Introduction
Dystonia is “a movement disorder (MD) characterized by involuntary sustained or intermittent muscle contractions, causing abnormal, often repetitive, movements, postures, or both” [Reference Albanese, Bhatia, Bressman, Delong, Fahn and Fung1–Reference Klein and Fahn7]. It is the third most common MD after essential tremor and Parkinson’s disease [Reference Grütz and Klein2, Reference Pana and Saggu8, Reference Stephen9] and can affect any muscle group in the body (see Table 1) [Reference Albanese, Bhatia, Bressman, Delong, Fahn and Fung1, Reference Grütz and Klein2, Reference Snaith and Derick4, Reference Rissardo, Vora, Mathew, Kashyap, Muhammad and Fornari Caprara10]. Focal dystonias are the most common forms seen in clinical practice, involving the neck (cervical dystonia), the eyes (oculogyric crisis), the larynx (laryngeal dystonia), the mouth and jaw (oromandibular dystonia), or the limb (limb dystonia) [Reference Rissardo, Vora, Mathew, Kashyap, Muhammad and Fornari Caprara10–Reference Karp and Alter12]. Prevalence rates seem to be higher in female individuals for most types of dystonia [Reference Kilic-Berkmen, Scorr, McKay, Thayani, Donsante and Perlmutter13].
Table 1. Classification of dystonia by body region [Reference Albanese, Bhatia, Bressman, Delong, Fahn and Fung1, Reference Grütz and Klein2, Reference Dressler, Altenmüller, Giess, Krauss and Adib Saberi11].
Dystonia may be inherited, idiopathic, or acquired [Reference Albanese, Bhatia, Bressman, Delong, Fahn and Fung1, Reference Grütz and Klein2, Reference van Egmond, Lagrand, Lizaitiene, Smit and Tijssen5]. Acquired dystonias result from apparent outside factors and can be attributed to a specific cause, such as medications [Reference Grütz and Klein2, Reference van Egmond, Lagrand, Lizaitiene, Smit and Tijssen5, 14]. Medications most commonly associated with this type of MD are antipsychotics [Reference van Egmond, Lagrand, Lizaitiene, Smit and Tijssen5, Reference Rissardo, Vora, Mathew, Kashyap, Muhammad and Fornari Caprara10, Reference Chouksey and Pandey15, Reference Park, Kwak and Lee16]. However, dystonia may also occur with many other kinds of medication, such as antidepressants, lithium, antiepileptics, and calcium channel blockers [Reference Albanese, Bhatia, Bressman, Delong, Fahn and Fung1, 14, Reference Chouksey and Pandey15, Reference Friedman17–Reference Dressler19]. Medication-induced dystonia (MID) can be acute (occurring within hours to days of exposure to the drug), subacute (building up more slowly after days to weeks of exposure), or tardive [following long-term therapy (months-years) with the offending drug] [Reference Rissardo, Vora, Mathew, Kashyap, Muhammad and Fornari Caprara10, Reference Duma and Fung20–Reference Steeves, Day, Dykeman, Jette and Pringsheim30]. MID mostly resolves within a few hours or days with adequate treatment. However, in some cases, it can be persistent [Reference Rissardo, Vora, Mathew, Kashyap, Muhammad and Fornari Caprara10].
Existing lacunae in understanding the epidemiology and phenomenology of MID face clinicians with substantial challenges in the diagnosis and management of this drug-induced MD [Reference O’Neill and Stephenson31–Reference Caroff, Hurford, Lybrand and Campbell33]. MID may be confused with different conditions such as partial seizure, encephalitis, tetanus, hysteria, or panic attacks. In exceptional cases (i.e. acute laryngeal dystonia), misdiagnosis can lead to a life-threatening situation [Reference Park, Kwak and Lee16, Reference Collins and Sager23, Reference Alkharboush and Alsalamah34–Reference Christodoulou and Kalaitzi37]. Early identification, therefore, is essential.
Until now, no extensive review on the epidemiology and phenomenology of MID across different non-antipsychotic medication groups has been conducted. Our objective therefore is to identify published evidence-based literature on the epidemiology and phenomenology of non-antipsychotic-induced dystonia in people without pre-existing MD by using a hybrid systematic-narrative strategy. This approach builds on the main components of both systematic and narrative reviews [Reference Turnbull, Chugh and Luck38].
Methods
The protocol of this systematic-narrative review has been registered with the Open Science Framework initiative (https://osf.io/uvpbn/).
Search strategy
A comprehensive and systematic literature search (from inception to November 2023), using the PubMed and Embase databases, was conducted without language restriction for articles reporting on non-antipsychotic-induced dystonia in people without pre-existing MDs. One of the authors (JD) constructed search strings for both databases. Generic and brand drug names were used to identify cases of non-antipsychotic dystonia. Full search strategies are available as Supplementary Material. Articles, identified through PubMed and Embase, were imported into EndNote X9 and duplicates were removed [Reference Bramer, Giustini, de Jonge, Holland and Bekhuis39]. After removing duplicates, titles and abstracts were screened by JD, using Rayyan QCRI. Articles that were deemed potentially relevant were selected. JD reviewed the full text of the selected articles and assessed their eligibility. Any doubts were solved by consensus or by the decision of a second and third reviewer (MDH, KC).
