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      Movement Disorders and Psychosis, a Complex Marriage

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          Abstract

          Most clinicians relate parkinsonism and dyskinesia directly to acute and tardive drug-induced movement disorders. However, parkinsonism and dyskinesia are also present in antipsychotic-naïve patients with psychotic disorders. In this paper, we want to highlight the clinical value of these spontaneous movement disorders and want to discuss the concept of “non-mental signs.” Acute Drug-Induced Movement Disorders Acute drug-induced movement disorders, such as acute dystonia, parkinsonism, and akathisia, are very common side effects of dopamine blocking agents. A causal relationship between these movement disorders and antipsychotics is beyond any doubt if (i) antipsychotic-naïve psychotic patients without movement disorders receive antipsychotics and develop these side effects, (ii) they disappear after dose reduction or cessation of the antipsychotics, and (iii) this on–off mechanism can be repeated. Tardive Syndromes The relationship between tardive syndromes and antipsychotics is far more complex because they start after months to years of treatment with antipsychotics and can also be suppressed by antipsychotics. Tardive suggests drug induced, and also spontaneous hyperkinetic dyskinesias, such as “grimacing” and “irregular movements of tongue and lips” (and also parkinsonism), are prevalent in antipsychotic-naïve psychotic patients and have been described by Kraepelin and Bleuler more than a 100 years ago (1). In patients with long-term use of antipsychotics, there is no test to differentiate between drug-induced tardive and spontaneous movement disorders. The prevalence of drug-induced tardive dyskinesia is substantial and increases with age, the same counts for spontaneous movement disorders such as dyskinesia, bradykinesia, and soft neurological signs related to schizophrenia (2–15). Also, a meta-analysis showed that in antipsychotic-naïve patients with schizophrenia the risk of dyskinesia and parkinsonism are three and five times higher than in healthy controls, respectively (16). Furthermore, another study in antipsychotic-naïve patients showed a prevalence of dyskinesia and parkinsonism of 13 and 18%, respectively, with the use of clinical rating scales, which increased to 20 and 28%, respectively, with the use of instrumental assessment (17). On the other hand, several findings suggest a direct relationship between antipsychotics and tardive dyskinesia. First, non-psychiatric patients may also develop tardive dyskinesia after long-term use of dopamine blocking agents, e.g., long-term use of metoclopramide to treat nausea, or antipsychotics for insomnia (18, 19). Furthermore, in older patients receiving first-generation antipsychotics for the first time the yearly incidence of tardive dyskinesia is extremely high, over 20%, which is much higher than the incidence of spontaneous dyskinetic movement in older patients (12, 13). Also, tardive dyskinesia may disappear after cessation of antipsychotics or after a switch to clozapine. These findings suggest a direct relationship between antipsychotics and tardive dyskinesia. Based on the studies mentioned above, it is clear that the assumption that antipsy- chotics are responsible for tardive dyskinesia is at least incomplete. Indeed, movement disorders can be considered an intrinsic feature of the disease process and implicate dysfunction in cortical–basal ganglia-cortical circuitry (11). The role of the antipsychotics may be modification of the disease-based motor disorder and anti- psychotics can both improve and unmask primary motor abnormalities (10). The clinical importance of spontaneous movement disorders is also emphasized by the relationship between spontaneous parkinsonism and cognitive dysfunction. In a prospective study in antipsychotic-naïve patients with first-episode psychosis, spontaneous parkinsonism at baseline showed high 6-month predictive values for cognitive impairment (9). Pathophysiology The pathogenesis of tardive dyskinesia remains unresolved. Several hypotheses have been proposed such as dopamine 2 (D2)-receptor hypersensitivity, striatal neurodegeneration, maladaptive synaptic plasticity, and enhanced serotonin 2 (5-HT2)-receptor signaling and recently up regulation of striatal D3 receptors had been suggested in a primate model (20). Although none of these models have been confirmed sufficiently they have in common the disturbance of the balance in the motor circuit of the basal ganglia in which dopamine plays a central role. The dopamine (and possibly also the acetylcholine) dysregulation in the basal ganglia-thalamo-cortical loops may result in hyper or hypokinetic movements whereas dopamine dysregulation in other brain areas may result in the development of psychosis (21). Another model is based on synaptic dysregulations in which the core hypothesis is that non-functional astrocytic receptors may cause an unconstrained synaptic information flux, such that glia lose their modulatory function in glial–neuronal interaction (tripartite synapses) (22). Dysregulation of tripartite synapses would occur with dopamine synapses throughout the brain and may be related to both motoric and mental symptoms. Clinical Relevance The clinical relevance for measuring dyskinesia and/or parkinsonism in first-episode psychotic disorders is based on several follow-up studies showing that they predict poor prognosis, increased cognitive impairment, poorer response to antipsychotics, and