RESUMO
Myasthenia gravis (MG) is a neuromuscular disease that results in compromised transmission of electrical signals at the neuromuscular junction (NMJ) from motor neurons to skeletal muscle fibers. As a result, patients with MG have reduced skeletal muscle function and present with symptoms of severe muscle weakness and fatigue. ClC-1 is a skeletal muscle specific chloride (Cl-) ion channel that plays important roles in regulating neuromuscular transmission and muscle fiber excitability during intense exercise. Here, we show that partial inhibition of ClC-1 with an orally bioavailable small molecule (NMD670) can restore muscle function in rat models of MG and in patients with MG. In severely affected MG rats, ClC-1 inhibition enhanced neuromuscular transmission, restored muscle function, and improved mobility after both single and prolonged administrations of NMD670. On this basis, NMD670 was progressed through nonclinical safety pharmacology and toxicology studies, leading to approval for testing in clinical studies. After successfully completing phase 1 single ascending dose in healthy volunteers, NMD670 was tested in patients with MG in a randomized, placebo-controlled, single-dose, three-way crossover clinical trial. The clinical trial evaluated safety, pharmacokinetics, and pharmacodynamics of NMD670 in 12 patients with mild MG. NMD670 had a favorable safety profile and led to clinically relevant improvements in the quantitative myasthenia gravis (QMG) total score. This translational study spanning from single muscle fiber recordings to patients provides proof of mechanism for ClC-1 inhibition as a potential therapeutic approach in MG and supports further development of NMD670.
Assuntos
Cloretos , Miastenia Gravis , Humanos , Ratos , Animais , Cloretos/uso terapêutico , Miastenia Gravis/tratamento farmacológico , Músculo Esquelético/fisiologia , Junção Neuromuscular , Canais de CloretoRESUMO
Ambient measurement systems (AMSs) can enable continuous assessment of functional performance at home, increasing the availability of data for monitoring of neuromuscular disease. An AMS passively measures movement whenever someone is in range of the sensor, without the need for any wearable sensors. The current study evaluates the performance of an AMS for three metrics associated with functional assessments in Duchenne muscular dystrophy (DMD): ambulation speed, rise-to-stand speed and arm-raise speed. Healthy paediatric subjects performed a series of functional tasks and were graded by both a human rater and an AMS. Linear mixed-effect models were fit to calculate agreement between the two measurement methods. For all activities, the AMS and human rater supplied similar measurements of average speed, with correlation coefficients of 0.76-0.92 and systematic differences ranging in magnitude from 0 to 0.48 m per second. The largest systematic difference was for the 10-m run, which was likely due to human rater reaction time. Systematic differences in arm-raise measurements were due to incomplete execution of movements by test participants. These results are consistent with previous studies comparing automated and manual measurements of movement. This study demonstrates that an AMS device is able to measure ambulation speed, rise-to-stand speed and arm-raise speed in a paediatric population in a controlled setting without the need for complicated installation, calibration or worn sensors.
Assuntos
Exercício Físico/fisiologia , Monitorização Ambulatorial/instrumentação , Telemedicina/instrumentação , Criança , Pré-Escolar , Feminino , Voluntários Saudáveis , Humanos , Masculino , Movimento/fisiologia , Distrofia Muscular de Duchenne/fisiopatologia , Reprodutibilidade dos TestesRESUMO
Preclinical data suggest that inhibition of the metabotropic glutamate receptor 5 (mGluR5) receptor might hold therapeutic benefits in Fragile X syndrome (FXS). Treatment of Fmr1 knockout mice with mGluR5-negative allosteric modulators (NAMs) has been reported to correct a broad range of phenotypes related to FXS. The early short-term clinical trials with mGluR5 NAMs, including basimglurant, assessing the effects in individuals with FXS, were supportive of further exploration in larger, well-controlled trials. We evaluated basimglurant, a potent and selective mGluR5 NAM, in a 12-week, double-blind, parallel-group study of 183 adults and adolescents (aged 14-50, mean 23.4 years) with FXS. Individuals with an FMR1 full mutation were randomized to placebo or one of two doses of basimglurant. The primary efficacy endpoint was the change from baseline in behavioral symptoms using the Anxiety Depression and Mood Scale (ADAMS) total score. All treatment arms showed marked behavioral improvements from baseline to week 12 with less improvement in the basimglurant 1.5 mg arm than placebo; however, basimglurant 0.5 mg was inferior to placebo in the ADAMs total score. Treatment with basimglurant was overall well-tolerated. A higher incidence of adverse events classified as psychiatric disorders were reported in patients treated with basimglurant, including three patients with hallucinations or psychosis. In this phase 2 clinical trial, basimglurant did not demonstrate improvement over placebo. Evaluation of the overall risk-benefit in younger patient populations is an important consideration for the design of potential further investigations of efficacy with this class of medications.
