Assuntos
Bruxismo , Transtornos de Deglutição , Cloridrato de Duloxetina , Discinesia Tardia , Humanos , Cloridrato de Duloxetina/efeitos adversos , Discinesia Tardia/induzido quimicamente , Transtornos de Deglutição/induzido quimicamente , Bruxismo/induzido quimicamente , Idoso de 80 Anos ou mais , Feminino , Masculino , Inibidores da Recaptação de Serotonina e Norepinefrina/efeitos adversosRESUMO
BACKGROUND AND HYPOTHESIS: There is a substantial gap in life expectancy between patients with severe mental illness (SMI) and the general population and it is important to understand which factors contribute to this difference. Research suggests an association between tardive dyskinesia (TD) and mortality; however, results are inconclusive. In addition, studies investigating associations between parkinsonism or akathisia and mortality are rare. We hypothesized that TD would be a risk factor for mortality in patients with SMI. STUDY DESIGN: We studied a cohort of 157 patients diagnosed predominantly with schizophrenia on the former Netherlands Antilles. TD, parkinsonism, and akathisia were assessed with rating scales on eight occasions over a period of 18 years. Twenty-four years after baseline, survival status and if applicable date of death were determined. Associations between movement disorders and survival were analyzed using Cox regression. Sex, age, antipsychotics, antidepressants and benzodiazepines at each measurement occasion were tested as covariates. STUDY RESULTS: Parkinsonism was a significant risk factor with an HR of 1.02 per point on the motor subscale of the Unified Parkinson's Disease Rating Scale (range 0-56). TD and akathisia were not significantly associated with mortality. CONCLUSIONS: Parkinsonism may be an important risk factor for mortality in SMI patients. This finding calls for more follow-up and intervention studies to confirm this finding and to explore whether treatment or prevention of parkinsonism can reduce excess mortality.
Assuntos
Antipsicóticos , Doenças dos Gânglios da Base , Discinesia Induzida por Medicamentos , Pessoas Mentalmente Doentes , Transtornos Parkinsonianos , Discinesia Tardia , Antipsicóticos/efeitos adversos , Doenças dos Gânglios da Base/induzido quimicamente , Doenças dos Gânglios da Base/diagnóstico , Doenças dos Gânglios da Base/epidemiologia , Curaçao , Discinesia Induzida por Medicamentos/diagnóstico , Discinesia Induzida por Medicamentos/epidemiologia , Discinesia Induzida por Medicamentos/etiologia , Humanos , Agitação Psicomotora , Síndrome , Discinesia Tardia/induzido quimicamenteRESUMO
Tardive dyskinesia (TD) is a side effect associated with the long-term use of certain antipsychotics. Considering the modulatory role of the endocannabinoid system upon dopaminergic neurotransmission, the present study tested the hypothesis that increasing endocannabinoid (anandamide and 2-arachidonoylglycerol) levels attenuates haloperidol-induced TD (vacuous chewing movements, VCMs) in male Wistar rats. The animals received administration of chronic haloperidol (38 mg/kg; 29 days) followed by acute FAAH (URB597, 0.1-0.5 mg/kg) or MAGL (JZL184, 1-10 mg/kg) inhibitors before VCM quantification. The underlying mechanisms were evaluated by pre-treatments with a CB1 receptor antagonist (AM251, 1 mg/kg) or a TRPV1 channel blocker (SB366791, 1 mg/kg). Moreover, CB1 receptor expression was evaluated in the striatum of high-VCM animals. As expected, haloperidol induced VCMs only in a subset of rats. Either FAAH or MAGL inhibition reduced VCMs. These effects were prevented by CB1 receptor antagonism, but not by TRPV1 blockage. Remarkably, CB1 receptor expression was increased high-VCM rats, with a positive correlation between the levels of CB1 expression and the number of VCMs. In conclusion, increasing endocannabinoid levels results in CB1 receptor-mediated protection against haloperidol-induced TD in rats. The increased CB1 receptor expression after chronic haloperidol treatment suggests a counter-regulatory protective mechanism.