Selection criteria
All types of study designs were eligible for inclusion. Although observational studies, case series, and case reports have lower levels of evidence, we found it important to implement this kind of evidence, as (randomized) clinical trials have limited power to detect rarer events, such as motor side effects [Reference Straus, Glasziou, Richardson, Haynes, Pattani and Veroniki40, Reference Stämpfli, Weiler and Burden41]. Only articles providing information on the epidemiology and phenomenology of non-antipsychotic-induced dystonia in people (children, adolescents, adults, and elderly) without a pre-existing MD were selected. A narrative synthesis of the systematically retrieved eligible articles was made.
Results
The search yielded 58,326 articles. After removing duplicates (n = 39,662) a total of 718 systematic reviews and/or meta-analyses and 17,946 other records were screened for eligibility. Of these 40 systematic reviews and/or meta-analyses and 1,998 other records were identified as eligible.
For each non-antipsychotic medication group we will discuss, if this information is available, (1) epidemiology, (2) phenomenology [onset and form(s) of dystonia], (3) risk factors, and (4) agents that are specifically associated with an increased risk for dystonia. Among risk factors, race or ethnicity are not discussed as potential moderators. Although there are some studies that have indicated that for certain medications Asian patients may be more likely to experience MID, this has not been systematically studied.
Antiemetics and gastrointestinal drugs
Antiemetics are widely used to treat nausea and vomiting that can be caused by a variety of medical conditions and situations, such as chemotherapy, surgery, migraine, and pregnancy [42–Reference Kwon, Rudkin and Langdorf49].
Metoclopramide can induce the entire phenomenological spectrum of dystonia, even with a single low dose [Reference Park, Kwak and Lee16, Reference Wijemanne, Jankovic and Evans24, Reference Fink, Bognar, Hengl, Paulmichl and Nofziger50–Reference Colman, Brown, Innes, Grafstein, Roberts and Rowe66]. Metoclopramide-induced acute dystonia has been seen in 0.2% up to 8.3% of adult cases [Reference Wijemanne, Jankovic and Evans24, Reference Kelley and Tepper44, Reference Chaudhary, Malla and Kadayat55, Reference Bateman, Rawlins and Simpson57, Reference Lee and Kuo59, Reference Šarac, Šarac, Božina, Šimičević, Borovečki and Henigsberg67–Reference Lau Moon Lin, Robinson, Flank, Sung and Dupuis76]. The risk can even be higher in children and elderly [54, Reference Valkova, Stamenov, Peychinska, Veleva, Dimitrova and Radeva70, Reference Olsen, Keng and Clark77], and is increased at higher doses or with long-term treatment [Reference Sheikh Hassan and Ahmed Nor75]. It typically occurs within 24–48 h of initiating treatment [Reference Lee and Kuo59].
Given the known risk of MID with metoclopramide, particularly with chronic use or in young people, the European Medicines Agency (EMA) and the Food and Drug Administration (FDA) restricted the indications for metoclopramide to short-term use (up to 5 days). In children, it should only be used as a second-choice treatment [78, Reference Nagel, Ghika, Runge, Wolf and Krauss79]. Metoclopramide (primarily metabolized by the cytochrome P450 enzyme CYP2D6) dosing should also be reduced in CYP2D6 poor metabolizers. It therefore should not be co-administered with strong CYP2D6 inhibitors [Reference Fink, Bognar, Hengl, Paulmichl and Nofziger50, Reference Zhou, Yan, Zhang, Pan and Zeng80–Reference van der Padt, van Schaik and Sonneveld83].
Acute or subacute dystonic reactions with prochlorperazine, first introduced as an antipsychotic in the 1950s [Reference Manteuffel84], are seen in up to 4% of cases [Reference Kirkpatrick, Sogawa and Cleves68, Reference Olsen, Keng and Clark77, Reference Golikhatir, Cheraghmakani, Bozorgi, Jahanian, Sazgar and Montazer85].
Several studies and case reports reported promethazine-induced acute dystonia in children and in pregnant women hospitalized for hyperemesis gravidarum [Reference Southard and Al Khalili86–Reference Malamed94]. Promethazine seems to be associated with a higher risk for dystonia, compared to metoclopramide [Reference Tan, Khine, Vallikkannu and Omar92, Reference Boelig, Barton, Saccone, Kelly, Edwards and Berghella93], sometimes inducing severe acute dystonic reactions (e.g. opisthotonus) in overdose cases [Reference Darwish, Grant, Haslam and Roth90]. In 2000, a warning section was added to the medication package insert stating that promethazine is contraindicated in children less than 2 years of age [Reference Starke, Weaver and Chowdhury91].
Dystonia is a very rare complication when using domperidone (0.01%), as it does not traverse the blood–brain barrier, unlike metoclopramide. Domperidone-induced acute dystonia usually occurs in infants and very young children (due to the poorly developed blood–brain barrier) or in the elderly [Reference Daripa and Lucchese45, Reference Shahbaz, Elahi, Affan, Shahid and Sabir46, Reference Junqueira, Bennett, Huh, Fahrbach, Neupane and Betts95–Reference Tonini, Cipollina, Poluzzi, Crema, Corazza and De Ponti98].
At recommended clinical dosages, dystonic reactions associated with levosulpiride occur in less than 1% [Reference Tonini, Cipollina, Poluzzi, Crema, Corazza and De Ponti98–Reference Choudhury, Chatterjee, Singh, Shubham, Trivedi and Chatterjee101]. Levosulpiride-induced MDs seem to occur more frequently in the elderly, requiring strict pharmacovigilance [Reference Anand, Pandey and Garg102, Reference Radhakrishnan and Goyal103]. In exceptional cases, even the use of low-dose levosulpiride can lead to persistent dystonia [104, Reference Radhakrishnan and Goyal105].
