Prolonged Tardive Dyskinesia Induced by Long-Acting Paliperidone Palmitate in Schizophrenia: A Case Report

Introduction

Tardive dyskinesia, including tardive dystonia, is a delayed-onset, often persistent movement disorder after dopamine-receptor–blocking agents [1,2]. Long-acting paliperidone is widely used for adherence, yet dystonic phenotypes remain a recognized risk [3–5]. We report a 6-year follow-up of cervical-predominant tardive dystonia emerging after transition from paliperidone palmitate once a month to once every 3 months, highlighting diagnostic distinctions, therapeutic decision-making, and the implications of extended pharmacokinetics [6–8].

Tardive dyskinesia is an umbrella term for the iatrogenic spectrum of abnormal involuntary movements that emerges after exposure to dopamine receptor–blocking agents (DRBAs) [9]. In contemporary usage, tardive dyskinesia encompasses oral–buccal–lingual stereotypies and chorea, as well as dystonia, akathisia, tics (including facial tics), myoclonus, and other hyperkinetic phenomena [9–11]. Within this spectrum, a dystonia predominant phenotype (“tardive dystonia”) manifests as sustained or intermittent, patterned muscle contractions causing abnormal, often repetitive, movements or postures (eg, cervical dystonia) [1,12]. These dystonic features are frequently disabling and may persist or remit only partially even after withdrawal of the offending drug [1,2]. Long acting injectable antipsychotics (LAIs) such as paliperidone palmitate are widely used to support adherence and reduce relapse and hospitalization risk in schizophrenia, but the injection route does not eliminate the possibility of tardive dyskinesia [3,5,13]. Complementing trial data, pharmacovigilance analyses of the Japanese adverse event database identified tardive dyskinesia reports with LAI paliperidone and estimated a lower adjusted reporting odds than with oral paliperidone, while major guidelines still recommend structured tardive dyskinesia monitoring (eg, Abnormal Involuntary Movement Scale [AIMS]) at routine visits for patients treated with antipsychotics [14].

Similar reports have linked paliperidone to tardive dystonia. Ma et al described tardive dystonia associated with LAI paliperidone palmitate, and Singh et al reported severe, refractory tardive dyskinesia with dystonic features following paliperidone palmitate, with 6-month management and follow-up [4,15]. In addition, Marques reported Meige syndrome (cranial dystonia) after once-monthly paliperidone palmitate, and Contrucci, Heikens, and Beex-Oosterhuis described blepharospasm following long-acting paliperidone injections [16,17].

This report describes a 40-year-old woman with schizophrenia treated with the antipsychotic long-acting paliperidone palmitate, with persistent tardive dyskinesia requiring long-term management.

Case Report

A 40-year-old divorced, unemployed, Taiwanese woman was admitted in April 2017 with persecutory delusions, thought broadcasting, disorganized behavior, and erotomanic delusions lasting for more than 1 year. She denied any history of tobacco, alcohol, or substance use. Also, there was no identified family history of psychiatric disorder. She lived with her parents. There was no history of physical disease. Diagnosed with schizophrenia, she was started on long-acting Paliperidone palmitate once a month (INVEGA SUSTENNA®, PP1M), which stabilized her condition. To improve treatment adherence, her regimen was switched to long-acting Paliperidone palmitate once every 3 months (INVEGA TRINZA®, PP3M) 525 mg in October 2017.

