Mirtazapine-associated movement disorders: A literature review : Tzu Chi Medical Journal

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Mirtazapine-associated movement disorders

A literature review

Rissardo, Jamir Pitton,*; Caprara, Ana Leticia Fornari

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Tzu Chi Medical Journal 32(4):p 318-330, Oct–Dec 2020. | DOI: 10.4103/tcmj.tcmj_13_20
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Adverse events or unintended pharmacologic effects that occur when a medication is administered are stressful situations for patients and, in some cases, can be a challenge for the physicians [1]. In this context, movement disorders (MDs) associated with drugs are even more difficult to describe or give a clear diagnosis because the clinical manifestations could overlap and provide a mixture of disorders in the same individuals, also every movement type can be induced by some drug or toxin. The most frequent causes of drug-induced MDs are dopamine receptor blocking drugs, including antipsychotics and antiemetics [2].

Mirtazapine (MTZ) is an atypical antidepressant, which first clinical studies started at the end of the 1980s [3]. In 1994, this medication was primarily approved for the management of major depressive disorder (MDD) in the Netherlands. About three years later, MTZ was approved by the Food and Drug Administration for the treatment of moderate-to-severe depression [4]. A recent systematic review comparing the efficacy of more than twenty different antidepressants revealed that MTZ is one of the most effective antidepressants when compared to other antidepressants. It also demonstrated a statistical advantage over current selective serotonin reuptake inhibitors (SSRIs) [5]. However, currently, guidelines such as the National Institute for Health and Care Excellence in the United Kingdom 2010 still recommended generic SSRIs as the first-line treatment for depression [6].

The mechanisms of action involved with MTZ are the antagonism of central presynaptic adrenergic (α2), histamine (H1), and serotonin (SER) (5-HT2A, 2C, and 3) receptors [Figure 1]. In addition, it has moderate antagonist effects on peripheral alpha-1 adrenergic and muscarinic receptors [7]. The interference in these receptors explains the several significant side effects related to MTZ. The adverse events that affect more than ten percent of users are drowsiness, weight gain, and xerostomia.

Figure 1:
Skeletal formula and pharmacodynamic of mirtazapine. The size of the arrow is inversely proportionally to the Ki (smaller the value stronger is the drug binds to the site). Mirtazapine acts as antagonism of serotoninergic (5-HT2A, 5-HT2C, and 5-HT3), noradrenergic (α-2), and histaminergic (H1) receptors

MTZ was only approved by the FDA for the treatment of MDD [8]. However, this drug is used off-label for the management of posttraumatic stress disorder, hot flushes, insomnia, panic disorder, obsessive–compulsive disorder, generalized anxiety disorder, and headaches [48].

MDs are uncommonly related to MTZ. In the label of REMERON® (MTZ) tablets, in one of the clinical experiences in short-term United States control studies, nine individuals of more than four hundred taking MTZ had tremors, and this was the only MD found in more than one percent of the participants [9]. Moreover, other postmarketing studies done throughout the last decades including hundreds of individuals did not report any MTZ-induced movement [3]. A recent literature review of only the PubMed database from 1990 to June 2017 focused on hyperkinetic movements related to MTZ found twelve cases already reported, which were in descending order of frequency, akathisias (AKTs) (5), dystonia (DTN) (4), dyskinesias (DKNs) (2), and periodic limb MD (PLMD) (1). Their results conclude that these adverse effects were more common in older individuals, and the best treatment is the cessation of the medication [10]. The aim of this literature review is to evaluate the clinical epidemiological profile, pathological mechanisms, and management of MTZ-associated MDs.


Search strategy

We searched six databases in an attempt to locate any and all existing reports on movement disorders secondary to mirtazapine published from 1990 to 2019 in electronic form. Excerpta Medica (Embase), Google Scholar, Latin American and Caribbean Health Sciences Literature (Lilacs), Medline, Scientific Electronic Library Online (Scielo), and ScienceDirect were searched. Search terms were “dystonia, restless legs syndrome, periodic limb movement disorder, akathisia, dyskinesia, tremor, stuttering, parkinsonism, tic, chorea, restlessness, ataxia, hyperkinetic, hypokinetic, bradykinesia, movement disorder, myoclonus, ballism.” These terms were combined with “mirtazapine, Org 3770” [Supplementary Material 1].

Supplementary Material 1 FreeText and MeSH search terms in the US National Library of Medicine

Inclusion and exclusion criteria

Original articles, case reports, case series, letters to editors, bulletins, and poster presentations published from 1990 to 2019 were included in this review with no language restriction. The two authors independently screened the titles and abstracts of all papers found from the initial search. Disagreements between the authors were resolved through discussion.

Cases where the cause of MD was already known and either motor symptoms did not worsen or were not related to MTZ were excluded. Furthermore, cases that were not accessible by electronic methods including after a formal request to the authors (by email) were excluded. Cases that had more than one contributing factor to the MD were evaluated based on the Naranjo algorithm to estimate the probability of the event occurring.

