Movement Disorders Secondary to Drugs: History
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Contributor:
Jamir Pitton Rissardo
,
Ana Letícia Fornari Caprara

Drug-induced movement disorders affect a significant percentage of individuals, and they are commonly overlooked and underdiagnosed in clinical practice. Many comorbidities can affect these individuals, making the diagnosis even more challenging. Several variables, including genetics, environmental factors, and aging, can play a role in the pathophysiology of these conditions. 

  • drug-induced
  • movement disorder

1. Introduction

Prescribed and illicit drugs can cause adverse neurological effects such as movement abnormalities. Dopamine-receptor-blocking agents, such as antipsychotics and antiemetics, are the most prevalent causes of drug-induced movement disorders [1]. In this context, abnormal movements secondary to drugs can range from tremors to life-threatening emergencies. The abnormal movements can be categorized as acute, subacute, or tardive syndromes based on the onset of the drug to the beginning of the movement disorder. Acute drug-induced movement abnormalities can occur minutes to days after the administration of the offending drug. Among them are akathisia, tremor, neuroleptic malignant syndrome, serotonin syndrome, parkinsonism, and acute dystonic symptoms. Subacute drug-induced movement disorders can occur within days to weeks following drug initiation. Tardive medication-induced movement syndromes develop after exposure to an offending drug or within weeks of drug discontinuation [2][3].

