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.

Reversal of haloperidol-induced orofacial dyskinesia and neuroinflammation by isoflavones.

BACKGROUND: Schizophrenia is a mental illness and its pharmacological treatment consists in the administration of antipsychotics like haloperidol. However, haloperidol often causes extrapyramidal motor disorders such as tardive dyskinesia (TD). So far, there is no effective treatment against TD and alternatives for it have been sought. Isoflafones have been studied as neuroprotector and inhibitor of monoamine oxidase enzyme. Thus, the objective is to evaluate the possible protective effect of isoflavones against the induction of involuntary movements induced by haloperidol in an animal model. METHODS AND RESULTS: Male Wistar rats were treated with haloperidol (1 mg/kg/day) and/or isoflavones (80 mg/kg) for 28 days. Rats were submitted to behavioral evaluation to quantify vacuous chewing movements (VCM) and locomotor activity. In addition, the levels of pro-inflammatory cytokines were measured in the striatum. Haloperidol treatment reduced the locomotor activity and increased the number of VCM in rats. Co-treatment with isoflavones was able to reverse hypolocomotion and reduce the number of VCM. Besides, haloperidol caused significant increase in the proinflammatory cytokines (interleukin-1ß:IL-1ß, tumor necrosis factor-α: TNF-α and IL-6 and the co-treatment with isoflavones was able to reduce the levels of IL-1ß and TNF-α, but not IL-6. CONCLUSIONS: It is believed that the beneficial effect found with this alternative treatment is related to its anti-inflammatory potential and to the action on estrogen receptors (based on scientific literature findings). Finally, further studies are needed to elucidate the mechanisms of isoflavones in reducing motor disorders induced by antipsychotics.

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.

Effects of CATECHIN on reserpine-induced vacuous chewing movements: behavioral and biochemical analysis.

This study evaluated the effect of (+)-catechin, a polyphenolic compound, on orofacial dyskinesia (OD) induced by reserpine in mice. The potential modulation of monoaminoxidase (MAO) activity, tyrosine hydroxylase (TH) and glutamic acid decarboxylase (GAD67) immunoreactivity by catechin were used as biochemical endpoints. The interaction of catechin with MAO-A and MAO-B was determined in vitro and in silico. The effects of catechin on OD induced by reserpine (1 mg/kg for 4 days, subcutaneously) in male Swiss mice were examined. After, catechin (10, 50 or 100 mg/kg, intraperitoneally) or its vehicle were given for another 20 days. On the 6th, 8th, 15th and 26th day, vacuous chewing movements (VCMs) and locomotor activity were quantified. Biochemical markers (MAO activity, TH and GAD67 immunoreactivity) were evaluated in brain structures. In vitro, catechin inhibited both MAO isoforms at concentrations of 0.34 and 1.03 mM being completely reversible for MAO-A and partially reversible for MAO-B. Molecular docking indicated that the catechin bound in the active site of MAO-A, while in the MAO-B it interacted with the surface of the enzyme in an allosteric site. In vivo, reserpine increased the VCMs and decreased the locomotor activity. Catechin (10 mg/kg), decreased the number of VCMs in the 8th day in mice pre-treated with reserpine without altering other behavioral response. Ex vivo, the MAO activity and TH and GAD67 immunoreactivity were not altered by the treatments. Catechin demonstrated a modest and transitory protective effect in a model of OD in mice.

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.

Resveratrol Protects Against Vacuous Chewing Movements Induced by Chronic Treatment with Fluphenazine.

Typical antipsychotics, which are commonly used to treat schizophrenia, cause motor disorders such as tardive dyskinesia (TD) in humans and orofacial dyskinesia (OD) in rodents. The disease mechanisms as well as treatment effectiveness are still unknown. In this study, we investigated the effect of resveratrol, a polyphenol with neuroprotective properties, on behavioral changes induced by chronic treatment with fluphenazine in rats and the possible relationship between monoamine oxidase (MAO) activity and vacuous chewing movements (VCMs). Rats were treated for 18 weeks with fluphenazine enantate [25 mg/kg, intramuscularly (i.m.), every 21 days] and/or resveratrol (20 mg/kg, offered daily in drinking water). Next, body weight gain, behavioral parameters (VCMs and open field tests-locomotor and rearing activity), and MAO activity were evaluated. Fluphenazine treatment reduced body weight gain, number of crossings and rearings, and the co-treatment with resveratrol did not affect these alterations. Fluphenazine increased the prevalence and intensity of VCMs and the co-treatment with resveratrol reduced the VCMs. Furthermore, a negative correlation was found between the number of VCMs and MAO-B activity in the striatum of rats. Our data suggest that resveratrol could be promissory to decrease OD. Moreover, MAO-B activity in the striatum seems to be related to VCMs intensity.