In April 2018, about 1 year after initiation of LAI treatment, she developed a focal cervical dystonia consistent with tardive dystonia, characterized by a sustained left laterocollis (head held in left lateral flexion) and a mask–like facial expression (hypomimia). The symptoms persisted during sitting, walking, and arm use, constantly throughout the visit. There was no associated torticollis (rotation), no anterocollis, no retrocollis, and no shoulder elevation or lateral shift. No head tremor was observed. The posture did not change in the supine position. Cervical AROM (active range of motion) and PROM (passive range of motion) were full, with tenderness of the left sternocleidomastoid muscle, and no focal weakness. Spurling’s test was negative bilaterally. No bradykinesia, rigidity, or resting tremor were detected. She had no orobuccolingual stereotypies, chorea, tics, or myoclonus, and denied inner restlessness, suggestive of no akathisia. She stated: “My neck has tended to bend to the left, and it feels tight”. Strength in the upper limbs was full and symmetric, sensation and deep tendon reflexes were normal and symmetric, and Hoffmann’s sign was negative. No additional abnormal involuntary movements were found on examination.

These features emerged after sustained exposure to a dopamine receptor–blocking agent and persisted despite dose reduction (PP3M decreased to 350 mg) and subsequent withdrawal, supporting a tardive time course; the predominantly cervical distribution was also typical for tardive dystonia. Given the persistence of dystonic symptoms, the LAI was discontinued, and our priority was exposure minimization to dopamine receptor–blocking agents. Oral aripiprazole (10 mg/day) was introduced in June 2019, selected for its partial dopamine D2 agonism to potentially reverse dopaminergic supersensitivity.

Over the ensuing months, several adjunctive medications were trialed to manage the dystonia. Trihexyphenidyl (up to 6 mg/day) was introduced as a first-line anticholinergic. Amantadine (300 mg/day) was added for its NMDA (N-methyl-D-aspartate) receptor antagonism [18–20]. Additional agents included bromocriptine (5 mg/day), tried as a dopaminergic agonist to counter hypothesized dopamine receptor supersensitivity underlying tardive syndromes after long-term DRBA (dopamine receptor-blocking agent) exposure, aiming to rebalance striatal dopaminergic tone; cyclobenzaprine (15 mg/day) and metaxalone (600 mg/day), used as skeletal–muscle relaxants for symptomatic relief of neck pain and spasm associated with cervical–predominant dystonia; and benzodiazepines (oxazepam 30 mg/day, clonazepam 2 mg/day), short–term adjuncts to enhance GABAergic (gamma-aminobutyric acidergic) inhibition and reduce dystonic contractions, anxiety, and sleep disruption that can exacerbate dystonia; but none of these provided substantial or sustained relief.

Due to ongoing symptoms and psychiatric instability, clozapine was initiated in December 2019 and titrated to 100 mg/day by February 2020. Chosen for its low risk of extrapyramidal symptoms and potential antidyskinetic properties [4,21,22], clozapine became her primary antipsychotic. While complete resolution was not achieved, she had gradual reduction in dystonic posturing over time. By 2024, family members occasionally observed neutral head positioning and less frequent neck tilting, suggesting partial improvement despite persistent baseline symptoms.

In May 2024, she was readmitted due to a relapse of psychotic symptoms, attributed in part to poor medication adherence. Neurology consultation reaffirmed the diagnosis of tardive dystonia. Parkinsonian features such as resting tremor and bradykinesia were absent, arguing against drug-induced parkinsonism. She was discharged on clozapine 25 mg q.h.s. and fluvoxamine 50 mg q.h.s., with recommendations for motor rehabilitation and regular outpatient follow-up with both Psychiatry and Neurology (Figure 1).

Discussion

This case shows that LAI paliperidone palmitate can be associated with refractory tardive dystonia, and symptoms may persist despite drug discontinuation and multi-modal treatment; this aligns with prior case reports and case series [4,15–17]. Given the potential for a more protracted course under long-acting exposure, especially in our case, PP3M, whose median apparent half life is ~84–95 days after deltoid and 118–139 days after gluteal injection, limiting rapid de-challenge once symptoms emerge, clinicians should apply heightened risk–benefit scrutiny when initiating or maintaining LAI formulations in vulnerable patients [23].

Management should prioritize early recognition and exposure minimization with a tiered strategy; in patients with suboptimal response to conventional measures, early consideration of VMAT-2 (vesicular monoamine transporter-2) inhibitors or a carefully monitored switch to clozapine is warranted, yet outcomes are often only partial and the course remains long-term [2,14,21,24–26].