Although uncommon, some setrons also have also been associated with acute dystonic reactions in adults, as well as children. Ondansetron, for example, can induce the entire phenomenological spectrum of dystonia [Reference Kwon, Rudkin and Langdorf49, Reference Barow, Schneider, Bhatia and Ganos65, Reference Aggarwal and Bhatt106–Reference Tolan, Fuhrman, Tsueda and Lippmann120].
Clebopride, a dopamine receptor blocking agent (DRBA) which is 10 times more potent than metoclopramide [Reference Tolan, Fuhrman, Tsueda and Lippmann120] but marketed only in some countries, is associated with the occurrence of different types of dystonic reactions (oromandibular dystonia, blepharospasm, torticollis) [Reference Choi and Hong48, Reference Barow, Schneider, Bhatia and Ganos65, Reference Tonini, Cipollina, Poluzzi, Crema, Corazza and De Ponti98, Reference Seo, Ko, Jang and Kim121–Reference Corominas Sánchez, Lleonart Bellfill and Pujol Farriols126], particularly in younger people, even after one single dose [Reference Seo, Ko, Jang and Kim121].
Droperidol-induced acute dystonia has, with the exception of few, been reported in several studies [Reference Ramsden, Pergjika, Janssen, Mudahar, Fawcett and Walkup127–Reference Bak, Weltens, Bervoets, De Fruyt, Samochowiec and Fiorillo133] and case reports [Reference Barow, Schneider, Bhatia and Ganos65, Reference Berna, Timbolschi, Diemunsch and Vidailhet134–Reference Arrowsmith and Gams138] and can be severe and persistent [Reference Walker and Samii136].
Other commonly used antiemetics or gastrointestinal drugs that have been rarely associated with dystonic reactions are cimetidine, ranitidine, cyclizine, and cisapride [Reference Fink, Bognar, Hengl, Paulmichl and Nofziger50, Reference Aggarwal and Bhatt106, Reference Dieckmann, Maurage, Rolland, Ramponi and Jonville108, Reference Duarte and Teive139–Reference Romisher, Felter and Dougherty148].
Antiepileptics
Antiepileptics (also known as antiseizure medications or anticonvulsants) are commonly prescribed for epilepsy/seizures prophylaxis or management, as well as for many other indications, such as bipolar disorder, anxiety, migraine, chronic pain, weight management, and insomnia [Reference Cascade, Kalali and Weisler149].
The relationship between antiepileptics and MDs is complex. Although antiepileptics are used as a treatment for hyperkinetic MDs (specifically for tremor, myoclonus, and restless legs syndrome), several also have the potential to induce or worsen MDs, including dystonia [Reference Sáenz-Farret, Tijssen, Eliashiv, Fisher, Sethi and Fasano150, Reference Zhou, Pavuluri, Snehal, Schmidt, Situ-Kcomt and Taraschenko151]. Four of these have been rarely (0.01 to 0.1%) associated with dystonia: valproate, carbamazepine, lamotrigine, and phenytoin. There have been more reports of MID with these agents in the middle-aged adult population.
Valproate is generally regarded as a first-choice agent for most forms of epilepsy, but it is also used to treat manic episodes, and as a medication for migraine prevention and impulse control [Reference Muralidharan, Rahman, Banerjee, Hakim Mohammed and Malik152]. Although tremor and parkinsonism are well-known side effects of valproate [Reference Sáenz-Farret, Tijssen, Eliashiv, Fisher, Sethi and Fasano150, Reference Zhou, Pavuluri, Snehal, Schmidt, Situ-Kcomt and Taraschenko151, Reference Baizabal-Carvallo and Morgan153–Reference Zhang, He, Hu and Sun155], dystonic reactions, most often subacute (> 3 weeks) and presenting as axial and cervical dystonia, have also been reported [Reference Zhou, Pavuluri, Snehal, Schmidt, Situ-Kcomt and Taraschenko151, Reference Rissardo, Caprara and Durante154]. Possible interactions with clozapine, risperidone, quetiapine, olanzapine, carbamazepine, ziprasidone, and butamirate citrate have been described [Reference Rissardo, Caprara and Durante154].
Particularly children and adolescents seem to be susceptible to the development of carbamazepine-induced dystonia [Reference Rissardo and Caprara156]. A recent systematic review identified 22 cases of carbamazepine-induced, mostly subacute (> 3 weeks), dystonia [Reference Zhou, Pavuluri, Snehal, Schmidt, Situ-Kcomt and Taraschenko151]. Generalized or segmental dystonia and oculogyric crises have been reported within normal and toxic plasma concentrations of carbamazepine. The combination of carbamazepine and isoniazid or lithium has been reported to induce oculogyric crisis and severe dystonic movements, including opisthotonos [Reference Sáenz-Farret, Tijssen, Eliashiv, Fisher, Sethi and Fasano150].
Lamotrigine, also used as a mood stabilizer for the treatment of bipolar disorder, most often is associated with the subacute (> 3 weeks) manifestation of blepharospasms, oculogyric crises, and oromandibular dystonia [Reference Sáenz-Farret, Tijssen, Eliashiv, Fisher, Sethi and Fasano150, Reference Zhou, Pavuluri, Snehal, Schmidt, Situ-Kcomt and Taraschenko151, Reference Rissardo and Fornari Caprara157].
