (-10.33, -1.81; t = -2.8, df = 127; two-sided nominal p = 0.006) for patients with depression onset <55 years and 3.1 (-4.51, 10.80; t = 0.8, two-sided nominal p = 0.407) for those ≥55 years. Patients who rolled over into the long-term open-label study showed continued improvement with esketamine following 4 additional treatment weeks. CONCLUSIONS: Esketamine/antidepressant did not achieve statistical significance for the primary endpoint. Greater differences between treatment arms were seen for younger patients (65-74 years) and patients with earlier onset of depression (<55 years).


Assuntos
Antidepressivos/uso terapêutico , Transtorno Depressivo Resistente a Tratamento/tratamento farmacológico , Ketamina/uso terapêutico , Administração Oral , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Antidepressivos/administração & dosagem , Método Duplo-Cego , Quimioterapia Combinada , Feminino , Humanos , Ketamina/administração & dosagem , Masculino , Sprays Nasais , Resultado do Tratamento
5.
Proc Natl Acad Sci U S A ; 114(22): E4462-E4471, 2017 05 30.
Artigo em Inglês | MEDLINE | ID: mdl-28500272

RESUMO

The molecular pathogenesis of bipolar disorder (BPD) is poorly understood. Using human-induced pluripotent stem cells (hiPSCs) to unravel such mechanisms in polygenic diseases is generally challenging. However, hiPSCs from BPD patients responsive to lithium offered unique opportunities to discern lithium's target and hence gain molecular insight into BPD. By profiling the proteomics of BDP-hiPSC-derived neurons, we found that lithium alters the phosphorylation state of collapsin response mediator protein-2 (CRMP2). Active nonphosphorylated CRMP2, which binds cytoskeleton, is present throughout the neuron; inactive phosphorylated CRMP2, which dissociates from cytoskeleton, exits dendritic spines. CRMP2 elimination yields aberrant dendritogenesis with diminished spine density and lost lithium responsiveness (LiR). The "set-point" for the ratio of pCRMP2:CRMP2 is elevated uniquely in hiPSC-derived neurons from LiR BPD patients, but not with other psychiatric (including lithium-nonresponsive BPD) and neurological disorders. Lithium (and other pathway modulators) lowers pCRMP2, increasing spine area and density. Human BPD brains show similarly elevated ratios and diminished spine densities; lithium therapy normalizes the ratios and spines. Consistent with such "spine-opathies," human LiR BPD neurons with abnormal ratios evince abnormally steep slopes for calcium flux; lithium normalizes both. Behaviorally, transgenic mice that reproduce lithium's postulated site-of-action in dephosphorylating CRMP2 emulate LiR in BPD. These data suggest that the "lithium response pathway" in BPD governs CRMP2's phosphorylation, which regulates cytoskeletal organization, particularly in spines, modulating neural networks. Aberrations in the posttranslational regulation of this developmentally critical molecule may underlie LiR BPD pathogenesis. Instructively, examining the proteomic profile in hiPSCs of a functional agent-even one whose mechanism-of-action is unknown-might reveal otherwise inscrutable intracellular pathogenic pathways.


Assuntos
Transtorno Bipolar , Células-Tronco Pluripotentes Induzidas/efeitos dos fármacos , Lítio/farmacologia , Modelos Biológicos , Processamento de Proteína Pós-Traducional/efeitos dos fármacos , Animais , Transtorno Bipolar/genética , Transtorno Bipolar/metabolismo , Transtorno Bipolar/fisiopatologia , Química Encefálica , Cálcio/metabolismo , Células Cultivadas , Humanos , Células-Tronco Pluripotentes Induzidas/fisiologia , Peptídeos e Proteínas de Sinalização Intercelular/química , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Camundongos , Proteínas do Tecido Nervoso/química , Proteínas do Tecido Nervoso/metabolismo , Proteômica
6.
Int J Neuropsychopharmacol ; 22(10): 616-630, 2019 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-31290965