Tardive dyskinesia is a persistent, iatrogenic hyperkinetic movement disorder marked by stereotyped, repetitive involuntary movements – classically orofacial but also truncal and limb – emerging after long-term exposure to DRBAs [2,24,27]. Antipsychotics are the prototypical culprits, but other DRBAs such as metoclopramide and non-DRBA medications (eg, certain antidepressants and antihistamines) have been implicated in tardive dyskinesia [14,28–31]. Mechanistically, chronic D2-receptor blockade can induce postsynaptic receptor upregulation and supersensitivity, and oxidative-stress–mediated neurotoxicity has also been proposed [9]. Epidemiologically, among people treated with first-generation antipsychotics, the average tardive dyskinesia prevalence is at least ~20% [9]. Risk rises with longer cumulative DRBA exposure, older age, female sex, prior extrapyramidal symptoms, and use of first rather than second generation antipsychotics, with long term anticholinergic therapy also potentially increasing risk [9]. Notably, postmenopausal women have incidence rates approaching ~30% after about 1 year of taking antipsychotics [9]. Diagnosis is clinical: DSM-5 TR defines tardive dyskinesia as a medication-induced movement disorder that persists despite dose reduction or discontinuation, with symptoms present for at least 1 month after discontinuation [9]. Baseline assessment with the AIMS before starting antipsychotics and a follow up screening within 3 months are recommended to detect emerging or progressive movements [9]. For continued surveillance, administering the AIMS every 3 to 6 months is advised [26]. Targeted laboratory testing and neuroimaging may be used when indicated to exclude mimics such as Huntington disease and Wilson disease [9]. Management prioritizes prevention – use the lowest effective antipsychotic dose for the shortest feasible duration – and prompt termination of exposure once tardive dyskinesia appears (dose reduction or discontinuation when clinically possible) [9]. If antipsychotic therapy must continue, switching to clozapine is reasonable given its comparatively low tardive dyskinesia risk [9]. For symptomatic therapy, vesicular monoamine transporter-2 (VMAT2) inhibitors are first-line: in the phase-3 KINECT-3 trial, once-daily valbenazine 80 mg improved AIMS dyskinesia scores by a least-squares mean of −3.2 points at week 6 versus −0.1 with placebo, with favorable tolerability [24]. Similarly, in the phase-3 AIM-TD trial, fixed-dose deutetrabenazine 24–36 mg/day significantly reduced AIMS scores over 12 weeks compared with placebo, with adverse-event rates comparable to placebo [25]. Evidence syntheses and guideline updates conclude that valbenazine and deutetrabenazine are established effective treatments (Level A) that should be recommended, while clonazepam and Ginkgo biloba probably help (Level B), and amantadine and tetrabenazine might be considered (Level C) [24,25,32].

Tardive dystonia is less common than Tardive dyskinesia, but is frequently more disabling. Reported tardive dystonia prevalence among antipsychotic-treated cohorts generally ranges from ~0.4% to 5% (method-dependent), with cervical/cranial predominance; male sex and younger onset are often cited, and many cases follow a months-to-years latency after DRBA exposure [1,33,34]. Even after de-challenge, tardive dystonia commonly persists or only partially remits over years, underscoring the importance of prevention and early recognition [1,2,17].

Tardive dystonia was delineated as a late-onset, persistent dystonia linked to antipsychotics, establishing the entity’s chronic and disabling nature [1]. Sustained D2 receptor blockade can induce dopaminergic receptor supersensitivity and neuroadaptations that can endure after antipsychotic withdrawal [17,35,36]. Beyond dopamine, striatal cholinergic interneurons critically shape sensorimotor integration via muscarinic and nicotinic signaling, providing a plausible node through which cholinergic therapies can influence tardive dystonia expression [1,37,38]. Disturbances in glutamatergic and GABAergic transmission can further destabilize basal ganglia output and cortical motor programs, aligning with a network-level model of Tardive dystonia [19,39–41]. Cumulatively, these findings support tardive dystonia as a multifactorial disorder of cortico-striato-thalamocortical circuit plasticity rather than a purely dopaminergic phenomenon [19,38,42,43].