Mostly subacute (> 3 weeks) dystonic reactions have been reported with phenytoin at therapeutic and toxic serum levels [Reference Chouksey and Pandey15, Reference Zhou, Pavuluri, Snehal, Schmidt, Situ-Kcomt and Taraschenko151, Reference Rissardo and Caprara158–Reference Rajkumar, Manokaran, Shubha and Shruthi161]. The most common presentation seems to be upper limb dystonia.
Dystonia, although very rarely (<0.01%), has also been reported in association with other antiepileptics (see Table 2 for an overview of these antiepileptics), sometimes related to polymedication [Reference Wolańczyk and Grabowska-Grzyb162–Reference Peacock, Yoneda, Siever, Vis-Dunbar and Boelman164].
Table 2. Higher risk medications that require special attention from healthcare professionals.
1 Very common (≥10%); common (≥1% to <10%); uncommon (≥0,1% to <1%); rare (≥0,01% to <0,1%).
Antidepressants
Selective serotonin reuptake inhibitors (SSRIs) and serotonin and norepinephrine reuptake inhibitors (SNRIs) are the most commonly prescribed types of antidepressant medication [Reference Edinoff, Akuly, Hanna, Ochoa, Patti and Ghaffar165, Reference Hawthorne and Caley166]. These medications have a number of approved indications (such as major depression, obsessive compulsive disorder, and anxiety disorders) [Reference Erden and Ferahkaya167, Reference Gupta, Ahmad, Kar and Shrivastava168], but are frequently used off-label as well. Tricyclic antidepressants (TCAs) and monoamine oxidase inhibitors (MAOIs) are prescribed less often because they tend to cause more side effects.
Although uncommon, cases of antidepressant-induced acute and tardive dystonia have been observed and reported for decades [Reference Barow, Schneider, Bhatia and Ganos65, Reference Duarte and Teive139, Reference Hawthorne and Caley166, Reference Gupta, Ahmad, Kar and Shrivastava168–Reference Leo180]. These side effects are seen more often with SSRIs than with SNRI’s, TCAs, MAOIs, or other antidepressants [Reference Hiremath and Desai169, Reference Revet, Montastruc, Roussin, Raynaud, Lapeyre-Mestre and Nguyen173, Reference Carvalho, Sharma, Brunoni, Vieta and Fava181, Reference Gill, DeVane and Risch182].
Selective serotonin reuptake inhibitors (SSRIs)
According to a review of Hawthorne & Caley [Reference Hawthorne and Caley166], citalopram, escitalopram, fluoxetine, and sertraline are most frequently involved in dystonia cases. In 63% of the cases, dystonia occurred mostly subacute within 7 days of treatment initiation or dose increase (although acute or tardive dystonia cases have also been observed). Most cases of dystonia occurred in adult patients who have been receiving normal dosing and when a DRBA (mostly an antipsychotic) was added to the SSRI. Cases across the whole spectrum of dystonic reactions were observed. After the publication of this review several new cases of MID have been reported with sertraline and escitalopram, mostly in the adult population [Reference Erden and Ferahkaya167, Reference Gupta, Ahmad, Kar and Shrivastava168, Reference Uvais, Sreeraj and Sathish Kumar174, Reference Raveendranathan and Rao175, Reference Šarac, Šarac, Henigsberg, Borovečki, Božina and Pašić183–Reference Caffrey, Sowden and Arsan186], but some of these also in the pediatric and adolescent population [Reference Erden and Ferahkaya167, Reference Kutuk, Güler Aksu, Tufan and Celik187–Reference Ayaydın and Bozkurt189].
An analysis of the WHO pharmacovigilance database found that the SSRIs fluoxetine, fluvoxamine, and paroxetine were statistically significantly associated with dystonia [Reference Revet, Montastruc, Roussin, Raynaud, Lapeyre-Mestre and Nguyen173].
Serotonin and norepinephrine reuptake inhibitors (SNRIs)
Without providing specific information on dystonia cases, an analysis of FDA Adverse Event Reporting System cases [Reference Madhusoodanan, Alexeenko, Sanders and Brenner177], as well as a large epidemiological study [Reference Guo, Etminan, Procyshyn, Kim, Samii and Kezouh190] identified the SNRI duloxetine as the antidepressant showing the highest association with EPS, compared with other antidepressants. A more recent analysis of MID reports in the WHO Pharmacovigilance database [Reference Revet, Montastruc, Roussin, Raynaud, Lapeyre-Mestre and Nguyen173], however, showed no statistically significant association between duloxetine and dystonia.
Serotonin receptor antagonist and reuptake inhibitors (SARIs)
Trazodone, the prototype drug of this class of drugs, is approved for the treatment of major depressive disorder but is also commonly used off-label to treat insomnia or delirium, particularly in the elderly [Reference Skarmeta, Katzmann, Valdés, Gaedechens and Montini170, Reference Kadota, Hori, Takayama, Okabe and Ohara191]. Although only few cases have been reported in the scientific literature [Reference Skarmeta, Katzmann, Valdés, Gaedechens and Montini170, Reference Kadota, Hori, Takayama, Okabe and Ohara191–Reference Kramer, Marcus, DiFerdinando and Dewey194], clinicians should be aware that long-term use of trazodone as a hypnotic, particularly when combined with an antipsychotic, such as risperidone, can cause tardive dystonia in elderly patients [Reference Kadota, Hori, Takayama, Okabe and Ohara191].
Serotonin and norepinephrine disinhibitors (SNDIs)
A literature review on mirtazapine, primarily used for the treatment of major depressive disorder, but also for several other off-label indications such as insomnia, migraine, and hot flushes, identified only five cases of dystonia (particularly in the elderly) [Reference Rissardo and Caprara195].