RESUMO

BACKGROUND: About one-third of patients with depression fail to achieve remission despite treatment with multiple antidepressants and are considered to have treatment-resistant depression. METHODS: This Phase 3, double-blind, multicenter study enrolled adults with moderate-to-severe depression and nonresponse to ≥2 antidepressants in the current depression episode. Eligible patients (N = 346) were randomized (1:1:1) to twice-weekly nasal spray treatment (esketamine [56 or 84 mg] or placebo) plus a newly initiated, open-label, oral antidepressant taken daily for 4 weeks. The primary efficacy endpoint was change from baseline to day 28 in the Montgomery-Asberg Depression Rating Scale total score, performed by blinded, remote raters. Based on the predefined statistical testing sequence, esketamine 84 mg/antidepressant had to be significant for esketamine 56 mg/antidepressant to be formally tested. RESULTS: Statistical significance was not achieved with esketamine 84 mg/antidepressant compared with antidepressant/placebo (least squares [LS] means difference [95% CI]: -3.2 [-6.88, 0.45]; 2-sided P value = .088). Although esketamine 56 mg/antidepressant could not be formally tested, the LS means difference was -4.1 [-7.67, -0.49] (nominal 2-sided P value = .027). The most common (>20%) adverse events reported for esketamine/antidepressant were nausea, dissociation, dizziness, vertigo, and headache. CONCLUSIONS: Statistical significance was not achieved for the primary endpoint; nevertheless, the treatment effect (Montgomery-Asberg Depression Rating Scale) for both esketamine/antidepressant groups exceeded what has been considered clinically meaningful for approved antidepressants vs placebo. Safety was similar between esketamine/antidepressant groups and no new dose-related safety concerns were identified. This study provides supportive evidence for the safety and efficacy of esketamine nasal spray as a new, rapid-acting antidepressant for patients with treatment-resistant depression. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02417064.


Assuntos
Antidepressivos/efeitos adversos , Antidepressivos/uso terapêutico , Transtorno Depressivo Resistente a Tratamento/tratamento farmacológico , Ketamina/efeitos adversos , Ketamina/uso terapêutico , Administração Intranasal , Administração Oral , Adolescente , Adulto , Antidepressivos/administração & dosagem , Citalopram/uso terapêutico , Preparações de Ação Retardada/uso terapêutico , Método Duplo-Cego , Quimioterapia Combinada/efeitos adversos , Cloridrato de Duloxetina/uso terapêutico , Feminino , Humanos , Ketamina/administração & dosagem , Masculino , Pessoa de Meia-Idade , Sertralina/uso terapêutico , Resultado do Tratamento , Cloridrato de Venlafaxina/uso terapêutico , Adulto Jovem
8.
Nat Rev Neurosci ; 13(5): 293-307, 2012 Apr 18.
Artigo em Inglês | MEDLINE | ID: mdl-22510887

RESUMO

Major psychiatric illnesses such as mood disorders and schizophrenia are chronic, recurrent mental illnesses that affect the lives of millions of individuals. Although these disorders have traditionally been viewed as 'neurochemical diseases', it is now clear that they are associated with impairments of synaptic plasticity and cellular resilience. Although most patients with these disorders do not have classic mitochondrial disorders, there is a growing body of evidence to suggest that impaired mitochondrial function may affect key cellular processes, thereby altering synaptic functioning and contributing to the atrophic changes that underlie the deteriorating long-term course of these illnesses. Enhancing mitochondrial function could represent an important avenue for the development of novel therapeutics and also presents an opportunity for a potentially more efficient drug-development process.