Assuntos
Antagonistas de Aminoácidos Excitatórios/uso terapêutico , Síndrome do Cromossomo X Frágil/tratamento farmacológico , Imidazóis/uso terapêutico , Psicotrópicos/uso terapêutico , Piridinas/uso terapêutico , Receptor de Glutamato Metabotrópico 5/antagonistas & inibidores , Adolescente , Adulto , Metilação de DNA , Método Duplo-Cego , Antagonistas de Aminoácidos Excitatórios/efeitos adversos , Feminino , Proteína do X Frágil da Deficiência Intelectual/genética , Síndrome do Cromossomo X Frágil/genética , Síndrome do Cromossomo X Frágil/metabolismo , Síndrome do Cromossomo X Frágil/psicologia , Humanos , Imidazóis/efeitos adversos , Masculino , Pessoa de Meia-Idade , Psicotrópicos/efeitos adversos , Piridinas/efeitos adversos , RNA Mensageiro/sangue , Receptor de Glutamato Metabotrópico 5/metabolismo , Falha de Tratamento , Adulto JovemRESUMO
IMPORTANCE: Antagonism of the postsynaptic metabotropic glutamate subtype 5 receptor is a novel approach to modulate glutamatergic function and has proven efficacy in a number of preclinical behavioral models of depression. OBJECTIVE: To evaluate the safety and efficacy of basimglurant modified-release (MR) vs placebo as adjunctive therapy to ongoing antidepressant medication therapy in patients with MDD who had inadequate response within the current episode. DESIGN, SETTING, AND PARTICIPANTS: In this phase 2b, double blind, randomized clinical trial of 333 adult patients with a DSM-IV-TR diagnosis of MDD across 59 research clinics globally, patients were assigned to 1 of 2 doses of basimglurant MR (0.5 or 1.5 mg) or placebo once daily, adjunctive to ongoing antidepressant medication therapy (selective serotonin reuptake inhibitor or serotonin and norepinephrine reuptake inhibitor). Patients were enrolled from October 5, 2011, through July 26, 2013. INTERVENTIONS: Six-week treatment with 0.5 mg of basimglurant MR, 1.5-mg basimglurant MR, or placebo once daily, adjunctive to ongoing antidepressant medication therapy. MAIN OUTCOMES AND MEASURES: The primary end point was the mean change from baseline score on the Montgomery-Åsberg Depression Rating Scale (MADRS), as rated by the clinician at week 6. Other measures included patient-rated MADRS, Quick Inventory of Depressive Symptomatology-Self-Report, Clinical Global Impression-Improvement, Patient Global Impression-Improvement, and Clinical Global Impression-Severity Scales and adverse events. RESULTS: A total of 596 patients were screened, and 333 were randomized into the study (mean [SD] age, 47 [11.2] years; 216 female [65.1%]). The primary end point (mean change in clinician-rated MADRS score from baseline to end of treatment) was not met (effect size [ES] = 0.16, P = .42; intent-to-treat [ITT] mixed-effects model for repeated measures [MMRM] analysis for comparing 1.5-mg basimglurant MR and placebo). Across secondary and exploratory end points, 1.5-mg basimglurant MR revealed larger improvements vs placebo on the patient-rated MADRS (-16.2 vs -13.3, ES = 0.28, nominal P = .04), Quick Inventory of Depressive Symptomatology-Self-Report (-7.5 vs -5.8; ES = 0.37, nominal P = .009), Clinical Global Impression-Improvement mean score, and Patient Global Impression-Improvement mean score. Improvements were also seen in the patient-rated MADRS remission rate (36.0% vs 22.0%; nominal P = .03) and response rate (50.5% vs 40.4%; nominal P = .13), A 0.5-mg dose of basimglurant MR had no benefit over placebo in any of these measures. The most common adverse event was dizziness, which was mostly transient and of mild intensity. CONCLUSIONS AND RELEVANCE: No difference was observed on the study's primary outcome measure, the clinician-rated MADRS change from baseline to end of treatment, between adjunctive basimglurant MR vs placebo. Adjunctive 1.5-mg basimglurant MR daily revealed, however, an antidepressant effect across secondary end points, particularly in patient-rated measures. These findings combined with good tolerability warrant further investigation with this compound in depressive disorders. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01437657.