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.

Cannabidiol Prevents Motor and Cognitive Impairments Induced by Reserpine in Rats.

Cannabidiol (CBD) is a non-psychotomimetic compound from Cannabis sativa that presents antipsychotic, anxiolytic, anti-inflammatory, and neuroprotective effects. In Parkinson's disease patients, CBD is able to attenuate the psychotic symptoms induced by L-DOPA and to improve quality of life. Repeated administration of reserpine in rodents induces motor impairments that are accompanied by cognitive deficits, and has been applied to model both tardive dyskinesia and Parkinson's disease. The present study investigated whether CBD administration would attenuate reserpine-induced motor and cognitive impairments in rats. Male Wistar rats received four injections of CBD (0.5 or 5 mg/kg) or vehicle (days 2-5). On days 3 and 5, animals received also one injection of 1 mg/kg reserpine or vehicle. Locomotor activity, vacuous chewing movements, and catalepsy were assessed from day 1 to day 7. On days 8 and 9, we evaluated animals' performance on the plus-maze discriminative avoidance task, for learning/memory assessment. CBD (0.5 and 5 mg/kg) attenuated the increase in catalepsy behavior and in oral movements - but not the decrease in locomotion - induced by reserpine. CBD (0.5 mg/kg) also ameliorated the reserpine-induced memory deficit in the discriminative avoidance task. Our data show that CBD is able to attenuate motor and cognitive impairments induced by reserpine, suggesting the use of this compound in the pharmacotherapy of Parkinson's disease and tardive dyskinesia.

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.

Behavioral and neurochemical effects induced by reserpine in mice.

RATIONALE: Reserpine, a monoamine-depleting agent, which irreversibly and non-selectively blocks the vesicular monoamine transporter, has been used as an animal model to study several neurological disorders, including tardive dyskinesia and Parkinson's disease. OBJECTIVE: The purpose of this study was to examine if motor deficits induced by reserpine in mice could be related to alterations in the expression of dopaminergic system proteins such as tyrosine hydroxylase (TH) and dopamine transporter (DAT) and in the activity of monoamine oxidase (MAO). METHODS: Mice received either vehicle or reserpine (0.1, 0.5, or 1 mg/kg, s.c.) for four consecutive days. Two, 20, or 60 days after reserpine withdrawal, behavioral, and neurochemical changes were evaluated. RESULTS: Reserpine at a dose of 0.5 and 1 mg/kg increased vacuous chewing movements (VCMs) and reduced locomotion. Behavioral changes were accompanied by reduction in TH immunoreactivity in the striatum evaluated on days 2 and 20 after the last injection of 1 mg/kg reserpine. Furthermore, negative correlations were found between VCM and MAO-A or MAO-B on day 2 and TH striatal immunoreactivity on day 20 after the last injection of 1 mg/kg reserpine. A positive correlation was observed between VCMs and DAT immunoreactivity in the substantia nigra on day 2 after the last injection of 0.5 mg/kg reserpine. CONCLUSIONS: These findings suggest that the pharmacological blockage of vesicular monoamine transporter (VMAT) by reserpine caused neurochemical and behavioral alterations in mice.