Assuntos
Metabolismo Energético , Transtornos Mentais/metabolismo , Transtornos Mentais/patologia , Mitocôndrias/metabolismo , Mitocôndrias/patologia , Doenças Mitocondriais/metabolismo , Doenças Mitocondriais/patologia , Animais , Metabolismo Energético/fisiologia , Humanos , Transtornos Mentais/terapia , Doenças Mitocondriais/terapia , Neurônios/metabolismo , Neurônios/patologia , Sinapses/metabolismo , Sinapses/patologia
10.
Bipolar Disord ; 18(1): 41-51, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26842627

RESUMO

OBJECTIVES: Neuroimaging studies have revealed lithium-related increases in the volume of gray matter in the prefrontal cortex (PFC) and hippocampus. Postmortem human studies have reported alterations in neuronal and glial cell density and size in the PFC of lithium-treated subjects. Rodents treated with lithium exhibit cell proliferation in the dentate gyrus (DG) of the hippocampus. However, it is not known whether hippocampal and PFC volume are also increased in these animals or whether cell number in the PFC is altered. METHODS: Using stereological methods, this study estimated the total numbers of neurons and glia, and the packing density of astrocytes in the DG and PFC of normal adult mice treated with lithium, and evaluated the total volume of these regions and the entire neocortex. RESULTS: Lithium treatment increased the total numbers of neurons and glia in the DG (by 25% and 21%, respectively) and the density of astrocytes but did not alter total numbers in the PFC. However, the volumes of the hippocampus and its subfields, the PFC and its subareas, and the entire neocortex were not altered by lithium. CONCLUSIONS: Both neuronal and glial cells accounted for lithium-induced cell proliferation in the DG. That the numbers of neurons and glia were unchanged in the PFC is consistent with the view that this region is not a neurogenic zone. Further studies are required to clarify the impact of lithium treatment on the PFC under pathological conditions and to investigate the dissociation between increased cell proliferation and unchanged volume in the hippocampus.


Assuntos
Astrócitos/efeitos dos fármacos , Giro Denteado/efeitos dos fármacos , Hipocampo/efeitos dos fármacos , Compostos de Lítio/farmacologia , Neuroglia/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Córtex Pré-Frontal/efeitos dos fármacos , Animais , Transtorno Bipolar/patologia , Contagem de Células , Giro Denteado/citologia , Giro Denteado/patologia , Hipocampo/citologia , Hipocampo/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Tamanho do Órgão/efeitos dos fármacos , Córtex Pré-Frontal/citologia , Córtex Pré-Frontal/patologia
11.
J Neurosci ; 34(19): 6583-95, 2014 May 07.
Artigo em Inglês | MEDLINE | ID: mdl-24806683

RESUMO

The brain encodes information about past experience in specific populations of neurons that communicate with one another by firing action potentials. Studies of experience-dependent neural plasticity have largely focused on individual synaptic changes in response to neuronal input. Indicative of the neuronal output transmitted to downstream neurons, persistent firing patterns are affected by prior experience in selective neuronal populations. However, little is known about the molecular and cellular mechanisms by which experience-related persistent firing patterns are regulated in specific neuronal populations. Using frontal cortical slices prepared from transgenic mice carrying a fluorescent reporter of Arc gene expression, this study investigates how behavioral experience and the activity-regulated Arc gene affect patterns of neuronal firing. We found that motor training increases Arc expression in subsets of excitatory neurons. Those neurons exhibit persistent firing in contrast to Arc-negative neurons from the same mice or neurons from the untrained mice. Furthermore, in mice carrying genetic deletion of Arc, the frontal cortical circuitry is still in place to initiate experience-dependent gene expression, but the level of persistent firing thereafter is diminished. Finally, our results showed that the emergence of persistent activity is associated with Arc-dependent changes in the function of NMDA-type glutamate receptors, rather than changes in AMPA-type receptors or membrane excitability. Our findings therefore reveal an Arc-dependent molecular pathway by which gene-experience interaction regulates the emergence of persistent firing patterns in specific neuronal populations.


