Movement Disorders and Mortality in Severely Mentally Ill Patients: The Curacao Extrapyramidal Syndromes Study XIV.

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.

Protective role of endocannabinoid signaling in an animal model of haloperidol-induced tardive dyskinesia.

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.

Covert Dyskinesia With Aripiprazole: Tip of the Iceberg? A Case Report and Literature Review.

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.

Haloperidol-Induced Preclinical Tardive Dyskinesia Model in Rats.

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.

Angiotensin II type 1/adenosine A 2A receptor oligomers: a novel target for tardive dyskinesia.

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.

Behavioral and neurochemical effects of alpha lipoic acid associated with omega-3 in tardive dyskinesia induced by chronic haloperidol in rats.

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.

Effect of Antipsychotic Type and Dose Changes on Tardive Dyskinesia and Parkinsonism Severity in Patients With a Serious Mental Illness: The Curaçao Extrapyramidal Syndromes Study XII.

OBJECTIVE: To test the efficacy of current treatment recommendations for parkinsonism and tardive dyskinesia (TD) severity in patients with severe mental illness (SMI). METHODS: We present an 18-year prospective study including all 223 patients with SMI (as defined by the 1987 US National Institute of Mental Health, which were based on DSM-III-R diagnostic criteria) receiving care from the only psychiatric hospital of the former Netherlands Antilles. Eight clinical assessments (1992-2009) focused on movement disorders and medication use. Tardive dyskinesia was measured by the Abnormal Involuntary Movement Scale and parkinsonism by the Unified Parkinson's Disease Rating Scale. Antipsychotics were classified into first-generation antipsychotic (FGA) versus second-generation antipsychotic (SGA) and high versus low dopamine 2 (D2) affinity categories. The effect that switching has within each category on subsequent movement scores was calculated separately by using time-lagged multilevel logistic regression models. RESULTS: There was a significant association between reduction in TD severity and starting/switching to an FGA (B = -3.54, P < .001) and starting/switching to a high D2 affinity antipsychotic (B = -2.49, P < .01). Adding an SGA to existing FGA treatment was associated with reduction in TD severity (B = -2.43, P < .01). For parkinsonism, stopping antipsychotics predicted symptom reduction (B = -7.76, P < .01 in FGA/SGA-switch model; B = -7.74, P < .01 in D2 affinity switch model), while starting a high D2 affinity antipsychotic predicted an increase in symptoms (B = 3.29, P < .05 in D2 affinity switch model). CONCLUSIONS: The results show that switching from an FGA to an SGA does not necessarily result in a reduction of TD or parkinsonism. Only stopping all antipsychotics reduces the severity of parkinsonism, and starting an FGA or a high D2 affinity antipsychotic may reduce the severity of TD.

Harpagophytum Procumbens Ethyl Acetate Fraction Reduces Fluphenazine-Induced Vacuous Chewing Movements and Oxidative Stress in Rat Brain.

Long-term treatment with fluphenazine is associated with manifestation of extrapyramidal side effects, such as tardive dyskinesia. The molecular mechanisms related to the pathophysiology of TD remain unclear, and several hypotheses, including a role for oxidative stress, have been proposed. Harpagophytum procumbens is an herbal medicine used mainly due to anti-inflammatory effects, but it also exhibits antioxidant effects. We investigated the effect of ethyl acetate fraction of H. procumbens (EAF HP) in fluphenazine-induced orofacial dyskinesia by evaluating behavioral parameters at different times (vacuous chewing movements (VCM's) and locomotor and exploratory activity), biochemical serological analyses, and biochemical markers of oxidative stress of the liver, kidney, cortex, and striatum. Chronic administration of fluphenazine (25 mg/kg, intramuscular (i.m) significantly increased the VCMs at all analyzed times (2, 7, 14, and 21 days), and this was inhibited by EAF HP (especially at a dose of 30 mg/kg). Fluphenazine decreased locomotion and exploratory activity, and EAF HP did not improve this decrease. Fluphenazine induced oxidative damage, as identified by changes in catalase activity and ROS levels in the cortex and striatum, which was reduced by EAF HP, especially in the striatum. In the cortex, EAF HP was protective against fluphenazine-induced changes in catalase activity but not against the increase in ROS level. Furthermore, EAF HP was shown to be safe, since affected serum biochemical parameters or parameters of oxidative stress in the liver and kidney. These findings suggest that the H. procumbens is a promising therapeutic agent for the treatment of involuntary oral movements.

Eficacia da clozapina no tratamento da discinesia tardia em pacientes esquizofrenicos

A discinesia tardia (DT) e um disturbio de movimento que ocorre em cerca de 20 por cento a 35 por cento dos pacientes apos uso prolongado de antipsicoticos. Na maioria dos pacientes os sintomas sao leves, mas em uma minoria sao incapacitantes e irreversiveis. Neste estudo foram selecionados sete pacientes com esquizofrenia e discinesia tardia moderada a grave e foi administrada clozapina (CLZ) por 6 meses. Foi avaliadas a gravidade da discinesia com as escalas AIMS e ESRS e da psicopatologia, com a PANSS. A dose media de clozapina foi de 392,86mg/dia. Observaram-se reducao media de 52 por cento na pontuacao de DT da ESRS, reducao da pontuacao de distonia de 50 por cento em um paciente e remissao total em outro e reducao de 27 por cento da pontuacao da PANSS. Deste modo a CLZ mostrou-se uma alternativa eficaz no tratamento de pacientes esquizofrenicos com DT grave.