Tricyclic antidepressants (TCAs)
Although less common than with SSRIs, dystonia cases have been reported with the TCAs amitriptyline, amoxapine, doxepin, imipramine, and clomipramine [Reference Barow, Schneider, Bhatia and Ganos65, Reference Revet, Montastruc, Roussin, Raynaud, Lapeyre-Mestre and Nguyen173, Reference Gill, DeVane and Risch182, Reference Thour and Marwaha196–Reference Allsbrook, Fries, Szafara and Regal198]. According to a review of 48 reports, examining the link between amitriptyline and MDs, patients with amitriptyline-induced dystonia (n = 19) tended to be younger and were prescribed a lower dose of amitriptyline [Reference Rissardo and Caprara197]. A postmarketing study in the world pharmacovigilance database [Reference Revet, Montastruc, Roussin, Raynaud, Lapeyre-Mestre and Nguyen173] found that amoxapine is the TCA associated with the highest risk for dystonia. It may induce several forms of subacute and tardive dystonia, including cervical dystonia and oculogyric crisis [Reference Hayashi, Ohyagi, Inoue, Arakawa, Taniwaki and Nakagawa199–Reference Hunt-Fugate, Zander and Lesar201].
Monoamine oxidase inhibitors (MAOIs)
EPS (including dystonia) have infrequently been reported during treatment with MAOIs [Reference Revet, Montastruc, Roussin, Raynaud, Lapeyre-Mestre and Nguyen173, Reference Gill, DeVane and Risch182]. According to a postmarketing study in the world pharmacovigilance database [Reference Revet, Montastruc, Roussin, Raynaud, Lapeyre-Mestre and Nguyen173], none of the studied MAOIs (isocarboxazid, phenelzine, tranylcypromine, moclobemide) was significantly associated with dystonia. Despite this, acute and subacute forms of dystonia have been reported with tranylcypromine (truncal dystonia) and phenelzine (oculogyric crisis and cervical dystonia), respectively [Reference Jarecke and Reid202, Reference Pande and Max203].
Combination drugs
Although most GPs are aware that antipsychotics can induce EPS, they may be less aware that patients treated with a combination drugFootnote 1, including an antipsychotic, may also be at risk to develop dystonia. One such example is a combination of the first-generation antipsychotic flupentixol (0.5 mg) and the tricyclic antidepressant melitracen (10 mg). Many GPs and neurologists prescribe this medication for depression, anxiety, or neurotic symptoms [Reference El Zahran, Al Hassan, Khalifeh, Aboukhater, Hammoud and Al Hariri204–Reference Kao, Shiah, Lee, Kuo, Huang and Ku206], for example in patients with irritable bowel syndrome [Reference Qin, Qin, Yang, Lv and Huang205]. Although no cases of dystonia in the scientific literature have been identified with this combination drug, there are indications that dystonia can be induced with long-term daily use of this medication (personal communication). Moreover, this combination drug is not approved for use and marketing in several developed countries, including the United States and the United Kingdom [Reference El Zahran, Al Hassan, Khalifeh, Aboukhater, Hammoud and Al Hariri204]. In India, it was even banned [Reference Bhaumik207]. Although still registered in Belgium, the Belgian Centre for Pharmacotherapeutic Information strongly advises against using this combination drug to treat patients with depression.
Lithium
A recent review [Reference Rissardo, Caprara, Durante and Rauber208] found dystonia to be the fourth most common MD with lithium (after parkinsonism, dyskinesia, and myoclonus). Twenty-two of the 436 identified MD cases concerned individuals who developed all forms of dystonia (including blepharospasm, oromandibular, cervical, distal segmental, axial, and lingual dystonia). Interestingly, one of every two individuals developing lithium-induced dystonia was from Asia. These patients were also significantly younger than the subjects presenting other MDs. The onset of dystonia varied between 1 day and 25 years. In about one-fourth of the identified cases, an antipsychotic was used. However, it is important to recognize dystonia as a potential complication of lithium, not only when administered in combination with an antipsychotic, but even when it is used as monotherapy or combined with small doses of other non-DRBA, especially during long-term use [Reference Nasrallah, Churchill and Hamdan-Allan209–Reference Chakrabarti and Chand211].
Stimulants
Methylphenidate (MPH) is often used as a treatment for children and adolescents with ADHD with or without comorbid conduct-dissocial disorder [Reference Pagliaro, Mattio, Paulson, Fromm and Vidal212]..Most reported MPH-induced dystonia cases in children and adolescents have occurred after initiation or up-titration of MPH. These cases involved MPH monotherapy [Reference Uzun, Korkmaz, Ekici and Kaymaz213] and combined MPH-second generation antipsychotic treatment [Reference Stämpfli, Weiler and Burden41, Reference Mohamoud, Chen, Croteau, Cheng, Burkhart and Volpe214, Reference Millichap and Yee215]. A review of case reports and an analysis of the WHO pharmacovigilance database on the occurrence of MDs in children and adolescents using a combination therapy of MPH and the antipsychotic risperidone identified 4 case reports and 32 individual case safety reports (ICSRs) describing dystonic movements in relation to the combination therapy. Among the ICSRs, dystonia was the second most reported MD, and cases across the whole spectrum of dystonic reactions were observed [Reference Stämpfli, Weiler and Burden41]. Dystonia with MPH has also been reported in combination with other antipsychotics and medications known to have a risk of inducing dystonia (aripiprazole, propofol) [Reference LeRiger, Williams, Duncan-Wiebe and Shukry216], after prolonged use [Reference Pagliaro, Mattio, Paulson, Fromm and Vidal212], or in the context of MPH withdrawal during psychostimulant detoxification [Reference Grau-López, Daigre, Mercado, Casas and Roncero217].