Assuntos
Proteínas do Citoesqueleto/fisiologia , Proteínas do Tecido Nervoso/fisiologia , Córtex Pré-Frontal/fisiologia , Potenciais de Ação/efeitos dos fármacos , Potenciais de Ação/fisiologia , Animais , Bicuculina/farmacologia , Membrana Celular/efeitos dos fármacos , Membrana Celular/fisiologia , Fenômenos Eletrofisiológicos , Potenciais Pós-Sinápticos Excitadores/efeitos dos fármacos , Potenciais Pós-Sinápticos Excitadores/fisiologia , Antagonistas GABAérgicos/farmacologia , Proteínas de Fluorescência Verde/biossíntese , Proteínas de Fluorescência Verde/genética , Aprendizagem/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Destreza Motora/fisiologia , Plasticidade Neuronal/efeitos dos fármacos , Plasticidade Neuronal/fisiologia , Equilíbrio Postural/fisiologia , Córtex Pré-Frontal/efeitos dos fármacos , Receptores de AMPA/fisiologia
12.
Int J Neuropsychopharmacol ; 16(2): 301-11, 2013 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-22676966

RESUMO

The N-methyl-d-aspartate (NMDA) receptor antagonist ketamine has rapid antidepressant effects in treatment-resistant major depressive disorder (MDD). In rats, ketamine selectively increased electroencephalogram (EEG) slow wave activity (SWA) during non-rapid eye movement (REM) sleep and altered central brain-derived neurotrophic factor (BDNF) expression. Taken together, these findings suggest that higher SWA and BDNF levels may respectively represent electrophysiological and molecular correlates of mood improvement following ketamine treatment. This study investigated the acute effects of a single ketamine infusion on depressive symptoms, EEG SWA, individual slow wave parameters (surrogate markers of central synaptic plasticity) and plasma BDNF (a peripheral marker of plasticity) in 30 patients with treatment-resistant MDD. Montgomery-Åsberg Depression Rating Scale scores rapidly decreased following ketamine. Compared to baseline, BDNF levels and early sleep SWA (during the first non-REM episode) increased after ketamine. The occurrence of high amplitude waves increased during early sleep, accompanied by an increase in slow wave slope, consistent with increased synaptic strength. Changes in BDNF levels were proportional to changes in EEG parameters. Intriguingly, this link was present only in patients who responded to ketamine treatment, suggesting that enhanced synaptic plasticity - as reflected by increased SWA, individual slow wave parameters and plasma BDNF - is part of the physiological mechanism underlying the rapid antidepressant effects of NMDA antagonists. Further studies are required to confirm the link found here between behavioural and synaptic changes, as well as to test the reliability of these central and peripheral biomarkers of rapid antidepressant response.


Assuntos
Ondas Encefálicas/efeitos dos fármacos , Fator Neurotrófico Derivado do Encéfalo/sangue , Transtorno Depressivo Maior/tratamento farmacológico , Antagonistas de Aminoácidos Excitatórios/uso terapêutico , Ketamina/uso terapêutico , Fases do Sono/efeitos dos fármacos , Adulto , Análise de Variância , Transtorno Depressivo Maior/sangue , Eletroencefalografia , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Escalas de Graduação Psiquiátrica , Riluzol/uso terapêutico , Método Simples-Cego , Estatística como Assunto , Fatores de Tempo
13.
Proc Natl Acad Sci U S A ; 107(25): 11573-8, 2010 Jun 22.
Artigo em Inglês | MEDLINE | ID: mdl-20534517