Assuntos
Antidepressivos/uso terapêutico , Transtorno Depressivo Maior/tratamento farmacológico , Imidazóis/uso terapêutico , Piridinas/uso terapêutico , Adolescente , Adulto , Idoso , Antidepressivos/efeitos adversos , Preparações de Ação Retardada , Transtorno Depressivo Maior/diagnóstico , Transtorno Depressivo Maior/psicologia , Relação Dose-Resposta a Droga , Método Duplo-Cego , Quimioterapia Combinada , Feminino , Humanos , Imidazóis/efeitos adversos , Masculino , Pessoa de Meia-Idade , Determinação da Personalidade , Piridinas/efeitos adversos , Resultado do Tratamento , Adulto JovemRESUMO
BACKGROUND: Risperidone long-acting injectable was previously approved for treatment of schizophrenia as biweekly injections in the gluteal muscle only. We present data on local injection-site tolerability and safety of risperidone long-acting injectable and comparability of systemic exposure of deltoid versus gluteal injections. METHODS: Risperidone long-acting injectable was administered in an open-label, single-dose, two-way crossover study, with patients randomized to receive either 25mg gluteal/37.5mg deltoid crossover in two treatment periods or 50mg gluteal/50mg deltoid injections crossover; each treatment period was separated by an 85-day observation period (Study 1) and an open-label, multiple-dose study (4 sequential 37.5mg or 50mg deltoid injections every 2 weeks) (Study 2). The pharmacokinetic results from both the studies have already been published. RESULTS: In Study 1 (n=170), the majority of patients had no local injection-site findings, based on investigator and patient-rated evaluations. In Study 2 (n=53), seven of the 51 patients who received at least two deltoid injections discontinued (primary endpoint). However, none of the discontinuations were due to injection-site related reasons. The 90-percent upper confidence limit of the true proportion of injection-site issue withdrawals was 5.7 percent. No moderate or severe injection-site reactions were reported. CONCLUSION: Intramuscular injections via the deltoid and gluteal sites are equivalent routes of administration of risperidone long-acting injectable with respect to local injection-site tolerability. The overall safety and tolerability profile of risperidone long-acting injectable was comparable when administered as an intramuscular injection in the deltoid (37.5mg and 50mg) and gluteal (25mg and 50mg) sites.
RESUMO
Paliperidone palmitate is a long-acting injectable antipsychotic agent. This 13-week, multicenter, randomized (1 : 1 : 1 : 1), double-blind, parallel-group study evaluated the efficacy, safety, and tolerability of fixed 25, 50, and 100 milligram equivalent (mg equiv.) doses of paliperidone palmitate vs placebo administered as gluteal injections on days 1 and 8, then every 4 weeks (days 36 and 64) in 518 adult patients with schizophrenia. The intent-to-treat analysis set (N=514) was 67% men and 67% White, with a mean age of 41 years. All paliperidone palmitate dose groups showed significant improvement vs placebo in the Positive and Negative Syndrome Scale (PANSS) total score (primary efficacy measure; 25 and 50 mg equiv., p=0.02; 100 mg equiv., p<0.001), as well as Clinical Global Impression Severity scores (p< or =0.006) and PANSS negative and positive symptom Marder factor scores (p< or =0.04). The Personal and Social Performance scale showed no significant difference between treatment groups. The overall incidence of treatment-emergent adverse events was similar between groups. Parkinsonism, the most frequently reported extrapyramidal symptom, was reported at similar rates for placebo (5%) and paliperidone palmitate (5-6% across doses). The mean body mass index and mean weight showed relatively small dose-related increases during paliperidone palmitate treatment. Investigator-evaluated injection-site pain, swelling, redness, and induration were similar across treatment groups; scores for patient-evaluated injection-site pain (visual analog scale) were similar across groups and diminished with time. All doses of once-monthly paliperidone palmitate were efficacious and generally tolerated, both locally and systemically. Paliperidone palmitate offers the potential to improve outcomes in adults with symptomatic schizophrenia.