Vitaminas B1, B6, B12 e complexo B na prevenção da discinesia orofacial induzida porhaloperidol em ratos: avaliação comportamental e mecanismos associados

A Discinesia tardia (DT) é caracterizada por movimentos involuntários, principalmente na parte inferior da face, próximos da boca, com espasmos que podem ser leves ou severos. É uma alteração motora grave relacionada, mas não restrita à terapia antipsicótica. Tratamentos com antipsicóticos principalmente os da classe dos típicos, como o haloperidol (HAL) aumentam os riscos de DT. A fisiopatologia da DT é associada a um desequilíbrio em sistemas de neurotransmissão, dentre eles dopaminérgico e colinérgico, bem como com desequilíbrio oxidativo, principalmente em áreas cerebrais relacionadas ao controle do movimento, como o corpo estriado. As vitaminas (vit.) B, por sua vez, apresentam efeitos antioxidantes sendo cofatores para enzimas relacionadas à síntese de neurotransmissores. Neste contexto, o presente trabalho teve como objetivo determinar os efeitos preventivos das vit. B1, B6, B12 ou Complexo B na discinesia orofacial (DO) induzida por HAL em ratos. Foram utilizados ratos Wistar machos tratados por via intraperitoneal com HAL (1 mg/kg, i.p.) por 21 dias ou concomitantemente com HAL e as vit. B1 (60 mg/kg), B6 (60 mg/kg) ou B12 (0,6 mg/kg) por via subcutânea, sozinhas ou em associação (complexo B). O complexo B consistiu na mistura das 3 vitaminas em iguais proporções. Um grupo de animais foi administrado clozapina (25 mg/kg), um antipsicótico atípico não relacionado ao desenvolvimento de DO. Os testes comportamentais foram realizados após 30 minutos no 1º, 7º e 21º dias de administração das fármacos e consistiram na determinação da atividade locomotora, catalepsia e movimentos de mastigação no vazio...

Tardive dyskinesia (TD) is characterized by involuntary movements, mostly at lower face, near the mouth, with convulsion that can be light or hard. Is one severe disorder related, but restricted the antipsychotic therapy. Antipsychotic treatments above all the class of typical, like haloperidol (HAL) increase the risk of TD. The pathophysiology of TD is associated to a instability in neurotransmission system, such as dopaminergic and cholinergic, among others, as well as with oxidative instability mainly in brain areas related to the control of movement, as the striatum. B vitamins, in turn, show antioxidants effect and are cofactors to enzymes related to the synthesis of neurotransmitters. In this context, the present study aimed to determine the preventive effects of B1, B6, B12 vitamins or B complex against orofacial dyskinesia (OD) induced by HAL in rats. To do this male Wistar rats were intraperitoneally administered HAL (1 mg/kg, i.p.) for 21 days or concomitantly received HAL, B1 (60 mg/kg), B6 (60 mg/kg) or B12 (0,6 mg/kg) vitamin subcutaneously alone or in association. B complex consisted in the mix of 3 vitamins in equal proportions. One group of animals was administered with clozapine (25 mg/kg), an atypical antipsychotic not related to the development of OD. Behavioral tests were performed at the 1st, 7th and 21st days of drugs administration. The behavioral tests performed were locomotor activity, catalepsy and chewing vacuous movements. At 21stday the animals were sacrificed and had their brain areas dissected for neurochemical analysis. The results showed that HAL increased catalepsy time at 7th day and OD at 21stday...

Effectiveness of melatonin in tardive dyskinesia / Efectividad de la melatonina en la discinesia tardía

Tardive Dyskinesia (TD) is a movement disorder associated with the clinical administration of antipsychotics. It is believed that TD is due, among other factors, to an increase in the oxidative damage produced by free radicals. Antioxidants, like vitamin E, have been used in the treatment of TD but there is no evidence of their effectiveness. Melatonin (MEL) is 6 to 10 times more effective, as an antioxidant, than vitamin E and it has been used with an apparent higher effectiveness in the treatment of TD, although the results have not been conclusive. A randomized, double blind, placebo controlled design was used to determine the effectiveness of MEL (20mg/day) during 12 weeks in 7 patients with TD. Six patients with TD were treated with placebo. The Abnormal Involuntary Movement Scale (AIMS) was chosen to assess the severity of TD initially and after 4, 8 and 12 weeks. The psychiatric evaluation was done following the Brief Psychiatric Rating Scale. In two patients treated with MEL a significant improvement (more than 60%) of the values of AIMS was detected. In the remainder five, as well as in the patients treated with placebo, no difference was observed during the 12 weeks. When compared the AIMS score in all the MEL-treated patients with the values in the placebo-treated patients, no significant differences were detected during the 12 weeks of the study. However, the significant clinical improvement observed in two patients must be considered before reaching a final conclusion on the usefulness of MEL in TD.