an increased risk for drug-induced movement disorders (9, 11, 23). Also, in individuals at ultra-high risk for psychosis (UHR group) the assessment of spontaneous movement disorders may be highly relevant. Several studies suggest that subtle abnormal movements are predictive for conversion to psychosis later. The current screening strategy focuses on mental symptoms and has a limited conversion rate to psychosis, around 20–40%, giving to many false positives. It could be that adding measurement of movement disorders to the screening strategy will reduce the number of false positives. Indeed, studies show (i) more abnormal movements in the UHR group than in the control group, (ii) a relationship between the severity of the abnormal movements and the severity of prodromal signs (positive, negative, and total) at baseline, (iii) a relationship between an increase in severity of the abnormal movements with an increase of prodromal signs during follow-up, and (iv) a higher risk to convert to psychosis at follow-up in the UHR groups with abnormal movements at baseline than those without (24, 25). Detection of those in the UHR group who will convert to psychosis is relevant as a meta-analysis showed the effectiveness of some interventions to prevent or postpone a first-episode of psychosis (26). Relationship between Movement, Cognitive, and Emotional Disorders Obeso et al. describe that the basal ganglia are intimately connected with the cortex through several segregated but parallel loops. These loops are subdivided into motor, associative (cognitive), and limbic (emotional) domains and are related to the control of movement, behavior and cognition, and reward and emotions, respectively. When one or more of these circuits become dysfunctional they can generate movement disorders, behavioral, cognitive abnormalities, or mood changes. They suggest, for example that the combination of nigrostriatal denervation and dopaminergic drugs, as seen in Parkinson’s disease, may induce behavioral disorders such as impulse control disorders and that this may be the behavioral counterpart of hyperkinetic disorders such as dyskinesia (27). Similar with this idea is the concept that dysregulation of dopaminergic activity in dopaminergic related brain areas lead to positive and negative symptoms in psychotic disorders and that these symptoms are the behavioral counterpart of dyskinesia and bradykinesia, respectively. It has been suggested that psychotic patients with abnormal movements, compared to those without, have a more severely dysregulated dopamine system (28). This may explain the clustering of abnormal movements with cognitive and negative symptoms and the relationship with poor prognosis. Also, a correlation has been found between tardive dyskinesia and cognitive symptoms (29). It could be that drug-induced movement disorders are related to a more vulnerable dopamine system and subsequently to an increased risk for dyskinesia and negative and cognitive symptoms. In line with the vulnerability concept is the relationship found between early extrapyramidal symptoms such as parkinsonism and an increased risk for developing tardive dyskinesia in the future (30, 31). However, the underlying dysfunction(s) that provoke(s) spontaneous movement abnormalities, tardive dyskinesia, cognitive impairment, negative symptoms, and emotional disturbances remains unclear. It is unlikely that one neurotransmitter, i.e., dopamine is responsible. Although, dysfunction of the modulatory activity of dopamine plays an important role in the clinical manifestations mentioned above, also acetylcholine, which is released across the entire striatal network by striatal cholinergic interneurons, has neuromodulatory properties in the basal ganglia. Furthermore, other neurotransmitters are involved, such as glutamatergic inputs from the cerebral cortex and thalamus to striatal spiny projection neurons (21). Non-Mental Signs Based on the presence of motor, associative (cognitive), and limbic (emotional) loops in the basal ganglia, we want to introduce the concept of non-mental signs (dyskinesia and parkinsonism) in psychotic disorders. This concept is the equivalent of non-motor signs (mood disorders, apathy, anxiety, etc.) in Parkinson’s disease (32). The severity of non-mental signs may have a direct relationship with the severity of dysregulation of the dopamine system. An advantage of non-mental signs is the possibility to measure them objectively and several research groups have developed instruments to measure these non-mental signs instrumentally. Instrumental assessment of movement disorders is sensitive, valid, and reliable and a motor test battery that will quantify the main motor functions has been suggested (33–38). In addition, instrumental measurement can also detect subclinical movement abnormalities and these assessments may be used to predict the course of a (pre)psychotic disorder and can be used to develop preventive strategies. In conclusion, we suggest classifying movement disorders in psychotic disorders or in UHR groups as non-mental signs. Instrumental measurements of these non-mental signs are objective and have clinical implications for prognosis, diagnosis, and treatment of psychotic disorders. In UHR groups adding non-mental signs to the screening strategy may reduce the number of false positives. Non-mental signs could become one of the first biomarkers in psychiatric screening programs. Conflict of Interest Statement The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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          Most cited references31