Assuntos
Antipsicóticos/uso terapêutico , Isoxazóis/uso terapêutico , Palmitatos/uso terapêutico , Esquizofrenia/tratamento farmacológico , Adulto , Doenças dos Gânglios da Base/induzido quimicamente , Índice de Massa Corporal , Peso Corporal/efeitos dos fármacos , Estudos de Casos e Controles , Relação Dose-Resposta a Droga , Método Duplo-Cego , Sistemas de Liberação de Medicamentos/métodos , Medicina Baseada em Evidências , Feminino , Humanos , Injeções , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Palmitato de Paliperidona , Escalas de Graduação Psiquiátrica , Resultado do TratamentoRESUMO
OBJECTIVE: The singular phenomenon of switching from depression to its opposite state of mania or hypomania, and vice versa, distinguishes bipolar disorder from all other psychiatric disorders. Despite the fact that it is a core aspect of the clinical presentation of bipolar disorder, the neurobiology of the switch process is still poorly understood. In this review, we summarize the clinical evidence regarding somatic interventions associated with switching, with a particular focus on the biologic underpinnings presumably involved in the switch process. DATA SOURCES: Literature for this review was obtained through a search of the MEDLINE database (1966-2008) using the following keywords and phrases: switch, bipolar disorder, bipolar depression, antidepressant, SSRIs, tricyclic antidepressants, norepinephrine, serotonin, treatment emergent affective switch, mania, hypomania, HPA-axis, glucocorticoids, amphetamine, dopamine, and sleep deprivation. STUDY SELECTION: All English-language, peer-reviewed, published literature, including randomized controlled studies, naturalistic and open-label studies, and case reports, were eligible for inclusion. DATA SYNTHESIS: Converging evidence suggests that certain pharmacologic and nonpharmacologic interventions with very different mechanisms of action, such as sleep deprivation, exogenous corticosteroids, and dopaminergic agonists, can trigger mood episode switches in patients with bipolar disorder. The switch-inducing potential of antidepressants is unclear, although tricyclic antidepressants, which confer higher risk of switching than other classes of antidepressants, are a possible exception. Several neurobiological factors appear to be associated with both spontaneous and treatment-emergent mood episode switches; these include abnormalities in catecholamine levels, up-regulation of neurotrophic and neuroplastic factors, hypothalamic-pituitary-adrenal axis hyperactivity, and circadian rhythms. CONCLUSIONS: There is a clear need to improve our understanding of the neurobiology of the switch process; research in this field would benefit from the systematic and integrated assessment of variables associated with switching.
Assuntos
Transtorno Bipolar/fisiopatologia , Antidepressivos/uso terapêutico , Antidepressivos Tricíclicos/uso terapêutico , Transtorno Bipolar/tratamento farmacológico , Transtorno Bipolar/psicologia , Ritmo Circadiano/fisiologia , Dopaminérgicos/uso terapêutico , Dronabinol/análogos & derivados , Sistema Hipotálamo-Hipofisário/fisiopatologia , Sistema Hipófise-Suprarrenal/fisiopatologia , Receptores de Catecolaminas/efeitos dos fármacos , Receptores de Catecolaminas/fisiologia , Inibidores Seletivos de Recaptação de Serotonina/uso terapêutico , Privação do Sono/fisiopatologiaRESUMO
The monovalent cation lithium partially exerts its effects by activating neurotrophic and neuroprotective cellular cascades. Here, we discuss the effects of lithium on oxidative stress, programmed cell death (apoptosis), inflammation, glial dysfunction, neurotrophic factor functioning, excitotoxicity, and mitochondrial stability. In particular, we review evidence demonstrating the action of lithium on cyclic adenosine monophosphate (cAMP)-mediated signal transduction, cAMP response element binding activation, increased expression of brain-derived neurotrophic factor, the phosphatidylinositide cascade, protein kinase C inhibition, glycogen synthase kinase 3 inhibition, and B-cell lymphoma 2 expression. Notably, we also review data from clinical studies demonstrating neurotrophic effects of lithium. We expect that a better understanding of the clinically relevant pathophysiological targets of lithium will lead to improved treatments for those who suffer from mood as well as neurodegenerative disorders.
Assuntos
Antipsicóticos/farmacologia , Compostos de Lítio/farmacologia , Fatores de Crescimento Neural/metabolismo , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Fármacos Neuroprotetores/farmacologia , Animais , HumanosRESUMO
BACKGROUND: Treatment adherence is a significant problem in patients with bipolar disorder. This study was designed to determine the efficacy of risperidone long-acting injectable (LAI) in the maintenance treatment of bipolar I disorder. METHODS: Eligible patients with current or recent manic or mixed episodes (n = 559, aged 18-65 years) were treated with open-label oral risperidone for 3 weeks (period II) and open-label risperidone LAI for 26 weeks (n = 501; period III). Patients who maintained response (n = 303) were randomly allocated 1:1 to placebo injections (n = 149) or to continue risperidone LAI (n = 154) for up to 24 months (period IV). RESULTS: Most (77%) patients on risperidone LAI received a dose of 25 mg every 2 weeks during period IV. Time to recurrence for any mood episode (primary outcome variable) was significantly longer in the risperidone LAI group versus placebo (p < .001); the difference was significant for time to recurrence of elevated-mood episode (p < .001) but not time to recurrence of depressive episode (p = .805). Weight gains > or = 7% (compared with the period's baseline) occurred in 15% of patients in period III; in 12% of patients on risperidone LAI and 3% of patients on placebo in period IV. CONCLUSIONS: Risperidone LAI monotherapy significantly delayed the time to recurrence of mood episodes, versus placebo, in this controlled, randomized study in patients with bipolar I disorder. Risperidone LAI was tolerable and no new safety concerns emerged compared with previous studies of risperidone LAI.