2. Overview of Movement Disorders Secondary to Drugs

Movement disorders are characterized as hyperkinetic or hypokinetic based on their major phenomenology. Tremor, dystonia, chorea, myoclonus, tics, and akathisia are hyperkinetic syndromes characterized by excess movement. The decreased movement in hypokinetic disorders unrelated to weakness or paralysis characterizes parkinsonism [4]. There are several proposed classification systems for the categorization of drug-induced movement disorders, but none include all types of drug-related abnormal movements. Thus, many patients with drug-induced movement disorders are probably misclassified [5]. The Diagnostic and Statistical Manual of Mental Disorders (DSM) and the International Statistical Classification of Diseases and Related Health Problems (ICD) are among the most commonly utilized to classify symptoms in electronic medical records (Table 1) [6].
Table 1. Classification of drug-induced movement disorders.
Movement Disorder DSM V TR, 2022 a ICD-10 Version 2019 b ICD-11 Version 2023 c
Code Description Code Description
Akathisia Medication-induced acute akathisia G25.8 Other specified extrapyramidal and movement disorders (drug-induced akathisia) 8A07.1 Akathisia
Ataxia NA R27.0 Ataxia, unspecified 8A03.3Y Other specified acquired ataxia
Dyskinesia Tardive dyskinesia NA NA 8A01.16 Drug-induced chorea
NA G25.4 Drug-induced chorea 8A01.16 Drug-induced chorea
NA G25.5 Other chorea 8A01.20 Hemichorea
NA 8A01.21 Ballism
NA 8A01.22 Hemiballism
Dystonia Medication-induced acute dystonia G24.0 Drug-induced dystonia 8A02.10 Drug-induced dystonia
Tardive dystonia
Myoclonus NA G25.3 Myoclonus (drug-induced myoclonus) 8A06.Y Other specified myoclonic disorders
Neuroleptic malignant syndrome Neuroleptic malignant syndrome G21.0 Malignant neuroleptic syndrome 8A0Y Other specified movement disorders
Parkinsonism Medication-induced parkinsonism G21.1 Other drug-induced secondary parkinsonism 8A00.24 Drug-induced parkinsonism
NA G21.2 Secondary parkinsonism due to other external agents 8A00.2Y Other specified secondary parkinsonism
Tics NA G25.6 Drug-induced tics and other tics of organic origin 8A05.1Y Other specified secondary tics
Tremor NA G25.1 Drug-induced tremor 8A04.31 Tremor due to chronic or acute substance use
Medication-induced postural tremor NA NA 8A04.32 Tremor due to drug withdrawal
NA NA NA 8A04.3Y Other specified secondary tremor
Other Other medication-induced movement disorder NA NA NA NA
Abbreviations: DSM V TR, The Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, Text Revision; ICD, International Statistical Classification of Diseases and Related Health Problems; NA, not available/not applicable. a https://www.appi.org/products/dsm (accessed on 16 July 2023). b https://icd.who.int/browse10/2019/en (accessed on 16 July 2023). c https://icd.who.int/browse11/l-m/en (accessed on 16 July 2023).
When properly managed, patients with movement disorders secondary to drugs can achieve full remission. Nevertheless, these disorders are often underrecognized in clinical practice, which could negatively impact the quality of life of patients and their caregivers for years [7]. Although they were primarily described with antipsychotic medications, several pharmacological substances were reported with movement disorders. Drug-induced movement disorders are a worldwide issue and usually occur while managing psychiatric and gastrointestinal motility disorders [8]. This is often the case because of the scarcity of medications that do not affect the nigrostriatal pathway. Acute antipsychotic-associated movement disorders, such as akathisia and parkinsonism, occur shortly after the initiation of the medication or titrations, and chronic antipsychotic-related movement disorders, such as tardive dyskinesia and tardive dystonia, usually occur after long-term exposure to antipsychotics [9]. Early identification and treatment increase the likelihood of mitigating adverse outcomes.
Differential diagnosis between the idiopathic nature of the disorder and the secondary cause from a drug could be challenging in clinical practice. The most common approach to the occurrence of a side effect is the discontinuation of the offending drug, but sometimes the medication causing the adverse effect is essential for the management of the patient. Thus, the significance of studying side effects and how to best manage them with dose adjustment may be great for patients with difficult and uncontrolled primary disease and comorbidities. The differential diagnosis of drug-induced movement disorders should always include functional movement disorders, which can present with any type of abnormal movement [10]. It is noteworthy that the most common presentation of functional movement disorder overlaps with those secondary to drugs, in which tremor represents the most common clinical manifestation, followed by dystonia, myoclonus, and gait disorders [11]. The distinction between drug-induced movements and functional movement disorders is based on two main characteristics: inconsistency and incongruence [12].
Basal ganglia are a diversified array of linked nuclei that play a significant role in movement execution and signal relay. The classical paradigm suggests a direct (striatonigral) and indirect (striatopallidal) pathway inside the basal ganglia, including striatal projection neuron subpopulations, in which GABA plays an important role in the modulation of cortical impulses. Moreover, the cortical pathways can alter dopamine-dependent signaling, increasing or decreasing locomotor activity [13]. These pathways’ selective contributions have been demonstrated in mice with dopamine- and cAMP-regulated phosphoprotein Mr 32 kDa (DARP-32) deletion in nigrostriatal neurons in response to tropane alkaloids, such as cocaine [14].
Several neurotransmitter systems may be associated with the development of movement disorders. Any of these changes may result in impairments of the motor and cognitive systems. In this context, the dopaminergic system is distributed all across the cortical and subcortical regions. The D1 and D2 receptors are the most abundant in basal ganglia cells, with other receptor subtypes being less expressed. Dopamine-receptor-containing medium spiny neurons express specific receptor subtypes in their projections. The striatonigral circuit expresses D1 receptors selectively, whereas the striatopallidal pathway expresses D2 receptors. D1, D2, and D3 receptors are primarily responsible for locomotor control [15]. Serotonin regulates extrapyramidal motor activity via serotonin receptors in numerous cortical locations and the striatum. There are several subtypes of serotoninergic receptors, which have distinct distribution patterns. For example, 5HT1F and 5HT3A are absent in the caudate, substantia nigra, or globus pallidus. However, others have moderate or low expression levels in the same locations in marmoset brains [16].
The serotoninergic system more commonly regulates cognition to the detriment of motor functions than the dopaminergic system. Experimental animal models show that serotonin might influence dopaminergic motor performance in the nigrostriatal system. GABA is the primary inhibitory transmitter in the central nervous system and can modulate motor function by activating the GABAA receptor. More than sixteen receptor subunits of neurotransmitters, which play a significant role in motor control, have been found across the central nervous system [16][17].