Assuntos
Agonistas de Receptores de Canabinoides/farmacologia , Discinesia Induzida por Medicamentos/tratamento farmacológico , Endocanabinoides/metabolismo , Haloperidol/efeitos adversos , Animais , Antipsicóticos/efeitos adversos , Ácidos Araquidônicos/farmacologia , Antagonistas de Receptores de Canabinoides/farmacologia , Corpo Estriado/efeitos dos fármacos , Modelos Animais de Doenças , Discinesia Induzida por Medicamentos/metabolismo , Endocanabinoides/farmacologia , Glicerídeos/farmacologia , Masculino , Mastigação/efeitos dos fármacos , Alcamidas Poli-Insaturadas/farmacologia , Ratos , Ratos Wistar , Receptor CB1 de Canabinoide/metabolismo , Canais de Cátion TRPV/metabolismo , Discinesia Tardia/tratamento farmacológico , Discinesia Tardia/metabolismoRESUMO
BACKGROUND: Tardive dyskinesia (TD) is an involuntary movement disorder most commonly involving the tongue, lips, and face and less commonly the trunk and limbs. Although TD is historically associated with conventional antipsychotics, it still occurs with newer agents. Covert dyskinesia (CD), a form of TD, occurs after the discontinuation of antipsychotics, and it differs from other withdrawal emergent dyskinesia by its persistence for more than 8 to 12 weeks after discontinuation of dopamine receptor-blocking agents. Although initially reported in the 1960s with conventional antipsychotics, multiple recent reports describe several cases in association with aripiprazole (APZ). METHODS: We used PubMed and the Google Scholar for CD reports during the past 20 years. We also report a recent case ofCD. RESULTS: We identified 11 case reports of CD. Six were related to APZ, 3 to risperidone, 1 to amisulpride, and 1 to haloperidol. Our patient was an 81-year-old woman with a history of major depressive disorder who was admitted for worsening depression. Before hospitalization, she had been on APZ 5 mg/d for 2 years, but it was discontinued 4 months prior, and then she developed repetitive involuntary movements in her tongue, lips, and jaw 2 months after APZ discontinuation. The Abnormal Involuntary Movement Scale score was 5. Reinstating APZ a few months later led to disappearance of movements. CONCLUSIONS: Literature to date suggests that APZ is the atypical antipsychotic most commonly reported with CD. A possible risk might be APZ's unique mechanism of action and its association with akathisia. Following up patients with serial Abnormal Involuntary Movement Scale after antipsychotic discontinuation is recommended.
Assuntos
Antipsicóticos/efeitos adversos , Aripiprazol/efeitos adversos , Discinesia Tardia/induzido quimicamente , Idoso de 80 Anos ou mais , Transtorno Depressivo Maior , Feminino , HumanosRESUMO
Haloperidol is a first-generation antipsychotic used in the treatment of psychoses, especially schizophrenia. This drug acts by blocking dopamine D2 receptors, reducing psychotic symptoms. Notwithstanding its benefits, haloperidol also produces undesirable impacts, in particular extrapyramidal effects such as tardive dyskinesia (TD), which limit the use of this and related drugs. TD is characterized by repetitive involuntary movements occurring after chronic exposure therapy with haloperidol. Symptoms most commonly manifest in the orofacial area and include involuntary movements, tongue protrusion, pouting lips, chewing in the absence of any object to chew, and facial grimacing. The most serious aspect of TD is that it may persist for months or years after drug withdrawal and is irreversible in some patients. This unit, aimed at facilitating the study of TD, describes methods to induce TD in rats using haloperidol, as well as procedures for evaluating the animals's TD-related symptoms. © 2019 by John Wiley & Sons, Inc.