La Discinesia Tardía (DT) es un trastorno de los movimientos asociado al uso crónico de antipsicóticos que parece producirse, entre otros factores, por un incremento en los procesos oxidativos. La vitamina E se ha utilizado en su tratamiento, pero no hay evidencia de su efectividad. Como la melatonina (MEL) es 6 a 10 veces más efectiva como antioxidante que la vitamina E, se ha utilizado con una aparente mayor efectividad, aunque los resultados no han sido concluyentes. Se realizó un estudio doble ciego, al azar y controlado con placebo, para determinar la efectividad de la administración de la MEL durante 12 semanas en 7 pacientes con DT. Seis pacientes con DT fueron tratados con placebo. La Escala de Movimientos Involuntarios Anormales (AIMS) se usó para evaluar la evolución de los movimientos al inicio y a las 4, 8 y 12 semanas de tratamiento. La evaluación clínica psiquiátrica se hizo con la Escala Breve de Evaluación Psiquiátrica. En dos pacientes tratados con MEL se observó una mejoría clínica superior al 60% pero en los restantes, así como en los tratados con placebo los valores de la AIMS no variaron significativamente en el transcurso de las 12 semanas. Cuando se compararon los valores de la AIMS de la totalidad de los pacientes tratados con MEL, con los del grupo placebo, no se detectó ninguna diferencia significativa. Sin embargo, la mejoría clínica significativa de dos de los pacientes estudiados debe considerarse para llegar a una conclusión sobre la utilidad de la MEL en la DT.

An examination of synaptic proteins following chronic haloperidol in a rat model of tardive dyskinesia

Tardive dyskinesia (TD) is a late-onset side effect mainly affecting the orofacial region of patients treated chronically with classic antipsychotic drugs such as haloperidol (HAL). The causes of TD remain unknown. We hypothesized that faulty synaptic re-organization might be related to TD-like syndromes and used the vacuous chewing movements (VCM) model in rats to investigate the expression of four synaptic proteins, synaptophysin, syntaxin, spinophilin and PSD-95, in brains of HAL-treated rats. Male Sprague-Dawley rats were treated for 14 weeks with either haloperidol decanoate (21 mg/kg once every 3 weeks, I.M) or vehicle and VCMs were monitored on a weekly basis. As expected, VCMs developed reliably and were consistently more pronounced in some rats than in others. Using immunohistochemistry in anatomically preserved brain sections as well as Western Blot analyses of whole cells or synaptosomal fractions in striatal tissue, we found no significant effect of chronic HAL on levels of these proteins. Neither did we find significant differences in the levels of the four synaptic markers when comparing rats showing High vs. Low levels of VCMs. These results suggest that structural synaptic alterations (e.g. involving increased number of synapses) may not be the underlying mechanism of oral dyskinesias induced by chronic antipsychotic drug treatment. The possibility that functional neuroplastic changes occur remains to be investigated.(AU)

An examination of synaptic proteins following chronic haloperidol in a rat model of tardive dyskinesia

Tardive dyskinesia (TD) is a late-onset side effect mainly affecting the orofacial region of patients treated chronically with classic antipsychotic drugs such as haloperidol (HAL). The causes of TD remain unknown. We hypothesized that faulty synaptic re-organization might be related to TD-like syndromes and used the vacuous chewing movements (VCM) model in rats to investigate the expression of four synaptic proteins, synaptophysin, syntaxin, spinophilin and PSD-95, in brains of HAL-treated rats. Male Sprague-Dawley rats were treated for 14 weeks with either haloperidol decanoate (21 mg/kg once every 3 weeks, I.M) or vehicle and VCMs were monitored on a weekly basis. As expected, VCMs developed reliably and were consistently more pronounced in some rats than in others. Using immunohistochemistry in anatomically preserved brain sections as well as Western Blot analyses of whole cells or synaptosomal fractions in striatal tissue, we found no significant effect of chronic HAL on levels of these proteins. Neither did we find significant differences in the levels of the four synaptic markers when comparing rats showing High vs. Low levels of VCMs. These results suggest that structural synaptic alterations (e.g. involving increased number of synapses) may not be the underlying mechanism of oral dyskinesias induced by chronic antipsychotic drug treatment. The possibility that functional neuroplastic changes occur remains to be investigated