Data extraction

A total of 3794 papers were found; 3444 were irrelevant and 298 were unrelated to the complication, duplicate, inaccessible electronically, or provided insufficient data [Figure 2]. Data abstraction was done. When provided, we extracted from the articles: authors' name, authors' department, year of publication, country of occurrence, number of patients affected, MTZ indication including off-label uses, time from first MTZ-dose until MD onset, time from MTZ withdrawal to symptoms improvement, patient's status at the last follow-up, and important findings of clinical history and management. The majority of the reports did not provide sufficient information about the neurological examination and the time from drug withdrawal to the improvement of the symptoms. The data were extracted by two independent authors, double-checked to ensure matching, and organized by whether the MD was a side effect of the MTZ use.

Figure 2:
Flowchart of the screening process

Statistical analysis

Categorical variables were represented as proportions; continuous variables were represented as mean, standard deviations (SDs), median, and range.


The clinical characteristics and definitions of the MDs such as DTN, restless legs syndrome (RLS), PLMD, AKT, DKN, tremor, parkinsonism, tic, chorea, ballism, and myoclonus were obtained from the reference Jankovic and Tolosa [11]. The clinical diagnosis for psychiatric disorders was obtained from the diagnostic and statistical manual of mental disorders (DSM-5®) [12]. The Naranjo algorithm was used for determining the likelihood of whether an adverse drug reaction was actually due to the drug rather than the result of other factors [13]. In the cases where the non-English literature was beyond the authors' proficiency (English, Portuguese, Spanish, Italian, French, and German) and the English abstract did not provide enough data, such as Japanese, Korean, Chinese, Russian, and Dutch, Google Translate service was used [14].


For 1990 and 2019, a total of 52 reports containing 179 individuals that developed a MD associated with MTZ were identified from 20 different countries [Table 1] [10151617181920212223242526272829303132333435363738394041424344454647484950515253545556575859606162636465]. 103 individuals were from European countries, 49 Asian, 17 Australian, 8 North American, and 2 South American. Figure 3 shows the number of reports associated with MDs and MTZ over time. The MDs associated with MTZ encountered were 6 DTNs (isolated axial, isolated cervical, and axial + cervical), 69 RLS (induced and worsening RLS symptoms), 9 PLMD, 10 AKT, 3 DKN (chorea and choreoathetosis), 35 tremors (action and resting), 2 parkinsonism, 1 tic (complex motor facial without vocalization), 4 rapid eye movement sleep behavior disorders, and others not clearly identified cases such as 18 restlessness, 15 hyperkinesis, and 1 extrapyramidal symptoms.

Table 1:
Clinical reports presenting with mirtazapine-associated movement disorder from 1990 to 2019
Figure 3:
Graphic showing the number of clinical reports of mirtazapine-associated movement disorder from 1990 to 2019

The mean and median age was 57 (SD: 15.16) and 58 years (age range: 17–85). The female was the predominant sex in 60% (33/55) of the individuals. The most common indication of MTZ was MDD in 51% (21/41) of the cases, followed by MDD + insomnia (12), insomnia alone (3), hot flushes (1), major depressive episode (1), major depressive episode + insomnia (1), MDD + panic attacks (1), and mild depression + insomnia (1). The mean and median MTZ dose, when the MD occurred, was 24.68 (SD: 14.41) and 15 mg (MTZ dose range, 7.5–60). There were: 21 individuals with 15 mg of MTZ when the MD occurred, 19 with 30 mg, 7 with 7.5 mg, 4 with 45 mg, and 4 with 60 mg.

The mean and median time from MTZ start and the abnormal movement onset was 7.54 (SD: 15.53) and 2 days. The MD occurred within a week of the MTZ start in 78% (35/45) of the patients. The correlation between MTZ dose and the time from the drug start to the MD onset demonstrated a moderate linear correlation 0.367 when outliers were excluded.

Only two individuals did not have a complete recovery after the management. The time from drug withdrawal and the improvement of symptoms was specifically reported by 23 cases. In 19 cases, the recovery occurred within one week of the management.

In 82% (45/55) of the individuals, the management was the withdrawal of the offending drug. Other options were more commonly attempted on the MTZ-induced RLS, in which the management involved the inclusion of a new drug (clonazepam, ropinirole, pramipexole, or gabapentin) to improve the symptoms. In the AKT group, other choices to alleviate restlessness were attempted such as starting concurrent propranolol needed-basis, and as using every three days MTZ. By the way, in one individual with DKN, MTZ was not discontinued, and the symptoms improved over time.



An important topic to discuss is the few numbers of clinical reports already reported in the literature of MTZ-induced MD. In this context, we believe that probably only were reported moderate to severe cases; on the other hand, those mild cases were only addressed by drug withdrawal without a report to the literature [66]. Some findings supporting this assumption are a large number of reports with thousands of cases about MTZ and MDs adverse effects on the FDA Adverse Event Reporting System [67]. In addition, more than eighty percent of the cases were diagnosed without the examination of a MD specialist. Thus, we presupposed that only the most severe cases with clear abnormal movements were published; also, it is worth mention that most cases did not clearly describe and lack significant features about the patients' neurological examination.