RESUMO

Lithium has been the gold standard in the treatment of bipolar disorder (BPD) for 60 y. Like lithium, glycogen synthase kinase 3 (GSK-3) inhibitors display both antimanic-like and antidepressant-like effects in some animal models. However, the molecular mechanisms of both lithium and GSK-3 inhibitors remain unclear. Here we show that the GSK-3 inhibitor AR-A014418 regulated alpha-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate (AMPA)-induced GluR1 and GluR2 internalization via phosphorylation of kinesin light chain 2 (KLC2), the key molecule of the kinesin cargo delivery system. Specifically, AMPA stimulation triggered serine phosphorylation of KLC2 and, subsequently, the dissociation of the GluR1/KLC2 protein complex. This suggests that GSK-3 phosphorylation of KLC2 led to the dissociation of AMPA-containing vesicles from the kinesin cargo system. The peptide TAT-KLCpCDK, a specific inhibitor for KLC2 phosphorylation by GSK-3beta, reduced the formation of long-term depression. Furthermore, the TAT-KLCpCDK peptide showed antimanic-like effects similar to lithium's on amphetamine-induced hyperactivity, a frequently used animal model of mania. It also induced antidepressant-like effects in the tail suspension and forced swim tests, two commonly used animal models of depression. Taken together, the results demonstrated that KLC2 is a cellular target of GSK-3beta capable of regulating synaptic plasticity, particularly AMPA receptor trafficking, as well as mood-associated behaviors in animal models. The kinesin cargo system may provide valuable novel targets for the development of new therapeutics for mood disorders.


Assuntos
Afeto , Transtorno Bipolar/tratamento farmacológico , Quinase 3 da Glicogênio Sintase/metabolismo , Cinesinas/metabolismo , Animais , Antidepressivos/farmacologia , Glicogênio Sintase Quinase 3 beta , Hipocampo/metabolismo , Lítio/farmacologia , Masculino , Camundongos , Proteínas Associadas aos Microtúbulos/metabolismo , Modelos Biológicos , Plasticidade Neuronal/efeitos dos fármacos , Receptores de AMPA/metabolismo , Sinapses/metabolismo , Tiazóis/farmacologia , Ureia/análogos & derivados , Ureia/farmacologia , Ácido alfa-Amino-3-hidroxi-5-metil-4-isoxazol Propiônico/metabolismo
14.
Front Neurosci ; 17: 1228455, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37592949

RESUMO

Bipolar disorder (BD) is characterized by extreme mood swings ranging from manic/hypomanic to depressive episodes. The severity, duration, and frequency of these episodes can vary widely between individuals, significantly impacting quality of life. Individuals with BD spend almost half their lives experiencing mood symptoms, especially depression, as well as associated clinical dimensions such as anhedonia, fatigue, suicidality, anxiety, and neurovegetative symptoms. Persistent mood symptoms have been associated with premature mortality, accelerated aging, and elevated prevalence of treatment-resistant depression. Recent efforts have expanded our understanding of the neurobiology of BD and the downstream targets that may help track clinical outcomes and drug development. However, as a polygenic disorder, the neurobiology of BD is complex and involves biological changes in several organelles and downstream targets (pre-, post-, and extra-synaptic), including mitochondrial dysfunction, oxidative stress, altered monoaminergic and glutamatergic systems, lower neurotrophic factor levels, and changes in immune-inflammatory systems. The field has thus moved toward identifying more precise neurobiological targets that, in turn, may help develop personalized approaches and more reliable biomarkers for treatment prediction. Diverse pharmacological and non-pharmacological approaches targeting neurobiological pathways other than neurotransmission have also been tested in mood disorders. This article reviews different neurobiological targets and pathophysiological findings in non-canonical pathways in BD that may offer opportunities to support drug development and identify new, clinically relevant biological mechanisms. These include: neuroinflammation; mitochondrial function; calcium channels; oxidative stress; the glycogen synthase kinase-3 (GSK3) pathway; protein kinase C (PKC); brain-derived neurotrophic factor (BDNF); histone deacetylase (HDAC); and the purinergic signaling pathway.

