[Show abstract][Hide abstract] ABSTRACT: The aim of this review is to assess new, emerging, and experimental treatment options for tardive dyskinesia (TD). The methods to obtain relevant studies for review included a MEDLINE search and a review of studies in English, along with checking reference lists of articles. The leading explanatory models of TD development include dopamine receptor supersensitivity, GABA depletion, cholinergic deficiency, neurotoxicity, oxidative stress, changes in synaptic plasticity, and defective neuroadaptive signaling. As such, a wide range of treatment options are available. To provide a complete summary of choices we review atypical antipsychotics along with resveratrol, botulinum toxin, Ginkgo biloba, tetrabenazine, clonazepam, melatonin, essential fatty acids, zonisamide, levetiracetam, branched-chain amino acids, drug combinations, and invasive surgical treatments. There is currently no US Food and Drug Administration-approved treatment for TD; however, prudent use of atypical antipsychotics with routine monitoring remain the cornerstone of therapy, with experimental treatment options available for further management.
Drug Design, Development and Therapy 11/2013; 7:1329-1340. DOI:10.2147/DDDT.S32328 · 3.03 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Parkinsonism (or Parkinson's syndrome [PS]) remains common in patients exposed to antipsychotic drugs. One clinical tool used in its detection and follow-up, the Simpson-Angus Scale (SAS), has been under revision lately. We further examined the discriminative power of the SAS to detect PS and its efficacy as a measure of PS intensity in chronic schizophrenia.
Fifty-six outpatients between 50 and 75 years of age, under stable antipsychotic drug therapy, provided consent to undergo an evaluation along the SAS and Unified Parkinson's Disease Rating Scale III motor subsection, split according to the presence or absence of PS defined in the UK Parkinson's Disease Society Brain Bank (UKPDSBB) criteria or Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition criteria.
The identification rate for PS was 39.3% based on UKPDSBB criteria applied to the Unified Parkinson's Disease Rating Scale III, compared with 62.5% and 87.5% according to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition criteria and SAS cutoff value greater than 0.3, respectively. Median SAS scores for PS and PS-free participants were comparable. The SAS yielded high sensitivity (90.9%) but low specificity (17.7%). κ Values generally revealed only slight agreement between the group allocation provided by the SAS and the UKPDSBB criteria. Receiver operating characteristic curve for screening performance of the SAS provided poor prediction of subject status.
The SAS lacks specificity and constitutes an imperfect detection and measurement tool for PS in older adults. Raising the cutoff score would avoid inflation in PS identification. The scale is probably best used as a measure of change relative to baseline score following an intervention, but results should be interpreted with caution.
[Show abstract][Hide abstract] ABSTRACT: Tardive dyskinesia (TD) is a delayed and potentially irreversible motor complication arising in patients chronically exposed to antipsychotic drugs. As several modern (so-called atypical) antipsychotic drugs are common offenders, combined with the widening clinical indications for prescription as well as exposure of vulnerable individuals, TD will remain a significant drug-induced unwanted side effect. In addition, the pathophysiology of TD remains elusive and therapeutics are difficult. Based on rodent experiments, we have previously shown that the transcriptional factor Nur77 (also known as nerve growth factor inducible gene B or Nr4a1) is induced in the striatum following antipsychotic drug exposure as part of a long-term neuroadaptive process. To confirm this, we exposed adult capuchin (Cebus apella) monkeys to prolonged treatments with haloperidol (median 18.5 months, N = 11) or clozapine (median 6 months, N = 6). Six untreated animals were used as controls. Five haloperidol-treated animals developed mild TD movements similar to those found in humans. No TD was observed in the clozapine group. Postmortem analysis of Nur77 expression measured by in situ hybridization revealed a stark contrast between the two drugs, as Nur77 mRNA levels in the caudate-putamen were strongly upregulated in animals exposed to haloperidol but were spared following clozapine treatment. Interestingly, within the haloperidol-treated group, TD-free animals showed higher Nur77 expression in putamen subterritories compared with dyskinetic animals. This suggests that Nur77 expression might be associated with a reduced risk of TD in this experimental model and could provide a novel target for drug intervention.
European Journal of Neuroscience 03/2013; 38(1). DOI:10.1111/ejn.12198 · 3.18 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Tardive dyskinesia remains an elusive and significant clinical entity that can possibly be understood via experimentation with animal models. We conducted a literature review on tardive dyskinesia modeling. Subchronic antipsychotic drug exposure is a standard approach to model tardive dyskinesia in rodents. Vacuous chewing movements constitute the most common pattern of expression of purposeless oral movements and represent an impermanent response, with individual and strain susceptibility differences. Transgenic mice are also used to address the contribution of adaptive and maladaptive signals induced during antipsychotic drug exposure. An emphasis on non-human primate modeling is proposed, and past experimental observations reviewed in various monkey species. Rodent and primate models are complementary, but the non-human primate model appears more convincingly similar to the human condition and better suited to address therapeutic issues against tardive dyskinesia.