Herein, we would like to discuss some of the MDs in subtopics to give a better comprehension of the data. Figure 4 shows a resume of the hypothesized pathophysiological mechanisms that we proposed for the development of MDs following the use of MTZ.

Figure 4:
Schematic diagram showing the pathophysiological mechanism of mirtazapine-associated movement disorders. (A) Receptors that are significantly antagonized by mirtazapine, which include H1, 5HT2A, HT2C, and α-2. (B) Dystonia mechanism associated with 5HT2A; mirtazapine? Represents that probably mirtazapine has some indirect action in the pathway between the frontal cortex and substantia nigra compact. D: Direct pathway, I: Indirect pathway. (C) Akathisia mechanism associated with 5HT2A and α-2; NAc: Nucleus accumbens, NE: Norepinephrine. (D) Restless legs syndrome mechanism associated with 5HT2A, HT2C, and α-2; IML: Intermediolateral cell column. (E) Acute dyskinesia mechanism related to H1, 5HT2C, 5HT2A, and α-2. (F) Tardive dyskinesia associated with serotonin receptors and H1 antagonism that lead to abnormal adaptation of striatal organization


In the cases related to DTN is observed the predominance of an elderly population, which could be explained by the reduced clearance of the drug that may increase the MTZ plasma levels and consequently the sensibility to the drug in this group of individuals [68]. In addition, most of the early studies about the efficacy of MTZ showed a higher percentage of side effects in the elderly population when compared to a younger population, even though only a small percentage of the total individuals belonged to this group [69]. Therefore, the initiation of MTZ in patients of sixty-five years or older should be at a low dose (7.5 mg or 15 mg) followed by a close follow-up.

When we analyzed the data found in Table 1 about all MDs, we can see that only in one patient MTZ-indication was not for a psychiatric disorder, which is important because it decreases the possibility of the MDs found in the literature be psychogenic disorders [65]. The most effective management was MTZ withdrawal.

The mechanism of DTN is poorly understood; as a result, we have many hypotheses in the literature [70]. Figure 4B shows the most common explanations for the MTZ-induced DTN found in the literature. One possible explanation for this association is an increased direct pathway stimulation by the frontal cortex in the substantia nigra compact due to the release of norepinephrine (NE) and SER from the 5HT2C antagonism in the raphe nucleus with cortical projections [71]; this is supported by studies showing frontal cortex hypermetabolism after MTZ [72]. Another theory could be the direct action in 5HT2A receptors in the thalamus, as was already found in animal models [7374], leading to an increase of the thalamocortical drive by increasing direct pathway stimulation or decreasing the inhibitory projections to the thalamus [75]. Both hypotheses above have a common pathway that is the cortico–striato–pallido–thalamo–cortical loop, which was first characterized in DTN secondary to stroke [7677].

Restless legs syndrome

RLS is probably the most underestimated of all abnormal movements secondary to MTZ. A prospective German study found that nine percent of patients receiving second-generation antidepressants had RLS-symptoms. In the study, 53 individuals were in use of MTZ, and more than twenty-five percent of these reported RLS-symptoms [40]. Thus, we believe that this study included individuals with mild symptoms of RLS rather than just moderate-severe reports like most of the data found in the literature. Furthermore, the use of specific questions during the appointments about RLS probably led the researches to increase the number of diagnoses. When evaluating depressed patients, another important feature that more commonly occurs with RLS than with other MDs is the mixture of the patients' symptoms, in which the RLS-symptoms go unnoticed or are ignored in the absence of a basic screening by the physician, and possibly occurs due to the various complaints from patients [78].

There are at least three hypotheses for the explanation of RLS [79]. The first hypothesis would be the prolonged use of dopamine antagonists, but we discard this theory because MTZ does not directly inhibit dopamine release. Another hypothesis is related to the central nervous system iron homeostasis, which was probably not the main mechanism responsible for the induced RLS because a long term alteration of the iron kinetic would be necessary to lead to abnormalities in the brain metabolism. The last hypothesis is an increase of SER in the brainstem [Figure 4D] [80]. In this context, the antagonism of 5HT2C and 5HT2A could lead to disinhibition of serotoninergic neurons, and consequently causing the release of SER [7181]. The SER release can affect the intermediolateral column and nucleus and provoke postganglionic adrenal glands to release NE, which causes the discomfort sensation in the limbs [82]. Another possible pathway co-occurring is an increased firing rate of the raphe nucleus leading to NE release. Furthermore, NE release in the brainstem provokes insomnia, which is a common symptom reported by RLS patients [8384].

It is worthy of mentioning that MTZ worsening RLS-symptoms of RLS symptoms is a common-sense association among MDs specialists. Hence, MTZ should be avoided in patients with a previous history of RLS [85]. In more than eighty percent of the MTZ-induced MDs, the management was drug withdrawal. However, in RLS, due to the lower severity of possible complications compared to other MDs, we may have more options depending on the situation. These choices include starting a new drug in association with MTZ to decrease the RLS symptoms, MTZ dose decrease, or even the rechallenge after a period of time. In this context, the MTZ rechallenge was attempted in two patients and was successful without the development of new symptoms.