15.
Int J Neuropsychopharmacol ; 15(8): 1135-48, 2012 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-21906419

RESUMO

Research suggests that dysfunctional glutamatergic signalling may contribute to depression, a debilitating mood disorder affecting millions of individuals worldwide. Ketamine, a N-methyl-D-aspartate (NMDA) receptor antagonist, exerts rapid antidepressant effects in approximately 70% of patients. Glutamate evokes the release of D-serine from astrocytes and neurons, which then acts as a co-agonist and binds at the glycine site on the NR1 subunit of NMDA receptors. Several studies have implicated glial deficits as one of the underlying facets of the neurobiology of depression. The present study tested the hypothesis that D-serine modulates behaviours related to depression. The behavioural effects of a single, acute D-serine administration were examined in several rodent tests of antidepressant-like effects, including the forced swim test (FST), the female urine sniffing test (FUST) following serotonin depletion, and the learned helplessness (LH) paradigm. D-serine significantly reduced immobility in the FST without affecting general motor function. Both D-serine and ketamine significantly rescued sexual reward-seeking deficits caused by serotonin depletion in the FUST. Finally, D-serine reversed LH behaviour, as measured by escape latency, number of escapes, and percentage of mice developing LH. Mice lacking NR1 expression in forebrain excitatory neurons exhibited a depression-like phenotype in the same behavioural tests, and did not respond to D-serine treatment. These findings suggest that D-serine produces antidepressant-like effects and support the notion of complex glutamatergic dysfunction in depression. It is unclear whether D-serine has a convergent influence on downstream synaptic plasticity cascades that may yield a similar therapeutic profile to NMDA antagonists like ketamine.


Assuntos
Antidepressivos/administração & dosagem , Depressão/tratamento farmacológico , Depressão/fisiopatologia , Serina/administração & dosagem , Análise de Variância , Animais , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/genética , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/metabolismo , Modelos Animais de Doenças , Reação de Fuga/efeitos dos fármacos , Antagonistas de Aminoácidos Excitatórios/farmacologia , Comportamento Exploratório/efeitos dos fármacos , Feminino , Desamparo Aprendido , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Resposta de Imobilidade Tônica/efeitos dos fármacos , Ketamina/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Atividade Motora/efeitos dos fármacos , Atividade Motora/genética , Fenilenodiaminas/farmacologia , RNA Mensageiro/metabolismo , Ratos , Ratos Endogâmicos WKY , Receptores de N-Metil-D-Aspartato/deficiência , Receptores de N-Metil-D-Aspartato/genética , Natação
16.
Behav Brain Funct ; 8: 15, 2012 Mar 20.
Artigo em Inglês | MEDLINE | ID: mdl-22433906

RESUMO

BACKGROUND: Apathy is frequently observed in numerous neurological disorders, including Alzheimer's and Parkinson's, as well as neuropsychiatric disorders including schizophrenia. Apathy is defined as a lack of motivation characterized by diminished goal-oriented behavior and self-initiated activity. This study evaluated a chronic restraint stress (CRS) protocol in modeling apathetic behavior, and determined whether administration of an anticholinesterase had utility in attenuating CRS-induced phenotypes. METHODS: We assessed behavior as well as regional neuronal activity patterns using FosB immunohistochemistry after exposure to CRS for 6 h/d for a minimum of 21 d. Based on our FosB findings and recent clinical trials, we administered an anticholinesterase to evaluate attenuation of CRS-induced phenotypes. RESULTS: CRS resulted in behaviors that reflect motivational loss and diminished emotional responsiveness. CRS-exposed mice showed differences in FosB accumulation, including changes in the cholinergic basal forebrain system. Facilitating cholinergic signaling ameliorated CRS-induced deficits in initiation and motivational drive and rescued immediate early gene activation in the medial septum and nucleus accumbens. CONCLUSIONS: Some CRS protocols may be useful for studying deficits in motivation and apathetic behavior. Amelioration of CRS-induced behaviors with an anticholinesterase supports a role for the cholinergic system in remediation of deficits in motivational drive.