[Show abstract][Hide abstract] ABSTRACT: Tardive dyskinesia (TD) is a neurological motor complication eventually arising in one-third of patients chronically exposed to antipsychotic drugs. Some orodental peripheral factors have been reported to influence TD.
To measure orodental factors such as temporomandibular joint function, static occlusal contacts, and denture condition, and attempt correlations with orofacial TD intensity.
In this exploratory cross-sectional pilot study, 31 subjects between 30 and 75 years of age were divided in two groups displaying minimal to mild, or moderate to severe orofacial TD, respectively, and underwent a detailed oral, dental, and prosthetic evaluation to capture various aspects of oral health compared between the two groups. Blinded video-based TD ratings along a validated scale were obtained to compare dentulous and edentulous subjects, and contrast TD intensity in complete denture wearers with and without their own prostheses.
None of the factors examined tightly correlated with orofacial TD intensity. However, edentulism was associated with a higher median orofacial TD rating compared to the dentulous group (p = 0.001). Further, a significant intra-subject difference was observed in the edentulous subjects rated with their own complete dentures in place or not (p = 0.028), the dentures attenuating the mean orofacial ratings by 21.8 ± 7.3%.
Of all orodental factors considered, only edentulism and complete denture wearing influenced oral TD expression, calling for the close monitoring of the dental status in antipsychotic drug-exposed patients to prevent tooth loss. Further studies to measure the impact of an adequate prosthodontic rehabilitation in edentulous subjects with orofacial TD seem warranted.
Journal of Psychiatric Research 03/2012; 46(5):684-7. DOI:10.1016/j.jpsychires.2012.02.003 · 3.96 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Drug-induced parkinsonism (DIP) is seen in one third of patients exposed to antipsychotic drugs and may lead to complications related to dysphagia and falls. Aside from skilled neurological examination, no tool has been validated to facilitate detection and follow-up.
In this pilot study, three validated screening instruments were tested in an age-biased cohort of schizophrenia patients, including four items of the Liverpool University Neuroleptic Side-Effects Rating Scale (LUNSERS) and two brief questionnaires designed for community survey of parkinsonism.
Fifty-six subjects living with chronic schizophrenia between 50 and 75 years of age underwent a motor evaluation along the original Unified Parkinson's Disease Rating Scale-section III and answered questions along the selected screening instruments, and results compared to those of 16 patients with Parkinson's disease (PD) and 15 neurologically unimpaired volunteers. Odds ratios, sensitivity, specificity, and their 95% confidence intervals, were calculated.
All three screening instruments correctly identified the PD state and distinguished PD from healthy participants. Eighteen (32%) schizophrenic patients displayed objective motor signs of parkinsonism. A single item of the LUNSERS (shakiness) significantly distinguished DIP from DIP-free patients, with a sensitivity of 61.1% and a specificity of 83.3%. The positive predictive value was 63.5% and the negative predictive value was 81.9%. The two other screening methods showed insufficient predictive value.
Apart from a single query on shakiness, none of the tools examined were adequate to screen for DIP in patients treated for schizophrenia. A different instrument is necessary to monitor this important adverse effect in schizophrenia.
Schizophrenia Research 02/2012; 137(1-3):230-3. DOI:10.1016/j.schres.2012.01.013 · 3.92 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Chunking of single movements into integrated sequences has been described during motor learning, and we have recently demonstrated
that this process involves a dopamine-dependant mechanism in animal (Levesque et al. in Exp Brain Res 182:499–508, 2007; Tremblay et al. in Behav Brain Res 198:231–239, 2009). However, there is no such evidence in human. The aim of the present study was to assess this question in Parkinson’s disease
(PD), a neurological condition known for its dopamine depletion in the striatum. Eleven PD patients were tested under their
usual levodopa medication (ON state), and following a 12-h levodopa withdrawal (OFF state). Patients were compared with 12
healthy participants on a motor learning sequencing task, requiring pressing fourteen buttons in the correct order, which
was determined by visual stimuli presented on a computer screen. Learning was assessed from three blocks of 20 trials administered
successively. Chunks of movements were intrinsically created by each participant during this learning period. Then, the sequence
was shuffled according to the participant’s own chunks, generating two new sequences, with either preserved or broken chunks.