Antihistamines
MID due to the use of antihistamines has been very rarely reported [Reference Sharawat and Dawman47, Reference Pellecchia, Esposito, Cozzolino, Squillante, Penza and Barone218–Reference Fraunfelder and Fraunfelder222].
Cetirizine is a frequently used antihistamine for the treatment of allergic disorders in children. Several cases of cetirizine-induced acute (even after a single oral dose at recommended dosages), subacute, or tardive dystonia, such as oculogyric crisis, cervical, and oromandibular dystonia, in (mostly) children and adults, have been reported in the literature [Reference Sharawat and Dawman47, Reference Barow, Schneider, Bhatia and Ganos65, Reference Pellecchia, Esposito, Cozzolino, Squillante, Penza and Barone218, Reference Esen, Demirpence, Yis and Kurul221–Reference Rajput and Baerg223].
Despite its widespread use in the management of MID [Reference Sicari and Zabbo224], the first-generation antihistaminergic diphenhydramine, paradoxically, has also been recognized as a contributor to acute dystonia in very rare cases. The onset of dystonic reactions is usually rapid, developing shortly after taking the antihistamine. However, such reactions may also occur after long-term therapy. Patients characteristically develop facial dystonia, torticollis, and extremities dystonia [Reference Serrano, Sanz-Cuesta, Villaronga, Hayek and Perez-Dueñas225–Reference Joseph and King231].
Although very uncommon (but probably more common than reported) [Reference Serrano, Sanz-Cuesta, Villaronga, Hayek and Perez-Dueñas225], MID with cough and cold preparations having antihistaminic properties (such as the widely used cloperastine-based cough syrup), has also been described. Oculogyric crisis and torticollis are among the most frequent dystonic reactions, with children being more susceptible than adults [Reference Pellecchia, Esposito, Cozzolino, Squillante, Penza and Barone218, Reference Serrano, Sanz-Cuesta, Villaronga, Hayek and Perez-Dueñas225, Reference Graudins and Fern232].
Finally, few cases of dystonia following hydroxyzine administration (widely used for skin allergies) have been reported [Reference Wijerathne233, Reference Gunduz, Karacayir and Ozkan234].
It is likely that the risk of MID increases when antipsychotics and (preparations containing) antihistamines are administered concomitantly, particularly in vulnerable individuals (e.g. chronic pretreatment with anti-dopaminergic drugs) [Reference Serrano, Sanz-Cuesta, Villaronga, Hayek and Perez-Dueñas225, Reference Linazasoro, Garmendia and Lizaso235].
Calcium channel blockers
Calcium channel blockers (CCBs) are medicines that are most often used to treat conditions of the heart and blood vessels, such as hypertension, angina, and cardiac arrhythmias. Besides these indications, they are also frequently prescribed for the treatment of migraine, vertigo, and cerebrovascular insufficiency [Reference Jhang, Huang and Nfor236].
Most CCB-induced MDs are reported with flunarizine and cinnarizine. According to an analysis of patients who have been taking flunarizine (n = 26,133) or cinnarizine (n = 7,186) for more than 1 month, both agents significantly increased the risk of subacute or tardive dystonia [incidence rates of flunarizine- and cinnarizine-induced dyskinesia/dystonia were 1.21(0.81–1.78) and 1.52(0.79–2.92) per 10,000 person months, respectively]. However, as many of the patients in this study used antipsychotics or metoclopramide concomitantly, the risk of flunarizine- or cinnarizine-related MDs might have been overestimated [Reference Jhang, Huang, Nfor, Tung, Ku, Lee and Liaw237]. In the study of Fabiani et al. [Reference Fabiani, Pastro and Froehner238] dystonia was diagnosed in 4% of the patients due to the chronic use of cinnarizine and flunarizine. Flunarizine-related MDs (including dystonia) are associated with a high-dose exposure, longer exposure duration, older age, history of essential tremor, and cardiovascular diseases [Reference Jhang, Huang and Nfor236].
Some case reports described acute and tardive (persistent) dystonic reactions induced by the CCBs verapamil [Reference Vadlamudi and Wijdicks239–Reference Hicks and Abraham241], nifedine [Reference Singh242, Reference Bayram, Bayram, Hiz and Turkmen243], and amlodipine (inducing cranial, cervical, pharyngo-laryngeal, or axial dystonia) [Reference Dressler18], and the antiarrhythmic drug flecainide [Reference Miller and Jankovic244].
Antimalarials
Acute dystonia (oromandibular dystonia and oculogyric crisis) induced by chloroquine, commonly used for both the prevention and treatment of malaria, is very rare [Reference Duarte and Teive139, Reference Nachane and Nayak245, Reference Busari, Fadare, Agboola, Gabriel, Elegbede and Oladosu246]. It mainly has been reported after a single dose of chloroquine, in the presence [Reference Achumba, Ette, Thomas and Essien247] (particularly in combination with the common antibiotic metronidazole) [Reference Adjei, Goka, Rodrigues, Hoegberg, Alifrangis and Kurtzhals248] or absence of other medications [Reference Busari, Fadare, Agboola, Gabriel, Elegbede and Oladosu246].