This entry is adapted from the peer-reviewed paper 10.3390/clinpract13040087

References

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  2. Ghadery, C.M.; Kalia, L.V.; Connolly, B.S. Movement Disorders of the Mouth: A Review of the Common Phenomenologies. J. Neurol. 2022, 269, 5812–5830.
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  4. Chouksey, A.; Pandey, S. Clinical Spectrum of Drug-Induced Movement Disorders: A Study of 97 Patients. Tremor Other Hyperkinet. Mov. 2020, 10, 48.
  5. Rissardo, J.P.; Caprara, A.L.F. Parkinson’s Disease Rating Scales: A Literature Review. Ann. Mov. Disord. 2020, 3, 3–22.
  6. Nussbaum, A.M. The Pocket Guide to the DSM-5-TRTM Diagnostic Exam; American Psychiatric Pub: Washington, DC, USA, 2022; ISBN 1-61537-357-8.
  7. Bera, R.; Bron, M.; Benning, B.; Cicero, S.; Calara, H.; Darling, D.; Franey, E.; Martello, K.; Yonan, C. Clinician Perceptions of the Negative Impact of Telehealth Services in the Management of Drug-Induced Movement Disorders and Opportunities for Quality Improvement: A 2021 Internet-Based Survey. Neuropsychiatr. Dis. Treat. 2022, 18, 2945–2955.
  8. Jain, K.K. Drug-Induced Movement Disorders. In Drug-Induced Neurological Disorders; Jain, K.K., Ed.; Springer International Publishing: Cham, Switzerland, 2021; pp. 325–346. ISBN 978-3-030-73503-6.
  9. Kumsa, A.; Girma, S.; Alemu, B.; Agenagnew, L. Psychotropic Medications-Induced Tardive Dyskinesia and Associated Factors Among Patients with Mental Illness in Ethiopia. Clin. Pharmacol. 2020, 12, 179–187.
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  11. Hallett, M.; Aybek, S.; Dworetzky, B.A.; McWhirter, L.; Staab, J.P.; Stone, J. Functional Neurological Disorder: New Subtypes and Shared Mechanisms. Lancet Neurol. 2022, 21, 537–550.
  12. Hess, C.W.; Espay, A.J.; Okun, M.S. Inconsistency and Incongruence: The Two Diagnostic Pillars of Functional Movement Disorder. Lancet 2022, 400, 328.
  13. Arber, S.; Costa, R.M. Networking Brainstem and Basal Ganglia Circuits for Movement. Nat. Rev. Neurosci. 2022, 23, 342–360.
  14. Frydecka, D.; Misiak, B.; Piotrowski, P.; Bielawski, T.; Pawlak, E.; Kłosińska, E.; Krefft, M.; Al Noaimy, K.; Rymaszewska, J.; Moustafa, A.A.; et al. The Role of Dopaminergic Genes in Probabilistic Reinforcement Learning in Schizophrenia Spectrum Disorders. Brain Sci. 2021, 12, 7.
  15. Latif, S.; Jahangeer, M.; Maknoon Razia, D.; Ashiq, M.; Ghaffar, A.; Akram, M.; El Allam, A.; Bouyahya, A.; Garipova, L.; Ali Shariati, M.; et al. Dopamine in Parkinson’s Disease. Clin. Chim. Acta 2021, 522, 114–126.
  16. Friedman, J.H. Movement Disorders Induced by Psychiatric Drugs That Do Not Block Dopamine Receptors. Park. Relat. Disord. 2020, 79, 60–64.
  17. Speranza, L.; di Porzio, U.; Viggiano, D.; de Donato, A.; Volpicelli, F. Dopamine: The Neuromodulator of Long-Term Synaptic Plasticity, Reward and Movement Control. Cells 2021, 10, 735.
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