Those new motor sequences had to be performed separately in a fourth and fifth blocks of 20 trials. Results showed that execution
time improved in every group during the learning period (from blocks 1 to 3). However, while motor chunking occurred in healthy
controls and ON-PD patients, it did not in OFF-PD patients. In the shuffling conditions, a significant difference was seen
between the preserved and the broken chunks conditions for both healthy participants and ON-PD patients, but not for OFF-PD
patients. These results suggest that movement chunking during motor sequence learning is a dopamine-dependent process in human.
KeywordsParkinson-Dopamine-Striatum-Motor learning-Movement-Sequence learning
Experimental Brain Research 09/2010; 205(3):375-385. DOI:10.1007/s00221-010-2372-6 · 2.04 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Le sommeil est un état physiologique et comportemental caractérisé par une isolation partielle de l’environnement. Lors du
sommeil, un événement perturbateur comme la douleur peut provoquer une réaction de microéveil brève et inconsciente vers un
réveil comportemental caractérisé par une réactivation thalamocorticale complète et un niveau plus élevé de conscience. Le
sommeil devient alors fragmenté et les plaintes de douleur se trouvent souvent exacerbées. La continuité oscillatoire de 90–110
minutes, rythme ultradien du sommeil léger et profond (non-REM: rapid eye movement) vers le sommeil paradoxal (REM), est alors rompue. Chez un patient souffrant de céphalée, on observe trois périodes durant
lesquelles surviennent les crises en relation avec le sommeil: 1) dans les heures avant l’initiation du sommeil, 2) durant
et, 3) après le sommeil. La céphalée de tension et la migraine, la céphalée de type hypnique, l’algie vasculaire de la face
(cluster headache) et l’hémicrânie paroxystique chronique peuvent survenir en relation avec le sommeil. Soulignons que la céphalée du réveil
est parfois associée à du bruxisme (serrement et grincement des dents), à un abus de médications antalgiques, à de l’hypertension,
à un trouble de l’humeur ou à des réductions du flux respiratoire lors du sommeil. Les céphalées suite à un traumatisme crânien
sont fréquentes et causent de l’insomnie, des réveils subits et prématurés et surtout des matins pénibles avec délai de phase
circadienne. Dans le contexte d’une céphalée survenant en relation avec l’insomnie ou la somnolence diurne, la recherche de
troubles respiratoires du sommeil, d’intrusions sous forme de mouvements périodiques des membres ou de bruxisme est indiquée.
La polygraphie peut être effectuée en laboratoire ou en ambulatoire. La gestion de ces céphalées suit les grands principes
de la médecine contemporaine tout en visant une hygiène du sommeil maximale par thérapie cognitive et comportementale, le
maintien d’un rythme circadien idéal, la prise de mélatonine, la correction du phénomène respiratoire. La prise d’hypnotique
ne semble pas un traitement de choix à long terme.
Sleep is a physiological and behavioral state where the person is partly isolated from the external environment. In the presence
of sleep intrusions such as pain, sleep becomes fragmented. The non REM to REM ultradian oscillations, occurring every 90
to 110 minutes, are then disrupted by several brief and transient arousals (rise in cardiac, brain, muscle, and respiratory
activities). The pain reports from these individuals tend to be exacerbated by the loss of sleep continuity. Tension headache,
migraine, and cluster headache may occur before sleep (delaying sleep onset), during sleep (e.g., migraine, hypnic headache,
cluster headache, and chronic paroxysmal hemicrania), or upon awakening (e.g., breathing disorder, bruxism, pain medication
overuse, and arterial hypertension). Minor traumatic brain injury is frequently associated with headache and circadian sleep
disturbances. Little is known on how to manage sleep-related headaches. A polygraphic search for breathing disturbances or
periodic limb movements is recommended if the complaints are recurrent and associated with daytime somnolence. Use of breathing
or oral devices is helpful if an upper airway resistance is present or if apnea-hypopnea is observed. Cognitive and behavioral
approaches related to sleep hygiene and lifestyle are valuable. Hypnotic medications probably have limited long-term value.
Mots clésSommeil-Céphalée-Migraine-Microéveils-Rythme circadien-Traumatisme crânien
KeywordsSleep-Headache-Migraine-Arousal-Circadian rhythm-Brain trauma
Douleur et Analgésie 01/2010; 23(3):175-180. DOI:10.1007/s11724-010-0207-7 · 0.09 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: This study examined discrete motor irregularities in ballistic aiming movements in patients with atypical parkinsonian syndromes (APS). Nine patients with APS were compared to 9 patients with idiopathic Parkinson's disease (PD) and 9 controls on ballistic arm extension movements performed on a digitizing tablet without visual feedback and without accuracy constraints. Patients with APS showed a higher number of irregularities in the acceleration and jerk time series compared to PD patients and controls. No difference was found between PD patients and controls. These discrete irregularities were not associated with general motor impairment, tremor, akinesia, or rigidity. These results suggest that atypical parkinsonism is associated with movement irregularities in ballistic movements, which may help differentiate APS from PD.