The clinical description of the patients that developed AKT after MTZ use was the most comprehensible after the DTN group. However, sometimes, it was difficult to distinguish AKT patients from the RLS individuals due to overlap of the clinical manifestations of both disorders, what we will call AKT/RLS [86]. One possible explanation for this common association with MTZ is that this drug interferes in a variety of pathways at the same time due to similar Ki values; as a result, MTZ interacts with noradrenergic, serotoninergic, and histaminergic receptors at the same time.

An interesting fact in the AKT subgroup was that the majority of the individuals were middle-aged adults with a mean age of 48 years, which is almost ten years younger than the general findings associated with MTZ, and with Asian origin. These findings can support the hypothesis of a probable genetic predisposition in this subgroup of individuals.

The pathophysiological mechanism of MTZ-induced AKT is based on psychopharmacological studies with substance use disorder, mainly with addict users that had drug-seeking behavior [Figure 4C] [87]. It was already shown in rat models that 5HT2A antagonism leads to a decrease of dopamine in the surroundings of the nucleus accumbens, which signs by projections to the brainstem for release NE [8788]. This neurotransmitter promotes the release of dopamine in the orbitofrontal cortex, leading to D1 hyperactivation and inducing AKT symptoms [8889]. Furthermore, in the same context, MTZ antagonist effects on the central presynaptic alpha-2 antagonists cause an increased release of SER and NE in the brainstem reinforcing the process [7].

This MD was the only to reappear in all individuals that the drug was reintroduced. Thus, the best management in these situations should be the MTZ withdrawal without rechallenge. Also, if available, the prescription of a benzodiazepine for a short period of time due to possible faster recovery.


In the literature there is a lot of explanation about DKN secondary to medications, and many mechanisms were already proposed [90]. In Figure 4, we divided the DKN in Figure 4E, which represents the acute DKN, and Figure 4F, which represents the tardive DKN [91]. We explained the tardive DKN associated with MTZ based on findings with serotoninergic neurotransmission in rat models, where probably the effects on 5HT and MTZ metabolites lead to damage by inflammation and oxidative stress, which culminate in an abnormal adaptation of the striatal organization leading to direct pathway overactivation [92]. Otherwise, the acute DKN is probably more associated with antagonism H1 due to the time for the occurrence of the process described above; it is well known that antihistaminic medication can lead to DKN [93]. The histamine receptors are commonly found throughout the central nervous system, but an important structure with a lot of H1 is the tuberomammillary nucleus, which has many connections with the cerebral cortex, neostriatum, hypothalamus, hippocampus, and nucleus accumbens [94]. In this way, we hypothesized that in susceptible individuals, the disturbance by MTZ antagonism effect in the H1 receptor, mainly localized, in the tuberomammillary nucleus may play a central role in the pathophysiological mechanism of the acute DKN.

Tremor, tics, and other movement disorders

Four patients were assumed to have a diagnosis of parkinsonism in the use of MTZ; only two were clinically reported as having secondary parkinsonism. Nevertheless, Yamada et al. and Uvais et al. did not clearly describe the neurological examination, and they lack information about the characterization of bradykinesia [5763]. Therefore, even though the diagnosis of parkinsonism in those cases is possible, we believe that a diagnosis of an exacerbation of physiological tremor, which can be explained by the increase of NE release in a situation such as stress and anxiety, is more probable more probable [95]. In this context, MTZ interference in the α2 receptor enhances the release of NE and SER in the central nervous system leading to tremors [96]. Or even another possible pathway correlated with the RLS/AKT mechanisms can be suspected. One supporting feature of this theory is the fact that the general description of the patients' symptoms [63]. Moreover, the PLMD may also be related in the same way as tremor and RLS/AKT overlap pathways [97].

Tics were only reported in one individual, and Liu et al. proposed that tics may result in a dopamine surge by the interaction between serotoninergic receptors and the dopaminergic system [49]. They include that the hyperadrenergic status by the MTZ antagonism in the alpha-2 receptor could contribute to the development of the tics.

Other movements not clearly defined in some reports include the description of restlessness and hyperkinesis that are general terms. We believe that these cases were referring AKT, but the data about the specific symptoms and physical examination of the patients were not provided by the studies [25]. In addition, Madhusoodanan et al. reviewed the literature and found one patient with extrapyramidal symptoms associated with MTZ, but they did not describe or give a reference for the study [42]. As is in the majority of the cases, the management in these conditions was the drug withdrawal and the follow-up had good outcomes with fast and full recovery.