Assuntos
Inibidores da Colinesterase/farmacologia , Impulso (Psicologia) , Motivação/efeitos dos fármacos , Anedonia , Animais , Ansiedade/psicologia , Comportamento Animal/efeitos dos fármacos , Peso Corporal/efeitos dos fármacos , Doença Crônica , Habituação Psicofisiológica/efeitos dos fármacos , Elevação dos Membros Posteriores , Processamento de Imagem Assistida por Computador , Imuno-Histoquímica , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Sistema Nervoso/fisiopatologia , Fenótipo , Fisostigmina/análogos & derivados , Fisostigmina/farmacologia , Proteínas Proto-Oncogênicas c-fos/metabolismo , Quinina/farmacologia , Restrição Física , Estresse Psicológico/psicologia , Natação/psicologia , Paladar
17.
Proc Natl Acad Sci U S A ; 106(9): 3543-8, 2009 Mar 03.
Artigo em Inglês | MEDLINE | ID: mdl-19202080

RESUMO

Glucocorticoids play an important biphasic role in modulating neural plasticity; low doses enhance neural plasticity and spatial memory behavior, whereas chronic, higher doses produce inhibition. We found that 3 independent measures of mitochondrial function-mitochondrial oxidation, membrane potential, and mitochondrial calcium holding capacity-were regulated by long-term corticosterone (CORT) treatment in an inverted "U"-shape. This regulation of mitochondrial function by CORT correlated with neuroprotection; that is, treatment with low doses of CORT had a neuroprotective effect, whereas treatment with high doses of CORT enhanced kainic acid (KA)-induced toxicity of cortical neurons. We then undertook experiments to elucidate the mechanisms underlying these biphasic effects and found that glucocorticoid receptors (GRs) formed a complex with the anti-apoptotic protein Bcl-2 in response to CORT treatment and translocated with Bcl-2 into mitochondria after acute treatment with low or high doses of CORT in primary cortical neurons. However, after 3 days of treatment, high, but not low, doses of CORT resulted in decreased GR and Bcl-2 levels in mitochondria. As with the in vitro studies, Bcl-2 levels in the mitochondria of the prefrontal cortex were significantly decreased, along with GR levels, after long-term treatment with high-dose CORT in vivo. These findings have the potential to contribute to a more complete understanding of the mechanisms by which glucocorticoids and chronic stress regulate cellular plasticity and resilience and to inform the future development of improved therapeutics.


Assuntos
Glucocorticoides/metabolismo , Mitocôndrias/metabolismo , Animais , Transporte Biológico , Sobrevivência Celular , Corticosterona/metabolismo , Potencial da Membrana Mitocondrial , Mifepristona/farmacologia , Mitocôndrias/efeitos dos fármacos , Neurônios/citologia , Neurônios/metabolismo , Oxirredução , Córtex Pré-Frontal/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Fatores de Tempo , Técnicas de Cultura de Tecidos
18.
Nat Rev Drug Discov ; 21(3): 224-244, 2022 03.
Artigo em Inglês | MEDLINE | ID: mdl-35039676

RESUMO

Over the past two decades, compelling evidence has emerged indicating that immune mechanisms can contribute to the pathogenesis of major depressive disorder (MDD) and that drugs with primary immune targets can improve depressive symptoms. Patients with MDD are heterogeneous with respect to symptoms, treatment responses and biological correlates. Defining a narrower patient group based on biology could increase the treatment response rates in certain subgroups: a major advance in clinical psychiatry. For example, patients with MDD and elevated pro-inflammatory biomarkers are less likely to respond to conventional antidepressant drugs, but novel immune-based therapeutics could potentially address their unmet clinical needs. This article outlines a framework for developing drugs targeting a novel patient subtype within MDD and reviews the current state of neuroimmune drug development for mood disorders. We discuss evidence for a causal role of immune mechanisms in the pathogenesis of depression, together with targets under investigation in randomized controlled trials, biomarker evidence elucidating the link to neural mechanisms, biological and phenotypic patient selection strategies, and the unmet clinical need among patients with MDD.