Assuntos
Transtorno Bipolar/tratamento farmacológico , Risperidona/administração & dosagem , Administração Oral , Adolescente , Adulto , Idoso , Antipsicóticos/administração & dosagem , Antipsicóticos/uso terapêutico , Método Duplo-Cego , Esquema de Medicação , Feminino , Humanos , Injeções Intramusculares , Estimativa de Kaplan-Meier , Masculino , Adesão à Medicação , Pessoa de Meia-Idade , Risperidona/uso terapêutico , Resultado do TratamentoRESUMO
OBJECTIVE: The aim of this study was to evaluate the efficacy and safety of two dose ranges of risperidone in adolescents with schizophrenia. METHODS: In a 6-week, randomized, double-blind, placebo-controlled study, adolescents aged 13-17 years with acute exacerbation of schizophrenia were randomized to placebo, flexible doses of risperidone 1-3 mg/day, or risperidone 4-6 mg/day. Assessments included the Positive and Negative Syndrome Scale (PANSS), clinical response (> or =20% reduction in PANSS total score), adverse event (AE) monitoring, and extrapyramidal symptom (EPS) scale ratings. RESULTS: A total of 160 subjects received placebo (n = 54), risperidone 1-3 mg/day (n = 55), or risperidone 4-6 mg/day (n = 51). Significant improvements occurred in both risperidone groups versus placebo (p < 0.001) in PANSS total change scores (placebo, -8.9 [16.1]; risperidone 1-3 mg, -21.3 [19.6]; risperidone 4-6 mg, -21.2 [18.3]) and clinical response rates (35%, 65%, 72%, respectively). Overall AE rates were more common in risperidone groups (75% and 76%) versus placebo (54%). Risperidone 4-6 mg/day had a higher incidence of extrapyramidal disorder, dizziness, and hypertonia than risperidone 1-3 mg. No prolactin-related AEs occurred. Overall EPS severity was low. CONCLUSIONS: Risperidone 1-3 mg/day and 4-6 mg/day were well tolerated and effective in adolescents experiencing acute episodes of schizophrenia. The benefit-risk profile suggests that a dose of 1-3 mg/day might be optimal for this population.
Assuntos
Comportamento do Adolescente/efeitos dos fármacos , Antipsicóticos/administração & dosagem , Risperidona/administração & dosagem , Esquizofrenia/tratamento farmacológico , Psicologia do Esquizofrênico , Adolescente , Antipsicóticos/efeitos adversos , Relação Dose-Resposta a Droga , Método Duplo-Cego , Discinesia Induzida por Medicamentos , Feminino , Humanos , Masculino , Placebos , Prolactina/efeitos dos fármacos , Escalas de Graduação Psiquiátrica , Risperidona/efeitos adversos , Índice de Gravidade de Doença , Resultado do TratamentoRESUMO
OBJECTIVE: Recent molecular, preclinical, and preliminary clinical studies suggest that the therapeutic effects of mood stabilizers may be mediated by modulating expression of potent neurotrophic and neuroprotective factors having the potential to reverse impairments of cellular resilience, reductions in brain volume, and cell death or atrophy. Our main goal was to investigate the potential clinical significance of these findings in relation to bipolar disorder. METHOD: The longitudinal effect of lithium on brain gray matter volume was investigated in well-characterized (DSM-IV criteria) bipolar depressed subjects (N = 28) at baseline (medication-free) and after lithium administration (4 weeks). Total brain gray matter, prefrontal gray matter, and left subgenual prefrontal gray matter volumes were determined using validated semiautomated segmentation and region of interest methodology. The study was conducted from November 1997 until April 2004 at Wayne State University School of Medicine, Detroit, Mich. RESULTS: Significant increases in total brain gray matter volume in bipolar subjects were observed after 4 weeks of lithium administration (p = .0043). Moreover, regional analyses in the bipolar subjects revealed significant differences between responders (>50% decrease in Hamilton Depression Rating Scale total score) and nonresponders; only responders showed a significant increase in gray matter volume in the prefrontal cortex (p = .003) and an increase at trend level in the left subgenual prefrontal cortex volume (p = .0786). CONCLUSION: The increase in gray matter volume in these areas, which various neuroimaging and postmortem neuropathology studies have implicated in the neuropathophysiology of bipolar disorder, suggests that the observed effects may be linked to clinical response. The findings also support the notion that future treatments that more directly target molecules in critical central nervous system pathways that regulate cellular plasticity hold promise as novel, improved, long-term treatments for mood disorders as well as some neurodegenerative conditions, such as Alzheimer's disease. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00870311.