MTZ is associated with RLS, tremors, AKT, PLMD, DTN, rapid eye movement sleep behavior disorders, DKN, parkinsonism, and tic. In the literature, the number of reports about MTZ-associated MD is probably of only moderate–severe cases with lacking data about mild conditions. However, in general, this drug is probably uncommonly related to abnormal movements. The management should be the MTZ withdrawal, except in RLS cases that other options are possible. In AKT, the MTZ should not be rechallenge, and if available, the prescription of a benzodiazepine may reduce recovery time. Further reports of MTZ-associated MDs need to focus on the times of MD onset and recovery, as well as the long follow-up of the patient. These data should be provided for a future assessment of the significance of these abnormal movements to predict the development of MDs such as Parkinson's disease.

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Conflicts of interest

There are no conflicts of interest.


1. Zádori D, Veres G, Szalárdy L, Klivényi P, Vécsei L. Drug-induced movement disorders Expert Opin Drug Saf. 2015;14:877–90
2. Duma SR, Fung VS. Drug-induced movement disorders Aust Prescr. 2019;42:56–61
3. Anttila SA, Leinonen EV. A review of the pharmacological and clinical profile of mirtazapine CNS Drug Rev. 2001;7:249–64
4. Jilani TN, Saadabadi A. Mirtazapine StatPearls [Internet]. 2020Last accessed on 2019 Oct 09 Treasure Island (FL) StatPearls Publishing Available from: https://www.ncbi.nlm.nih.gov/books/NBK519059/
5. Wang SM, Han C, Bahk WM, Lee SJ, Patkar AA, Masand PS, et al Addressing the side effects of contemporary antidepressant drugs: A comprehensive review Chonnam Med J. 2018;54:101–12
6. Davidson JR. Major depressive disorder treatment guidelines in America and Europe J Clin Psychiatry. 2010;71(Suppl E1):e04
7. Nutt D. Mirtazapine: Pharmacology in relation to adverse effects Acta Psychiatr Scand Suppl. 1997;391:31–7
8. Nutt DJ. Tolerability and safety aspects of mirtazapine Hum Psychopharmacol. 2002;17(Suppl 1):S37–41
9. Organon. REMERON® (Mirtazapine) Food and Drug Administration. 2007Last accessed on 2020 Jan 21 Available from: https://wwwaccessdatafdagov/drugsatfda_docs/label/2007/020415s019,021208s010lblpdf
10. Yoon WT. Hyperkinetic movement disorders induced by mirtazapine: Unusual case report and clinical analysis of reported cases J Psychiatry. 2018;21:1000437
11. Jankovic J, Tolosa E Parkinson's Disease and Movement Disorders. 2007 Philadelphia, PA, USA Lippincott Williams and Wilkins
12. Association AP. Diagnostic and Statistical Manual of Mental Disorders (DSM-5®). 2013 Arlington, VA, US American Psychiatric Pub
13. Naranjo CA, Busto U, Sellers EM, Sandor P, Ruiz I, Roberts EA, et al A method for estimating the probability of adverse drug reactions Clin Pharmacol Ther. 1981;30:239–45
14. De Vries E, Schoonvelde M, Schumacher G. No longer lost in translation: Evidence that google translate works for comparative bag-of-words text applications Polit Anal. 2018;26:417–30
15. Ruigt GS, Kemp B, Groenhout CM, Kamphuisen HA. Effect of the antidepressant Org 3770 on human sleep Eur J Clin Pharmacol. 1990;38:551–4
16. Montgomery SA. Safety of mirtazapine: A review Int Clin Psychopharmacol. 1995;10(Suppl 4):37–45
17. Markkula J, Lauerma H. Mirtazapine-induced restless legs Human Psychopharmacol Clin Exp. 1997;12:497–9
18. Bonin B, Vandel P, Kantelip JP. Mirtazapine and restless leg syndrome: A case report Therapie. 2000;55:655–6
19. Bahk WM, Pae CU, Chae JH, Jun T, Kim KS, Lew TY. A case of mirtazapine induced restless legs syndrome Korean J Psychopharmacol. 2001;12:147–50
20. Lee SH, Nam M, Chung YC. Three cases of mirtazapine iduced Aakathisia J Korean Soc Biol Psychiatry. 2001;8:162–6
21. Agargün MY, Kara H, Ozbek H, Tombul T, Ozer OA. Restless legs syndrome induced by mirtazapine J Clin Psychiatry. 2002;63:1179
22. Girishchandra BG, Johnson L, Cresp RM, Orr KG. Mirtazapine-induced akathisia Med J Aust. 2002;176:242
23. Lu R, Hurley AD, Gourley M. Dystonia induced by mirtazapine J Clin Psychiatry. 2002;63:452–3
24. Teive H, de Quadros A, Barros FC, Werneck LC. Sindrome das pernas inquietas com heranca autossomica dominante piorada pelo uso de mirtazapina: Relato de caso Arq Neuropsiquiatr. 2002;60:1025–9