The are some case-reports of artesunate/amodiaquine and artemether/lumefantrine-induced acute dystonia (oculogyric crisis) in the literature [Reference Adjei, Goka, Rodrigues, Hoegberg, Alifrangis and Kurtzhals248, Reference Akindele and Odejide249]. Artemether/lumefantrine treatment may cause dystonic reactions in patients at any age, even at therapeutic dosages [Reference Amponsah, Sodnom-Ish, Anyetei-Anum, Frimpong and Kim250].
Other medications
Dystonic reactions, although rarely observed, have been reported with several antibiotics [Reference Barow, Schneider, Bhatia and Ganos65, Reference Bayram, Bayram, Hiz and Turkmen243, Reference Omrani, Rohani, Hosseinpour and Tavasoli251–Reference Deshayes, Coquerel and Verdon265] and antiviral drugs [Reference Dubow, Panush, Rezak and Leikin266, Reference Song, Hu and Zhang267] (see Table 3), which usually are acute and may involve the whole spectrum of dystonia. Many other medications have been found to induce dystonia (particularly when used in combination with other agents), in most cases involving the head and neck: several opioid analgesics (e.g. fentanyl) [Reference Burkhard21, Reference Duarte and Teive139, Reference Bayram, Bayram, Hiz and Turkmen243, Reference Patel and Park268–Reference Burstein and Fullerton271], the non-opioid anesthetic propofol [Reference Burkhard21, Reference Elhusseiny, Grush and Dagi113, Reference Duarte and Teive139, Reference Wijerathne233, Reference Patel and Park268, Reference Schramm and Orser272–Reference Bragonier, Bartle and Langton-Hewer280] (sometimes inducing full opisthotonus or laryngeal dystonia), the inhalational anesthetic sevoflurane (particularly associated with an increased risk of laryngospasm, potentially leading to laryngeal dystonia, especially in children) [Reference Burkhard21, Reference Jitprapaikulsan and Srivanitchapoom269, Reference Bernard, Le Roux and Péréon281–Reference Sharawat and Suthar288], the analgesic and antipyretic drug paracetamol (although acute dystonia with therapeutic doses of paracetamol is very unusual) [Reference Sharawat and Suthar288], several antitussives [Reference Serrano, Sanz-Cuesta, Villaronga, Hayek and Perez-Dueñas225, Reference Graudins and Fern232, Reference Linazasoro, Garmendia and Lizaso235, Reference Mahadevappa, Attri, Chalasani and Syed289–Reference Warden, Diekema and Robertson293] (often associated with cervical dystonia), the anthelminthic drug albendazole (particularly in sensitive children) [Reference Yılmaz-Topa, Tuygun, Akça, Polat and Karacan294, Reference Incecik, Hergüner, Ozcan and Altunbaşak295], the histamine analog betahistine (largely used in the treatment of Ménière’s disease and also having the propensity to induce tardive dystonia after prolonged use) [Reference De Riu, Sanna and De Riu296–Reference López-Blanco, Guerrero-Molina, González-de la Aleja and Ruiz-Morales298], the cytostatic drug capecitabine [Reference Cengiz, Aybay, Sarıcı, Öner, Arslan and Cengiz299–Reference Ngeow, Prakash, Chowbay, Quek and Choo301] (typically associated with oromandibular dystonia), tetrabenazine (a medication mainly used in patients with hyperkinetic MDs, including dystonia, that may, however, worsen dystonia particularly in vulnerable young adults) [Reference Barow, Schneider, Bhatia and Ganos65, Reference Duarte and Teive139, Reference Janik and Figura302–Reference Kenney, Hunter and Jankovic305], isotretinoin (a medication used to treat severe acne that can induce oculogyric crisis) [Reference Bigby and Stern306], and the immunosuppressant agents cyclosporine (rarely causing limb or focal hand dystonia that may persist after cyclosporine withdrawal) [Reference Miklavčič, Avčin, Jazbec, Vipotnik Vesnaver, Todorova and Trošt307, Reference Taque, Peudenier, Gie, Rambeau, Gandemer and Bridoux308] and tacrolimus (strongly associated with dystonia, particularly in female pediatric patients) [Reference Liu, Yan, Zhao, Deng and Zu309]. Concerning analgesic-induced dystonia particularly female patients seem to be vulnerable, as women might respond differently to general anesthetic agents, compared to men [Reference Wasilczuk, Rinehart, Aggarwal, Stone, Mashour and Avidan310]. Cholinesterase inhibitors, widely used in patients with Alzheimer’s disease and in patients with myasthenia gravis, seem to be particularly associated with the Pisa Syndrome, also known as pleurothotonus, a term used to describe a type of acute or tardive truncal dystonia [Reference Barow, Schneider, Bhatia and Ganos65, Reference Ikeda, Yanagihashi, Sawada, Hanashiro, Kawabe and Iwasaki311–Reference Zannas, Okuno and Doraiswamy318]. Finally, several benzodiazepines have been associated with acute and tardive dystonia (including opisthotonus) in adults and children [Reference Komur, Arslankoylu and Okuyaz319–Reference Hooker and Danzl322] (See Table 3). For example, long-term use of etizolam, zolpidem, and brotizolam may result in blepharospasms, especially in women [Reference Wakakura, Yamagami and Iwasa323, Reference Wakakura, Tsubouchi and Inouye324].
Table 3. Medications very rarely (<0,01%) associated with dystonia or for which this risk cannot be precisely estimated.