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          Review article: metoclopramide and tardive dyskinesia.

          Metoclopramide is a dopamine receptor antagonist which has been used for treatment of a variety of gastrointestinal symptoms over the last thirty years. In 2009, the FDA issued a black box warning regarding long-term or high-dose use of this medication because of the risk of developing tardive dyskinesia. To review the mechanism of action and pharmacokinetic properties of metoclopramide, the risk of metoclopramide-induced tardive dyskinesia, potential mechanisms that may alter and to summarize the clinical context for appropriate use of the drug. We conducted a PubMed search using the following key words and combined searches: metoclopramide, neuroleptics, tardive dyskinesia, incidence, prevalence, dopamine, receptors, pharmacokinetic, pharmacology, pharmacogenetics, DRD3 Ser9Gly polymorphism, cytochrome P450, p-glycoprotein, risk factors, gastroparesis, outcome, natural history. Available data show that risk of tardive dyskinesia from metoclopramide use is likely to be <1%, much less than the estimated 1-10% risk previously suggested in national guidelines. Tardive dyskinesia may represent an idiosyncratic response to metoclopramide; pharmacogenetics affect pharmacokinetic and dopamine receptor pharmacodynamics in response to neuroleptic agents that cause similar neurological complications. Community prevalence and pharmacogenetic mechanisms involved in metoclopramide-induced tardive dyskinesia require further study to define the benefit-risk ratio more clearly.
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            Increased dopamine D2 receptor binding after long-term treatment with antipsychotics in humans: a clinical PET study.

            Dopamine D2 receptor upregulation in the striatum is regularly seen in response to the administration of traditional antipsychotics in animal experiments. This is associated with hyperactivity and, for this reason, D2 receptor upregulation has long been postulated as central to tardive dyskinesia (TD). Using positron emission tomography (PET), the present study attempted to determine whether antipsychotic-induced D2 receptor up-regulation also occurs in humans. The long-term effects of traditional and novel antipsychotics on dopamine D2 receptors were investigated in nine subjects meeting DSM-IV criteria for schizophrenia who were deemed eligible for temporary treatment washout. Subjects had been treated with traditional antipsychotics (haloperidol n=3, perphenazine n=1) and novel antipsychotics (risperidone n=3, olanzapine n=2) in the moderate to high dosage range. Fourteen days after treatment withdrawal, the binding potentials (BPs) of dopamine D2 receptors were measured using 11[C] raclopride. The obtained BPs were compared to the BPs from antipsychotic-naive control subjects with schizophrenia. There was a significant increase in the D2 BP in both groups combined that reached 34%. The increases in the D2 BPs in the groups treated with conventional and novel antipsychotics were 37% and 31%, respectively. Significantly, the patients showing the highest degree of D2 receptor upregulation (98%) developed severe and persistent TD shortly after being started on a new antipsychotic with low affinity for D2 receptors. This study demonstrates for the first time, using in vivo neuroreceptor imaging, that dopamine D2 receptor binding is increased after long-term treatment with antipsychotics in humans. The data suggest that both traditional and novel antipsychotics with high affinity for dopamine D2 receptors are associated with a substantial increase in D2 receptor binding. The present data in humans agree well with animal data that implicate D2 receptor-mediated mechanisms in motor hyperactivity.
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              Quetiapine for insomnia: A review of the literature.