25. ADRAC. Australina Adverse Drug Reactions Bulletin Woden Valley. 2003Last accessed on 2020 Jan 21 Australia ADRAC Available from: https://wwwtgagovau/publication-issue/australian-adverse-drug-reactions-bulletin-vol-22-no-5
26. Onofrj M, Luciano AL, Thomas A, Iacono D, D'Andreamatteo G. Mirtazapine induces REM sleep behavior disorder (RBD) in parkinsonism Neurology. 2003;60:113–5
27. Pae C, Kim TS, Kim JJ, Chae JH, Lee CU, Lee SJ, et al Re-administration of mirtazapine could overcome previous mirtazapine-associated restless legs syndrome? Psychiatry Clin Neurosci. 2004;58:669–70
28. Brown LK, Dedrick DL, Doggett JW, Guido PS. Antidepressant medication use and restless legs syndrome in patients presenting with insomnia Sleep Med. 2005;6:443–50
29. Kim SW, Lee JY, Shin IS, Kim JM, Yang SJ, Yoon JS. A single low dose of mirtazapine can induce restless legs syndrome: Report of two cases Korean J Psychopharmacol. 2005;16:169–73
30. Konitsiotis S, Pappa S, Mantas C, Mavreas V. Acute reversible dyskinesia induced by mirtazapine Mov Disord. 2005;20:771
31. van den Bosch S, Bouckaert F, Peuskens J. Mirtazapine-induced dystonia in a patient with Alzheimer's disease. A case study Tijdschr Psychiatr. 2006;48:153–7
32. Chang CC, Shiah IS, Chang HA, Mao WC. Does domperidone potentiate mirtazapine-associated restless legs syndrome? Prog Neuropsychopharmacol Biol Psychiatry. 2006;30:316–8
33. Freynhagen R, Muth-Selbach U, Lipfert P, Stevens MF, Zacharowski K, Tölle TR, et al The effect of mirtazapine in patients with chronic pain and concomitant depression Curr Med Res Opin. 2006;22:257–64
34. Prospero-Garcia KA, Torres-Ruiz A, Ramirez-Bermudez J, Velazquez-Moctezuma J, Arana-Lechuga Y, Teran-Perez G. Fluoxetine-mirtazapine interaction may induce restless legs syndrome: Report of 3 cases from a clinical trial J Clin Psychiatry. 2006;67:1820
35. Wålinder J, Prochazka J, Odén A, Sjödin I, Dahl ML, Ahlner J, et al Mirtazapine naturalistic depression study (in Sweden) — MINDS (S): Clinical efficacy and safety Hum Psychopharmacol. 2006;21:151–8
36. Gulsun M, Doruk A. Mirtazapine-induced akathisia J Clin Psychopharmacol. 2008;28:467
37. Kim SW, Shin IS, Kim JM, Park KH, Youn T, Yoon JS. Factors potentiating the risk of mirtazapine-associated restless legs syndrome Hum Psychopharmacol. 2008;23:615–20
38. Ozyildirim I, Kosecioglu S. P01-119 mirtazapine induced tardive akathisia: A case report Eur Psychiatry. 2009;24:S507
39. Park YM, Lee HJ, Kang SG, Cho JH, Kim L. Resolution of pregabalin and mirtazapine associated restless legs syndrome by bupropion in a patient with major depressive disorder Psychiatry Investig. 2009;6:313–5
40. Rottach KG, Schaner BM, Kirch MH, Zivotofsky AZ, Teufel LM, Gallwitz T, et al Restless legs syndrome as side effect of second generation antidepressants J Psychiatr Res. 2008;43:70–5
41. Balaz M, Rektor I. Gradual onset of dyskinesia induced by mirtazapine Neurol India. 2010;58:672–3
42. Madhusoodanan S, Alexeenko L, Sanders R, Brenner R. Extrapyramidal symptoms associated with antidepressants – A review of the literature and an analysis of spontaneous reports Ann Clin Psychiatry. 2010;22:148–56
43. Markoula S, Konitsiotis S, Chatzistefanidis D, Lagos G, Kyritsis AP. Akathisia induced by mirtazapine after 20 years of continuous treatment Clin Neuropharmacol. 2010;33:50–1
44. Bondon-Guitton E, Perez-Lloret S, Bagheri H, Brefel C, Rascol O, Montastruc JL. Drug-induced parkinsonism: A review of 17 years' experience in a regional pharmacovigilance center in France Mov Disord. 2011;26:2226–31
45. Chopra A, Pendergrass DS, Bostwick JM. Mirtazapine-induced worsening of restless legs syndrome (RLS) and ropinirole-induced psychosis: Challenges in management of depression in RLS Psychosomatics. 2011;52:92–4
46. Mattoo SK, Mahajan S, Sarkar S, Nebhinani N. PLMD-like nocturnal movements with mirtazapine Gen Hosp Psychiatry. 2013;35:576e7–8
47. Fulda S, Kloiber S, Dose T, Lucae S, Holsboer F, Schaaf L, et al Mirtazapine provokes periodic leg movements during sleep in young healthy men Sleep. 2013;36:661–9