Assuntos
Antipsicóticos/toxicidade , Modelos Animais de Doenças , Haloperidol/toxicidade , Mastigação/efeitos dos fármacos , Discinesia Tardia/induzido quimicamente , Animais , Avaliação Pré-Clínica de Medicamentos/métodos , Masculino , Mastigação/fisiologia , Ratos , Ratos Wistar , Discinesia Tardia/fisiopatologiaAssuntos
Humanos , Feminino , Adulto , Antipsicóticos/uso terapêutico , Clozapina/uso terapêutico , Discinesia Tardia/etiologia , Discinesia Tardia/tratamento farmacológico , Transtorno Obsessivo-Compulsivo/tratamento farmacológico , Escalas de Graduação Psiquiátrica , Fatores de Tempo , Antipsicóticos/administração & dosagem , Antipsicóticos/efeitos adversos , Resultado do Tratamento , Clozapina/administração & dosagem , Risperidona/efeitos adversos , Transtorno Obsessivo-Compulsivo/complicaçõesAssuntos
Antipsicóticos/uso terapêutico , Clozapina/uso terapêutico , Transtorno Obsessivo-Compulsivo/tratamento farmacológico , Discinesia Tardia/tratamento farmacológico , Discinesia Tardia/etiologia , Adulto , Antipsicóticos/administração & dosagem , Antipsicóticos/efeitos adversos , Clozapina/administração & dosagem , Feminino , Humanos , Transtorno Obsessivo-Compulsivo/complicações , Escalas de Graduação Psiquiátrica , Risperidona/efeitos adversos , Fatores de Tempo , Resultado do TratamentoAssuntos
Terapia por Exercício/métodos , Patinação , Discinesia Tardia/terapia , Adulto , Feminino , Análise da Marcha , HumanosRESUMO
Tardive dyskinesia (TD) is a serious motor side effect that may appear after long-term treatment with neuroleptics and mostly mediated by dopamine D2 receptors (D2Rs). Striatal D2R functioning may be finely regulated by either adenosine A2A receptor (A2AR) or angiotensin receptor type 1 (AT1R) through putative receptor heteromers. Here, we examined whether A2AR and AT1R may oligomerize in the striatum to synergistically modulate dopaminergic transmission. First, by using bioluminescence resonance energy transfer, we demonstrated a physical AT1R-A2AR interaction in cultured cells. Interestingly, by protein-protein docking and molecular dynamics simulations, we described that a stable heterotetrameric interaction may exist between AT1R and A2AR bound to antagonists (i.e. losartan and istradefylline, respectively). Accordingly, we subsequently ascertained the existence of AT1R/A2AR heteromers in the striatum by proximity ligation in situ assay. Finally, we took advantage of a TD animal model, namely the reserpine-induced vacuous chewing movement (VCM), to evaluate a novel multimodal pharmacological TD treatment approach based on targeting the AT1R/A2AR complex. Thus, reserpinized mice were co-treated with sub-effective losartan and istradefylline doses, which prompted a synergistic reduction in VCM. Overall, our results demonstrated the existence of striatal AT1R/A2AR oligomers with potential usefulness for the therapeutic management of TD.
Assuntos
Multimerização Proteica , Receptor A2A de Adenosina/metabolismo , Receptor Tipo 1 de Angiotensina/metabolismo , Antagonistas do Receptor A2 de Adenosina/química , Antagonistas do Receptor A2 de Adenosina/farmacologia , Bloqueadores do Receptor Tipo 1 de Angiotensina II/química , Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Animais , Células Cultivadas , Células HEK293 , Humanos , Camundongos , Modelos Moleculares , Ligação Proteica , Conformação Proteica , Receptor A2A de Adenosina/química , Receptor Tipo 1 de Angiotensina/química , Discinesia Tardia/tratamento farmacológico , Discinesia Tardia/metabolismoRESUMO
Tardive dyskinesia (TD) is characterized by involuntary movements of the lower portion of the face being related to typical antipsychotic therapy. TD is associated with the oxidative imbalance in the basal ganglia. Lipoic acid (LA) and omega-3 (ω-3) are antioxidants acting as enzyme cofactors, regenerating antioxidant enzymes. This study aimed to investigate behavioral and neurochemical effects of supplementation with LA (100 mg/kg) and ω-3 (1 g/kg) in the treatment of TD induced by chronic use of haloperidol (HAL) (1 mg/kg) in rats. Wistar male rats were used, weighing between 180-200 g. The animals were treated chronically (31 days) with LA alone or associated with HAL or ω-3. Motor behavior was assessed by open-field test, the catalepsy test, and evaluation of orofacial dyskinesia. Oxidative stress was accessed by determination of lipid peroxidation and concentration of nitrite. LA and ω-3 alone or associated caused an improvement in motor performance by increasing locomotor activity in the open-field test and decreased the permanence time on the bar in the catalepsy test and decreased the orofacial dyskinesia. LA and ω-3 showed antioxidant effects, decreasing lipid peroxidation and nitrite levels. Thus, the use of LA associated with ω-3 reduced the extrapyramidal effects produced by chronic use of HAL.