BDZ: Benzodiazepine
(!!!): Belgian Centre for Pharmacotherapeutic Information strongly advises against the use of this medication
Discussion
The rates of MID probably are underestimated [Reference Anand, Pandey and Garg102, Reference Emorinken and Agbadaola325, Reference Haddad, Das, Keyhani and Chaudhry326]. The Hannover epidemiology study [Reference Dressler, Altenmüller, Giess, Krauss and Adib Saberi11], which considered all forms of dystonia (including DRBA-induced dystonia) in highly specialized centers, estimated dystonia rates to be at least four times higher than previously thought. There are indications that dystonia is also underreported for several other classes of medications, including antidepressants, antiemetics, and cholinesterase inhibitors [Reference Pasricha, Pehlivanov, Sugumar and Jankovic63, Reference Sheikh Hassan and Ahmed Nor75, Reference Revet, Montastruc, Roussin, Raynaud, Lapeyre-Mestre and Nguyen173, Reference Raveendranathan and Rao175, Reference Leo180, Reference Zannas, Okuno and Doraiswamy318, Reference Emorinken and Agbadaola325]. Revet et al. [Reference Revet, Montastruc, Roussin, Raynaud, Lapeyre-Mestre and Nguyen173], for example, identified 5,113 dystonia cases (0.50%) (on a total of 1,027,405 reported cases containing at least one of the 58 selected antidepressant drugs) in the WHO pharmacovigilance database during the time period of January 1967 to February 2017. This means that the prevalence of dystonia for antidepressants, as a group, lies between ≥0.1% to <1% (= uncommon side effect), while the frequency of this side effect for each antidepressant has been rated by the authors of this article as rare or very rare (see Tables 2 and 3).
There are several reasons why MID might be underreported. Firstly, only few individual studies or systematic reviews/meta-analyses on medication-induced EPS mention dystonia as a separate category because of the smaller numbers of this MD, compared to these for other MD, such as dyskinesia, akathisia, or parkinsonism. Secondly, although it is generally well-known to GPs that dystonia is commonly associated with the use of DRBAs such as high-potency antipsychotics, they do not expect it to be an adverse drug reaction (ADR) associated with medications widely used in general clinical practice, such as antidepressants, antibiotics, antivirals, antiallergics, and antitussives. Moreover, many GPs are not familiar with the clinical presentation of acute dystonia. This leads to a higher likelihood of misdiagnosis [Reference Emorinken and Agbadaola325]. Finally, the severity spectrum of dystonia can be extremely large. Dystonia might be a subtle finding, rather than a complaint, without a serious consequence for the patient [Reference Dressler, Altenmüller, Giess, Krauss and Adib Saberi11]. Under these circumstances, GPs may interpret this ADR as not important. However, in exceptional cases (i.e. laryngeal dystonia) MID can be life-threatening [Reference Duma and Fung20, Reference O’Neill and Stephenson31, Reference Christodoulou and Kalaitzi37, Reference Lamond277, Reference Pandey, Pitakpatapee, Saengphatrachai, Chouksey, Tripathi and Srivanitchapoom327–Reference de Oliveira, Girao, Fitzgerald and McCarthy336]. The patient can develop acute respiratory distress through upper airway obstruction showing signs, such as cyanosis, stridor, gasping, and an inability to manage secretions [Reference Alkharboush and Alsalamah34, Reference Chakrabarti and Chand211, Reference Yagmur, Ulusoy, Buyukoglan and Kaya337, Reference Modestin, Krapf and Böker338]. Acute laryngeal dystonia can easily be misdiagnosed as anaphylaxis, epiglottitis, hysteria, panic attack, or acute anxiety [Reference Collins and Sager23, Reference Alkharboush and Alsalamah34–Reference Chakravarty36]. Prompt recognition therefore can save lives. The sudden onset of symptoms with rapid progression in the presence of a dystonia risk profile should caution the health professional [Reference Balint, Mencacci, Valente, Pisani, Rothwell and Jankovic339]. Characteristic symptoms of laryngeal dystonia are dyspnea, laryngeal stridor, and extreme distress. Laryngeal dystonia may also be accompanied by dystonia in other parts of the body [Reference O’Neill and Stephenson31, Reference Christodoulou and Kalaitzi37].
The treatment of dystonia typically involves discontinuing the offending drug (due to the risk of a recurrent dystonic reaction) and administration of medications that block the acetylcholine receptors (i.e. anticholinergics, benzodiazepines, and certain antihistamines) [Reference Dressler, Altenmüller, Giess, Krauss and Adib Saberi11, Reference Duma and Fung20, Reference Wijemanne, Jankovic and Evans24, Reference Pandey, Pitakpatapee, Saengphatrachai, Chouksey, Tripathi and Srivanitchapoom327]. However, symptoms may reoccur within hours after initial treatment. In these cases, clinicians should give another dose of the medication or administer the medication for several days to prevent the reoccurrence of dystonia [Reference Pandey, Pitakpatapee, Saengphatrachai, Chouksey, Tripathi and Srivanitchapoom327, Reference Sáenz-Farret, Micheli, Dressler, Altenmüller and Krauss340].
Supplementary material
The supplementary material for this article can be found at http://doi.org/10.1192/j.eurpsy.2025.18.
Financial support
This work has been financed by the fund secondary dystonia, managed by the King Baudouin Foundation Belgium, Brederodestraat 21, 1000 Brussels, under grant agreement no 2023-j5210910–230851 (https://kbs-frb.be/en/fund-secondary-dystonia) [Reference Catthoor, De Hert and Detraux341], and by an unrestricted grant from Johnson & Johnson, Lundbeck and Eli Lilly.
Competing interest
The authors declare that there are no conflicts of interest relevant to this work [Reference Wager and Wiffen342].
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