48. Méndez Guerrero A, Llamas S, Murcia FJ, Ruíz J. Acute Pisa syndrome after administration of a single dose of mirtazapine Clin Neuropharmacol. 2013;36:133–4
49. Liu YW, Tai YM, Cheng YM. Tics induced by mirtazapine in a young patient Taiwan J Psychiatry (Taipei). 2014;28:186–7
50. Makiguchi A, Nishida M, Shioda K, Suda S, Nisijima K, Kato S. Mirtazapine-induced restless legs syndrome treated with pramipexole J Neuropsychiatry Clin Neurosci. 2015;27:e76
51. Raveendranathan D, Swaminath GR. Mirtazapine induced akathisia: Understanding a complex mechanism Indian J Psychol Med. 2015;37:474–5
52. Hong JY, Sunwoo MK, Oh JS, Kim JS, Sohn YH, Lee PH. Persistent drug-induced parkinsonism in patients with normal dopamine transporter imaging PLoS One. 2016;11:e0157410
53. Volkan Solmaz EE, Erbaş O. Restless leg syndrome developing due to usage of mirtazapine and paroxetine FNG and Bilim Tı Dergisi. 2016;2:60–2
54. Sung YH, Noh Y, Lee J, Kim EY. Drug-induced parkinsonism versus idiopathic parkinson disease: Utility of nigrosome 1 with 3-T imaging Radiology. 2016;279:849–58
55. Espi Forcen F, Root JC, Alici Y. Antipsychotic-induced akathisia in cancer settings Psychooncology. 2017;26:1053–6
56. Odabaş FÖ, Uca AU. Is there any association between antidepressants and restless legs syndrome in a large Turkish population receiving mono or combined treatment? A cross-sectional comparative study Psychiatry Clin Psychopharmacol. 2019;29:565–9
57. Yamada Y, Takano H, Yamada M, Satake N, Hirabayashi N, Okazaki M, et al Pisa syndrome associated with mirtazapine: A case report BMC Pharmacol Toxicol. 2018;19:82
58. Hsu YC, Yang HY, Huang WT, Chen SC, Lee HS. Use of antidepressants and risks of restless legs syndrome in patients with irritable bowel syndrome: A population-based cohort study PLoS One. 2019;14:e0220641
59. Hutchins D, Hall J, Sharma A. Mirtazapine-induced transient dyskinesia Prim Care Companion CNS Disord. 2019;21:18l02377
60. Koller K. Propranolol for mirtazapine-induced akathisia: Single case report Ment Health Clin. 2019;9:61–3
61. Ocak D, Kotan VO, Paltun SC, Aydemir MÇ. Is restless legs syndrome related with depression/anxiety disorders or medications used in these disorders? A cross-sectional, clinic-based study Psychiatry Clin Psychopharmacol. 2019;29:832–9
62. Yatri Patel NC, Darji VM, Shah ND. Restless Leg Syndrome (RLS) caused by mirtazapine, improved with pramipexole Indian J Psychiatry. 2019;61(Suppl 3):S521–631
63. Uvais NA, Sreeraj VS, Shihabudheen P, Mohammed TP. Mirtazapine induced tremors: A case report Indian J Psychol Med. 2019;41:190–2
64. Ya ND. Restless leg syndrome developing due to usage of mirtazapine Klinik Psikofarmakoloji Bulteni. 2019;29:241
65. Rissardo JP, Caprara AL. Cervical and axial dystonia secondary to mirtazapine: A case report and literature review Ann Mov Disord. 2020;3:47–50
66. Alam A, Voronovich Z, Carley JA. A review of therapeutic uses of mirtazapine in psychiatric and medical conditions Prim Care Companion CNS Disord. 2013;15 PCC13r01525
67. Administration FD. The FDA Adverse Event Reporting System (FAERS) Food and Drug Administration. 2019Last accessed on 2020 Jan 21 Available from: https://fisfdagov/hub/stream
68. Schatzberg AF, Kremer C, Rodrigues HE, Murphy GM Jr. Mirtazapine vs Paroxetine Study Group.Double-blind, randomized comparison of mirtazapine and paroxetine in elderly depressed patients Am J Geriatr Psychiatry. 2002;10:541–50
69. Benjamin S, Doraiswamy PM. Review of the use of mirtazapine in the treatment of depression Expert Opin Pharmacother. 2011;12:1623–32
70. Ikoma K, Samii A, Mercuri B, Wassermann EM, Hallett M. Abnormal cortical motor excitability in dystonia Neurology. 1996;46:1371–6
71. Serrats J, Mengod G, Cortés R. Expression of serotonin 5-HT2C receptors in GABAergic cells of the anterior raphe nuclei J Chem Neuroanat. 2005;29:83–91
72. Devoto P, Flore G, Pira L, Longu G, Gessa GL. Mirtazapine-induced corelease of dopamine and noradrenaline from noradrenergic neurons in the medial prefrontal and occipital cortex Eur J Pharmacol. 2004;487:105–11
73. Zhang G, Stackman RW Jr. The role of serotonin 5-HT2A receptors in memory and cognition Front Pharmacol. 2015;6:225