Assuntos
Antimaníacos/farmacologia , Antimaníacos/uso terapêutico , Transtorno Bipolar/tratamento farmacológico , Transtorno Bipolar/fisiopatologia , Carbonato de Lítio/farmacologia , Carbonato de Lítio/uso terapêutico , Córtex Pré-Frontal , Adulto , Transtorno Bipolar/diagnóstico , Manual Diagnóstico e Estatístico de Transtornos Mentais , Feminino , Seguimentos , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Córtex Pré-Frontal/anatomia & histologia , Córtex Pré-Frontal/efeitos dos fármacos , Córtex Pré-Frontal/fisiopatologia , Índice de Gravidade de Doença , Inquéritos e Questionários , Adulto JovemRESUMO
Bipolar disorder (BPD) has traditionally been conceptualized as a neurochemical disorder, but there is mounting evidence for impairments of cellular plasticity and resilience. Here, we review and synthesize the evidence that critical aspects of mitochondrial function may play an integral role in the pathophysiology and treatment of BPD. Retrospective database searches were performed, including MEDLINE, abstract booklets, and conference proceedings. Articles were also obtained from references therein and personal communications, including original scientific work, reviews, and meta-analyses of the literature. Material regarding the potential role of mitochondrial function included genetic studies, microarray studies, studies of intracellular calcium regulation, neuroimaging studies, postmortem brain studies, and preclinical and clinical studies of cellular plasticity and resilience. We review these data and discuss their implications not only in the context of changing existing conceptualizations regarding the pathophysiology of BPD, but also for the strategic development of improved therapeutics. We have focused on specific aspects of mitochondrial dysfunction that may have major relevance for the pathophysiology and treatment of BPD. Notably, we discuss calcium dysregulation, oxidative phosphorylation abnormalities, and abnormalities in cellular resilience and synaptic plasticity. Accumulating evidence from microarray studies, biochemical studies, neuroimaging, and postmortem brain studies all support the role of mitochondrial dysfunction in the pathophysiology of BPD. We propose that although BPD is not a classic mitochondrial disease, subtle deficits in mitochondrial function likely play an important role in various facets of BPD, and that enhancing mitochondrial function may represent a critical component for the optimal long-term treatment of the disorder.
Assuntos
Transtorno Bipolar/fisiopatologia , Transtorno Bipolar/terapia , Mitocôndrias/fisiologia , Plasticidade Neuronal/fisiologia , Animais , Transtorno Bipolar/patologia , Humanos , Mitocôndrias/patologia , Resultado do TratamentoRESUMO
OBJECTIVE: This study was designed to assess possible antidepressant effects of memantine, a selective N-methyl-D-aspartate (NMDA) receptor antagonist in humans. METHOD: In a double-blind, placebo-controlled study, 32 subjects with major depression were randomly assigned to receive memantine (5-20 mg/day) (N=16) or placebo (N=16) for 8 weeks. Primary efficacy was assessed by performance on the Montgomery-Asberg Depression Rating Scale (MADRS). RESULTS: The linear mixed models for total MADRS scores showed no treatment effect. CONCLUSIONS: In an 8-week trial, the low-to-moderate-affinity NMDA antagonist memantine in doses of 5-20 mg/day was not effective in the treatment of major depressive disorder.
Assuntos
Transtorno Depressivo Maior/tratamento farmacológico , Antagonistas de Aminoácidos Excitatórios/uso terapêutico , Memantina/uso terapêutico , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Transtorno Depressivo Maior/diagnóstico , Transtorno Depressivo Maior/psicologia , Método Duplo-Cego , Esquema de Medicação , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Placebos , Escalas de Graduação Psiquiátrica , Índice de Gravidade de Doença , Resultado do TratamentoRESUMO
BACKGROUND: Preclinical and clinical evidence indicate that the glutamatergic system might play a role in the pathophysiology of mood disorders. This study was conducted to determine the efficacy and safety of riluzole, a glutamate-modulating agent, in bipolar depression. METHODS: This was an 8-week add-on study of riluzole in combination with lithium in acutely depressed bipolar patients aged 18 years and older. After open treatment with lithium for a minimum period of 4 weeks, subjects who continued to have a Montgomery-Asberg Depression Rating Scale (MADRS) score of >/=20 received riluzole (50-200 mg/day) for 8 weeks. RESULTS: Fourteen bipolar depressed patients entered the study. The linear mixed models for total MADRS score showed a significant treatment effect. No switch into hypomania or mania was observed. Overall, riluzole was well tolerated. CONCLUSIONS: Although preliminary, these results suggest that riluzole might indeed have antidepressant efficacy in subjects with bipolar depression.