Iatrogenia farmacologica em psiquiatria

O autor faz uma revisao iatrogenia farmacologia em psiquiatria. Inicialmente, discorre sobre o conceito de iatrogenia, chamando atencao para sua distincao de erro medico e de efeito colateral de um medicamento. A seguir, cita os dois tipos de iatrogenia farmacologica em psiquiatria (disturbios nao-psiquiatricos causados pelos psicofarmacos e disturbios psiquiatricos provocados por medicamentos nao-psicotropicos), dando exemplos de cada um deles. Da enfase a discinesia tardia, sindrome maligna do neuroleptico, dependencia e morte subita pela sua gravidade e importancia em psiquiatria clinica. Alem disso, comenta outros efeitos colaterais dos psicofarmacos e relata alguns disturbios psiquiatricos causados por medicamentos nao-psicotropicos comumente utilizados na pratica. Conclui que: 1) Os disturbios iatrogenicos sao, na grande maioria das vezes efeitos secundarios, incidentais ou inesperados, de tratamento bem intencionado; 2) Os psiquiatras e profissionais de saude mental familiarizados com eles estao em melhor posicao para preveni-los; e 3) Os pacientes devem ser informacoes sobre a possibilidade de desenvolvimento de reacoes indesejaveis para que auxiliem na sua deteccao precoce.

Valproato de sodio na discinesia tardia: estudo duplo-cego

Partindo de uma confirmada acao antidiscinetica dos agonista gabaergicos, os autores utilizaram o valproato de sodio em 10 pacientes discineticos, enquanto oito outros receberam placebo, de modo duplo-cego. Utilizando-se da AIMS (Abnormal Involuntary Movements Scale) constataram que oito obtiveram melhora e 10 permaneceram inalterados. Os resultados sao estatisticamente nao significativos, confirmando outros dados da literatura.

Discinesia tardia: uma breve revisao

A discinesia tardia (DT) representa uma seria complicacao da terapia neuroleptica, pela sua irreversibilidade, ausencia de tratamento e natureza iatrogenica. O autor, neste artigo, realiza uma breve revisao do tema, abordando os aspectos clinicos, epidemiologicos, fisiopatologicos e terapeuticos, enfatizando a prevencao e o uso criterioso dos neurolepticos como a melhor estrategia de tratamento da sindrome.

Discinesia tardia residual 24 meses apos a suspensao do uso da flunarizina

O autor descreve um caso de discinesia tardia (DT) de aparecimento apos a suspensao do uso da flunarizina (Fz). A paciente procurou atendimento por sindrome de Parkinson (SP) atipica, pelo parasitismo de movimentos coreoatetosicos, refrataria a ldopa e anticolinergicos. Usava a Fz para tratamento de vertigens por provavel insuficiencia vertebro-basilar. Suspenso o uso da Fz houve melhora progressiva da SP mas na mesma medida que desaparecia a SP a DT se fez mais evidente e persistente 24 meses apos a suspensao da Fz. O objetivo e alertar para esse efeito colateral grave da Fz, uma droga cuja comercializacao nao e liberada em varios paises do mundo mas que se indica atualmente para afeccoes comuns como a enxaqueca como faz o Goodman e Gilman (1990) mas nao aponta como efeitos colaterais nem a SP nem a DT.

Discinesia tardia: estudo epidemiologico em pacientes esquizofrenicos ambulatoriais

Cento e treze pacientes ambulatoriais esquizofrenicos e em uso de neurolepticos foram estudados quanto a discinesia tardia. Foi utilizada a Escala de Simpson (Abbreviated Dyskinesia Rating Scale) para avaliar a localizacao e a garvidade dos sintomas discineticos. Utilizamos o Coeficiente de Correlacao de Pearson para avaliar a confiabilidade entre os examinadores no preenchimento da Escala de Simpson, que foi de 96 por cento (P=0,001). A taxa de prevalencia total de discinesia tardia foi de 26, 3 por cento, sendo de 15,0 por cento para homens e de 13,3 por cento para mulheres. A idade e o tempo de uso de neuroleptico influi diretamente e com significado estatistico a taxa de prevalencia da discinesia tardia.

Discinesia tardia: clinica, fatores de risco e tratamento

A discinesia tardia e um disturbio decorrente do uso prolongado de neurolepticos. Inumeros fatores parecem contribuir para o seu aparecimento, alem do uso das drogas antipsicoticas. Apesar das varias tentativas terapeuticas, seu tratamento parece indefinido para a reversao total da sintomatologia.

Patogenese e fisiopatologia da discinesia tardia

O autor duscute a patogenese e a fisiopatologia da discinesia tardia, levando em consideracao as evidencias clinicas, farmacologicas e neuroquimicas que apontam para a existencia de uma hiperatividade funcional dopaminergica, particularmente ao nivel do corpo estriado.