Assuntos
Transtorno Depressivo Maior , Antidepressivos/farmacologia , Antidepressivos/uso terapêutico , Biomarcadores , Depressão/tratamento farmacológico , Transtorno Depressivo Maior/tratamento farmacológico , Humanos , Medicina de Precisão
19.
J Neurochem ; 119(3): 617-29, 2011 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-21838781

RESUMO

Bipolar disorder is a devastating illness that is marked by recurrent episodes of mania and depression. There is growing evidence that the disease is correlated with disruptions in synaptic plasticity cascades involved in cognition and mood regulation. Alleviating the symptoms of bipolar disorder involves chronic treatment with mood stabilizers like lithium or valproate. These two structurally dissimilar drugs are known to alter prominent signaling cascades in the hippocampus, but their effects on the post-synaptic density complex remain undefined. In this work, we utilized mass spectrometry for quantitative profiling of the rat hippocampal post-synaptic proteome to investigate the effects of chronic mood stabilizer treatment. Our data show that in response to chronic treatment of mood stabilizers there were not gross qualitative changes but rather subtle quantitative perturbations in post-synaptic density proteome linked to several key signaling pathways. Our data specifically support the changes in actin dynamics on valproate treatment. Using label-free quantification methods, we report that lithium and valproate significantly altered the abundance of 21 and 43 proteins, respectively. Seven proteins were affected similarly by both lithium and valproate: Ank3, glutamate receptor 3, dynein heavy chain 1, and four isoforms of the 14-3-3 family. Immunoblotting the same samples confirmed the changes in Ank3 and glutamate receptor 3 abundance. Our findings support the hypotheses that BPD is a synaptic disorder and that mood stabilizers modulate the protein signaling complex in the hippocampal post-synaptic density.


Assuntos
Antipsicóticos/administração & dosagem , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Lítio/administração & dosagem , Densidade Pós-Sináptica/efeitos dos fármacos , Proteoma/efeitos dos fármacos , Proteoma/metabolismo , Ácido Valproico/administração & dosagem , Animais , Esquema de Medicação , Redes Reguladoras de Genes/efeitos dos fármacos , Redes Reguladoras de Genes/fisiologia , Masculino , Transtornos do Humor/tratamento farmacológico , Densidade Pós-Sináptica/genética , Densidade Pós-Sináptica/metabolismo , Proteoma/genética , Ratos , Ratos Endogâmicos WKY , Resultado do Tratamento
20.
Int J Neuropsychopharmacol ; 14(4): 545-51, 2011 May.
Artigo em Inglês | MEDLINE | ID: mdl-21029512

RESUMO

The D2/D3 receptor agonist pramipexole has clinical efficacy as an antidepressant, but its neural mechanisms are unknown. We used ¹8FDG-PET to investigate the cerebral metabolic effects of pramipexole augmentation of mood stabilizers in bipolar II depression. Fifteen bipolar II depressed patients on mood stabilizers were imaged at baseline and following 6 wk of pramipexole (n=7) or placebo (n=8) augmentation. Relative to placebo, pramipexole treatment was associated with reductions in normalized metabolism in bilateral orbitofrontal cortex, left ventrolateral prefrontal cortex (PFC), and right anteromedial PFC. Voxel-wise analyses additionally showed decreased normalized metabolism in the left inferior parietal cortex and medial frontopolar cortical (BA 10P) area of the anteromedial PFC following pramipexole treatment. These pramipexole-induced effects on regional metabolism suggest a mechanism of antidepressant action distinct from that previously reported under serotonin reuptake inhibitor treatment and appear compatible with evidence that the central dopaminergic system plays a role in the pathophysiology of bipolar depression.


Assuntos
Antidepressivos/uso terapêutico , Antimaníacos/uso terapêutico , Benzotiazóis/uso terapêutico , Transtorno Bipolar/tratamento farmacológico , Agonistas de Dopamina/uso terapêutico , Sistema Límbico/metabolismo , Córtex Pré-Frontal/metabolismo , Adulto , Transtorno Bipolar/metabolismo , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Feminino , Fluordesoxiglucose F18/metabolismo , Humanos , Sistema Límbico/efeitos dos fármacos , Masculino , Placebos , Pramipexol , Córtex Pré-Frontal/efeitos dos fármacos , Compostos Radiofarmacêuticos/farmacologia
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