74. Barre A, Berthoux C, De Bundel D, Valjent E, Bockaert J, Marin P, et al Presynaptic serotonin 2A receptors modulate thalamocortical plasticity and associative learning Proc Natl Acad Sci U S A. 2016;113:E1382–91
75. Rissardo JP, Caprara AL. Comment: Dystonia and asterixis in acute thalamic infarct: Proposed mechanism Ann Mov Disord. 2019;2:138
76. Krystkowiak P, Martinat P, Defebvre L, Pruvo JP, Leys D, Destée A. Dystonia after striatopallidal and thalamic stroke: Clinicoradiological correlations and pathophysiological mechanisms J Neurol Neurosurg Psychiatry. 1998;65:703–8
77. Mitchell IJ, Luquin R, Boyce S, Clarke CE, Robertson RG, Sambrook MA, et al Neural mechanisms of dystonia: Evidence from a 2-deoxyglucose uptake study in a primate model of dopamine agonist-induced dystonia Mov Disord. 1990;5:49–54
78. Picchietti D, Winkelman JW. Restless legs syndrome, periodic limb movements in sleep, and depression Sleep. 2005;28:891–8
79. Patatanian E, Claborn MK. Drug-induced Restless Legs Syndrome Ann Pharmacother. 2018;52:662–72
80. Ferré S, García-Borreguero D, Allen RP, Earley CJ. New insights into the neurobiology of Restless Legs Syndrome Neuroscientist. 2019;25:113–25
81. An Y, Chen C, Inoue T, Nakagawa S, Kitaichi Y, Wang C, et al Mirtazapine exerts an anxiolytic-like effect through activation of the median raphe nucleus-dorsal hippocampal 5-HT pathway in contextual fear conditioning in rats Prog Neuropsychopharmacol Biol Psychiatry. 2016;70:17–23
82. Appel NM, Elde RP. The intermediolateral cell column of the thoracic spinal cord is comprised of target-specific subnuclei: Evidence from retrograde transport studies and immunohistochemistry J Neurosci. 1988;8:1767–75
83. Yamamura S, Abe M, Nakagawa M, Ochi S, Ueno S, Okada M. Different actions for acute and chronic administration of mirtazapine on serotonergic transmission associated with raphe nuclei and their innervation cortical regions Neuropharmacology. 2011;60:550–60
84. Cui SY, Li SJ, Cui XY, Zhang XQ, Yu B, Huang YL, et al Ca2+ in the dorsal raphe nucleus promotes wakefulness via endogenous sleep-wake regulating pathway in the rats Mol Brain. 2016;9:71
85. Aggarwal S, Dodd S, Berk M. Restless leg syndrome associated with atypical antipsychotics: Current status, pathophysiology, and clinical implications Curr Drug Saf. 2015;10:98–105
86. Poewe W, Högl B. Akathisia, restless legs and periodic limb movements in sleep in Parkinson's disease Neurology. 2004;63:S12–6
87. Stahl SM, Lonnen AJ. The Mechanism of Drug-induced Akathsia CNS Spectr. 2011;16:7–10
88. Hurd YL, Suzuki M, Sedvall GC. D1 and D2 dopamine receptor mRNA expression in whole hemisphere sections of the human brain J Chem Neuroanat. 2001;22:127–37
89. Dalley JW, Mar AC, Economidou D, Robbins TW. Neurobehavioral mechanisms of impulsivity: Fronto-striatal systems and functional neurochemistry Pharmacol Biochem Behav. 2008;90:250–60
90. Pandey S, Srivanitchapoom P. Levodopa-induced dyskinesia: Clinical features, pathophysiology, and medical management Ann Indian Acad Neurol. 2017;20:190–8
91. Cornett EM, Novitch M, Kaye AD, Kata V, Kaye AM. Medication-induced tardive dyskinesia: A review and update Ochsner J. 2017;17:162–74
92. Lepping P, Delieu J, Mellor R, Williams JH, Hudson PR, Hunter-Lavin C. Antipsychotic medication and oxidative cell stress: A systematic review J Clin Psychiatry. 2011;72:273–85
93. Barone DA, Raniolo J. Facial dyskinesia from overdose of an antihistamine N Engl J Med. 1980;303:107
94. Blandina P, Munari L, Provensi G, Passani MB. Histamine neurons in the tuberomamillary nucleus: A whole center or distinct subpopulations? Front Syst Neurosci. 2012;6:33
95. Herbert R. Shaking when stirred: Mechanisms of physiological tremor J Physiol. 2012;590:2549
96. Shuman M, Chukwu A, Van Veldhuizen N, Miller SA. Relationship between mirtazapine dose and incidence of adrenergic side effects: An exploratory analysis Ment Health Clin. 2019;9:41–7
97. Ohayon MM, Roth T. Prevalence of restless legs syndrome and periodic limb movement disorder in the general population J Psychosom Res. 2002;53:547–54

Drug-induced; Mirtazapine; Movement disorder; Org 3770; Review

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