[Show abstract][Hide abstract] ABSTRACT: Les désordres oromoteurs se caractérisent par la présence de mouvements oromandibulaires excessifs, désordonnés ou incoordonnés,
de nature hyperkinétique (dystonie, dyskinésie, stéréotypie, bruxisme de l’éveil et du sommeil) ou hypokinétique (parkinsonisme).
Ces désordres constituent une source non négligeable et hétérogène de douleur et de complications buccodentaires. Une connaissance
de la prise en charge dentaire est essentielle afin de prévenir et soulager rapidement la condition buccale et minimiser les
Oromotor disorders are characterized by the presence of excessive, disorganized, or uncoordinated oromandibular movements
of a hyperkinetic (dystonia, dyskinesia, stereotypy, wakeful or sleep bruxism) or hypokinetic (Parkinsonism) nature. Together,
these disorders constitute a non-negligible and heterogeneous source of orodental pain and complications. A sound knowledge
of dental management is essential to effectively prevent and treat the oral condition and minimize useless strategies.
Douleur et Analgésie 06/2009; 22(2):103-111. DOI:10.1007/s11724-009-0131-x · 0.09 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Motor learning disturbances have been shown in diseases involving dopamine insufficiency such as Parkinson's disease and schizophrenic patients under antipsychotic drug treatment. In non-human primates, motor learning deficits have also been observed following systemic administration of raclopride, a selective D2-receptor antagonist. These deficits were characterized by persistent fluctuations of performance from trial to trial, and were described as difficulties in consolidating movements following a learning period. Moreover, it has been suggested that these raclopride-induced fluctuations can result from impediments in grouping separate movements into one fluent sequence. In the present study, we explore the hypothesis that such fluctuations during movement consolidation can be prevented through the use of sumanirole - a highly selective D2 agonist - if administered before raclopride. Two monkeys were trained to execute a well known sequence of movements, which was later recalled under three pharmacological conditions: (1) no drug, (2) raclopride, and (3) sumanirole+raclopride. The same three pharmacological conditions were repeated with the two monkeys, trained this time to learn new sequences of movements. Results show that raclopride has no deleterious effect on the well known sequence, nor the sumanirole+raclopride co-administration. However, results on the new sequence to be learned revealed continuous fluctuations of performances in the raclopride condition, but not in the sumanirole+raclopride condition. These fluctuations occurred concurrently with a difficulty in merging separate movement components, known as a "chunking deficit". D2 receptors seem therefore to be involved in the consolidation of new motor skills, and this might involve the chunking of separate movements into integrated motor sequences.
Behavioural brain research 12/2008; 198(1):231-9. DOI:10.1016/j.bbr.2008.11.002 · 3.03 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Increasing evidence suggests that the pathophysiology of movement disorders in Parkinson's disease (PD) includes deficits in sensory processing and integration. However, the exact nature of these deficits and the ability of dopamine medication to correct them have not been thoroughly examined in previous studies. For instance, it remains unclear whether PD patients have globally impaired sensorimotor integration functions or selective deficiencies in processing proprioception. We evaluated the specific deficits of PD patients in sensorimotor integration and proprioceptive processing by testing their ability to perform three-dimensional (3D) reaching movements in four conditions in which the sensory signals defining target and hand positions (visual and/or proprioceptive) varied. Ten healthy subjects and 11 PD patients, ON dopamine medication and in the OFF state, were tested. PD patients in the OFF state showed a greater mean level of 3D errors relative to controls when the only available sensory information about target and hand position came from proprioception, but this difference did not reach significance. This indicates that deficient proprioception is not an early key feature of PD. Interestingly, the inaccuracies of a number of PD subjects further increased in the ON medicated state relative to healthy controls when reaching to proprioceptively-defined targets, and this between group difference was statistically significant. However, dopamine medication did not consistently degrade the reaching accuracy of PD patients, with both negative and positive effects on accuracy of reaching to proprioceptive-defined targets. Together, these findings indicate that dopamine replacement therapy not only did not normalize sensorimotor performance to the level of controls, but also induced deficits in the processing of proprioceptive information in some of the PD patients tested. Furthermore, the diversity of effects of medication on accuracy of reaching to proprioceptively-defined targets supports the idea that dysfunction of dopaminergic circuits within the basal ganglia is not primarily responsible for the proprioceptive processing deficits of PD patients.