Assuntos
Transtorno Bipolar/tratamento farmacológico , Antagonistas de Aminoácidos Excitatórios/uso terapêutico , Lítio/uso terapêutico , Riluzol/uso terapêutico , Adolescente , Adulto , Idoso , Quimioterapia Combinada , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Inventário de Personalidade , Escalas de Graduação Psiquiátrica , Fatores de Tempo , Resultado do TratamentoRESUMO
Bipolar affective disorder is a common, severe, chronic, and often life-threatening illness, associated with other medical and psychiatric conditions (i.e., co-morbidity). The treatment of this devastating disorder was revolutionized by the discovery of lithium's antimanic effects over fifty years ago. Recent molecular and cellular biological studies have identified a number of unexpected targets for this monovalent cation, notably glycogen synthase kinase-3 and neurotrophic signaling cascades. These findings are leading to a reconceptualization of the biological underpinnings of bipolar disorder and are resulting in considerable interest in utilizing lithium for the treatment of certain neurodegenerative disorders. We review recent insights into lithium's actions including its direct inhibitory actions on inositol monophosphatase, inositol polyphosphate 1-phosphatase, glycogen synthase kinase-3, fructose 1,6-bisphosphatase, bisphosphate nucleotidase, and phosphoglucomutase enzymes. We also discuss lithium's intracellular downstream targets including adenylate cyclase, the phosphoinositol cascade (and its effect on protein kinase C), arachidonic acid metabolism, and effects on neurotrophic cascades. Many of the new insights of lithium's actions may lead to the strategic development of improved therapeutics for the treatment of bipolar disorder.
Assuntos
Inibidores Enzimáticos/farmacologia , Compostos de Lítio/farmacologia , Transtorno Bipolar/tratamento farmacológico , Transtorno Bipolar/enzimologia , Transtorno Bipolar/metabolismo , Humanos , Compostos de Lítio/uso terapêutico , Transdução de Sinais/efeitos dos fármacosRESUMO
BACKGROUND: The original serotonergic and noradrenergic hypotheses do not fully account for the neurobiology of depression or mechanism of action of effective antidepressants. Research implicates a potential role of the dopaminergic system in the pathophysiology of bipolar disorder. The current study was undertaken as a proof of the concept that dopamine agonists will be effective in patients with bipolar II depression. METHODS: In a double-blind, placebo-controlled study, 21 patients with DSM-IV bipolar II disorder, depressive phase on therapeutic levels of lithium or valproate were randomly assigned to treatment with pramipexole (n = 10) or placebo (n = 11) for 6 weeks. Primary efficacy was assessed by the Montgomery-Asberg Depression Rating Scale. RESULTS: All subjects except for one in each group completed the study. The analysis of variance for total Montgomery-Asberg Depression Rating Scale scores showed a significant treatment effect. A therapeutic response (>50% decrease in Montgomery-Asberg Depression Rating Scale from baseline) occurred in 60% of patients taking pramipexole and 9% taking placebo (p =.02). One subject on pramipexole and two on placebo developed hypomanic symptoms. CONCLUSIONS: The dopamine agonist pramipexole was found to have significant antidepressant effects in patients with bipolar II depression.
Assuntos
Antidepressivos/administração & dosagem , Antimaníacos/uso terapêutico , Transtorno Bipolar/tratamento farmacológico , Agonistas de Dopamina/administração & dosagem , Receptores de Dopamina D2/agonistas , Tiazóis/administração & dosagem , Adulto , Benzotiazóis , Relação Dose-Resposta a Droga , Método Duplo-Cego , Esquema de Medicação , Quimioterapia Combinada , Feminino , Humanos , Lítio/uso terapêutico , Masculino , Pessoa de Meia-Idade , Fatores de Crescimento Neural/administração & dosagem , Projetos Piloto , Pramipexol , Receptores de Dopamina D3 , Ácido Valproico/uso terapêuticoRESUMO
There is increasing evidence from a variety of sources that severe mood disorders are associated with regional reductions in brain volume, as well as reductions in the number, size, and density of glia and neurons in discrete brain areas. Although the precise pathophysiology underlying these morphometric changes remains to be fully elucidated, the data suggest that severe mood disorders are associated with impairments of structural plasticity and cellular resilience. In this context, it is noteworthy that a growing body of data suggests that the glutamaiergic system (which is known to play a major role in neuronal plasticity and cellular resilience) may be involved in the pathophysiology and treatment of mood disorders. Glutamate α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) GluR1 receptor trafficking plays a critical role in regulating various forms of neural plasticity. It is thus noteworthy that recent studies have shown that structurally dissimilar mood stabilizers lithium and valproate regulate GluR1 receptor subunit trafficking and localization at synapses. These studies suggest that regulation of glutamatergically mediated synaptic plasticity may play a role in the treatment of mood disorders, and raises the possibility that agents more directly affecting synaptic GluR1 represent novel therapies for these devastating illnesses.