              The safety and efficacy of quetiapine for the treatment of insomnia in adults are reviewed. Quetiapine was developed for the treatment of psychiatric disorders, but its antagonism of histamine H1- and serotonin type 2A receptors has the added effect of causing sedation. As such, quetiapine is widely used off-label as a treatment for insomnia. Due to quetiapine's potential adverse effects, guidelines for the treatment of insomnia have recommended the drug's use only in patients with specific comorbid psychiatric disorders. The use of quetiapine for the treatment of insomnia in the absence of comorbid conditions has been evaluated in only two clinical trials of 31 patients in total, and very few studies have evaluated quetiapine use in patients with insomnia and other comorbidities. No trials have been conducted comparing quetiapine with an active control (e.g., zolpidem); the data that exist compare quetiapine to a placebo or there is no comparison and all patients are treated with quetiapine. Very few studies have evaluated quetiapine's efficacy in the treatment of insomnia using sleep objective testing, another limitation of the available data on quetiapine. Robust studies evaluating the safety and efficacy of quetiapine for the treatment of insomnia are lacking. Given its limited efficacy data, its adverse-effect profile, and the availability of agents approved by the Food and Drug Administration for the treatment of insomnia, quetiapine's benefit in the treatment of insomnia has not been proven to outweigh potential risks, even in patients with a comorbid labeled indication for quetiapine.
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                Author and article information

                Contributors
                URI : http://frontiersin.org/people/u/161744
                URI : http://frontiersin.org/people/u/193621
                URI : http://frontiersin.org/people/u/199174
                URI : http://frontiersin.org/people/u/25257
                URI : http://frontiersin.org/people/u/195222
                Journal
                Front Psychiatry
                Front Psychiatry
                Front. Psychiatry
                Frontiers in Psychiatry
                Frontiers Media S.A.
                1664-0640
                12 October 2014
                09 January 2015
                2014
                : 5
                : 190
                Affiliations
                [1] 1Psychiatric Centre GGz Centraal, Innova , Amersfoort, Netherlands
                [2] 2School for Mental Health and Neuroscience, Maastricht University , Maastricht, Netherlands
                [3] 3Department of Neurology, University Medical Center Groningen, University of Groningen , Groningen, Netherlands
                Author notes

                Edited by: Manuel Morrens, University of Antwerp, Belgium

                Reviewed by: Bernhard J. Mitterauer, Volitronics-Institute for Basic Research Psychopathology and Brain Philosophy, Austria; Manuel Morrens, University of Antwerp, Belgium

                This article was submitted to Schizophrenia, a section of the journal Frontiers in Psychiatry.

                Article
                10.3389/fpsyt.2014.00190
                4288124
                25620934
                8d0586c0-6be0-49f2-9961-33351b278453
                Copyright © 2015 van Harten, Bakker, Mentzel, Tijssen and Tenback.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 11 October 2014
                : 12 December 2014
                Page count
                Figures: 0, Tables: 0, Equations: 0, References: 38, Pages: 3, Words: 2887
                Categories
                Psychiatry
                Opinion Article

                Clinical Psychology & Psychiatry
                movement disorders,psychotic disorders,tardive dyskinesia,schizophrenia,instrumental assessment

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