RESUMO
OBJECTIVES: Monotherapy is often inadequate and combination drug regimens have become the norm for the treatment of bipolar disorder. Virtually all classes of psychotropic drugs have been used in bipolar disorder in combination for a variety of indications. This article reviews the available published data from controlled, blinded studies regarding combination treatments in the different treatment phases of bipolar disorder. METHODS: Articles for this review were obtained from a search of the Medline database (1966-2002), using the following keywords and phrases: add-on, antipsychotic, anticonvulsant, antidepressant, combination treatment, lithium, neuroleptic, and polypharmacy. The search was augmented by data presented at scientific meetings. Data included in this article were only from controlled studies that evaluated combinations of two or more agents. RESULTS: For acute mania, the most useful combination treatments as determined by controlled studies, appear to be an antipsychotic drug with a mood-stabilizer. The combination of lithium and valproate, even though widely used for acute mania, is lacking in controlled data. For acute bipolar depression, the controlled combination studies reviewed fail to show clear advantages in efficacy of an antidepressant with a mood-stabilizer versus two stabilizers or a mood-stabilizer alone. Large, controlled, randomized, long-term studies with modern antidepressants are not available. Controlled combination studies of mood-stabilizers suggest gains in efficacy over monotherapy in the long-term treatment of bipolar disorder. CONCLUSIONS: Controlled combination studies in bipolar disorder are uncommon. Increased attention should be given to study combination treatments in all phases of bipolar illness to determine the most efficacious and safest combinations.
Assuntos
Transtorno Bipolar/tratamento farmacológico , Psicotrópicos/uso terapêutico , Antimaníacos/uso terapêutico , Quimioterapia Combinada , HumanosRESUMO
There is growing evidence from neuroimaging and ostmortem studies that severe mood disorders, which have traditionally been conceptualized as neurochemical disorders, are associated with impairments of structural plasticity and cellular resilience. It is thus noteworthy that recent preclinical studies have shown that critical molecules in neurotrophic signaling cascades (most notably cyclic adenosine monophosphate [cAMP] response element binding protein, brain-derived neurotrophic factor, bcl-2, and mitogen activated protein [MAP] kinases) are long-term targets for antidepressant agents and antidepressant potentiating modalities. This suggests that effective treatments provide both trophic and neurochemical support, which serves to enhance and maintainnormal synaptic connectivity, thereby allowing the chemical signal to reinstate the optimal functioning of critical circuits necessary for normal affective functioning. For many refractory patients, drugs mimicking "traditional" strategies, which directly or indirectly alter monoaminergic levels, may be of limited benefit. Newer "plasticity enhancing" strategies that may have utility in the treatment of refractory depression include N-methyl-D-aspartate antagonists, alpha-amino-3-hydroxy-5-methylisoxazole propionate (AMPA) potentiators, cAMP phosphodiesterase inhibitors, and glucocorticoid receptor antagonists. Small-molecule agents that regulate the activity f growth factors, MAP kinases cascades, and the bcl-2 family of proteins are also promising future avenues. The development of novel, nonaminergic-based therapeutics holds much promise for improved treatment of severe, refractory mood disorders.
Assuntos
Antidepressivos/uso terapêutico , Transtorno Depressivo Maior/tratamento farmacológico , Transtorno Depressivo Maior/fisiopatologia , Plasticidade Neuronal/efeitos dos fármacos , Neurônios/fisiologia , Animais , Fator Neurotrófico Derivado do Encéfalo/fisiologia , Sobrevivência Celular/efeitos dos fármacos , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/fisiologia , Transtorno Depressivo Maior/patologia , Glucocorticoides/fisiologia , Glutamatos/fisiologia , Hipocampo/citologia , Hipocampo/crescimento & desenvolvimento , Humanos , Sistema Hipotálamo-Hipofisário/efeitos dos fármacos , Sistema Hipotálamo-Hipofisário/fisiologia , Transtornos do Humor/tratamento farmacológico , Transtornos do Humor/fisiopatologia , Fatores de Crescimento Neural/fisiologia , Neurônios/efeitos dos fármacos , Neurônios/patologia , Proteínas Proto-Oncogênicas c-bcl-2/fisiologia , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologia , Estresse Psicológico/patologia , Estresse Psicológico/fisiopatologiaRESUMO
Clinical studies over the past decades have attempted to uncover the biological factors mediating the pathophysiology of bipolar disorder (BD) utilizing a variety of biochemical and neuroendocrine strategies. Indeed, assessments of cerebrospinal fluid chemistry, neuroendocrine responses to pharmacological challenge, and neuroreceptor and transporter binding have demonstrated a number of abnormalities in the amine neurotransmitter systems in this disorder. However, recent studies have also implicated critical signal transduction pathways as being integral to the pathophysiology and treatment of BD, in addition to a growing body of data suggesting that impairments of neuroplasticity and cellular resilience may also underlie the pathophysiology of the disorder. It is thus noteworthy that mood stabilizers and antidepressants indirectly regulate a number of factors involved in cell survival pathways - including MAP kinases, CREB, BDNF and bcl-2 protein - and may thus bring about some of their delayed long-term beneficial effects via underappreciated neurotrophic effects.