LAIs are widely used to support adherence, and their use remained stable during pandemic-related service disruptions, underscoring their real-world importance [44]. However, tardive syndromes have been reported with LAI paliperidone in case reports and pharmacovigilance analyses, and clinical-trial databases suggest a low absolute overall incidence [3,4,14,15]. Risk is modulated by factors such as age and cumulative antipsychotic drug exposure, and pharmacogenetic susceptibility likely contributes to the variability [45–47]. Compared with case reports describing onset within the first few years and partial improvement after switching (including to clozapine), more protracted and refractory courses are also documented [2,4,15,48–50].

Singh et al reported the case of a young man who developed severe, refractory tardive dyskinesia including tardive dystonia, during treatment with once-monthly paliperidone palmitate (PP1M), with details of a 6-month follow-up course [15]. Ma et al described a woman who developed oropharyngeal-predominant tardive dystonia after PP1M, with remission following conversion to low-dose clozapine plus speech therapy within about 6 months [4]. Marques reported a case of Meige syndrome (cranial dystonia) approximately 1 month after administering PP1M 150 mg, with resolution after discontinuation/switch, published as a peer-reviewed Letter-to-the-Editor in PCC [16]. Contrucci et al reported blepharospasm after PP1M (150 mg monthly, after loading), with a Naranjo score of 9 (“almost certain”) and persistence of symptoms for nearly 1.5 years after discontinuation [17].

In comparison, our patient – a middle-aged woman – developed cervical-predominant tardive dystonia 13 months after initiation of paliperidone palmitate LAI, and tardive dystonia persisted long after discontinuation. Given PP3M’s longer-acting profile (compared to PP1M and oral form) and the product label note that responses to dose adjustments may not be apparent for several months, heightened surveillance and a low threshold to reassess PP3M may be prudent when patients are at risk for, or show early signs of, protracted tardive phenomena [23,51].

Overall certainty of the effectiveness of interventions for tardive dystonia remains low to moderate, with heterogeneous and often inconsistent responses across phenotypes and studies that are predominantly small trials, observational designs, or case series [2,4,15,19,21,52]. Anticholinergics such as trihexyphenidyl may benefit a subset of tardive dystonia patients, but effects are variable and classic choreiform tardive dyskinesia can worsen, so any trial should be individualized and closely monitored rather than routine [1,53–57]. Amantadine shows mixed and generally limited evidence in tardive syndromes; a small randomized, placebo-controlled study suggested benefit, but guideline strength remains modest [19,20,32,58,59]. Switching to clozapine can attenuate tardive dystonia for some patients, but the conclusions are inconsistent, largely due to nonrandomized data (systematic reviews and retrospective series), so expectations should be modest and decisions individualized [4,21,48,60–62].

VMAT-2 inhibitors (valbenazine, deutetrabenazine) have robust randomized-trial efficacy for reducing AIMS-rated movements in tardive dyskinesia, but dedicated trials in isolated dystonic phenotypes are lacking and extrapolation to pure tardive dystonia should be cautious [4,24,25,27,63]. For function-limiting focal or cervical dystonia, botulinum toxin is an evidence-based first-line therapy in primary dystonia and is commonly extrapolated to tardive dystonia for regional symptomatic relief, although it is not disease-modifying [64–69]. In severe, refractory cases, globus pallidus internal segment deep-brain stimulation can yield substantial benefit according to systematic reviews of case series, but high-quality randomized data are lacking, making careful selection and specialized follow-up essential [41,43,70–72].

In practice, prevention (minimum effective D2 exposure and duration), vigilant early detection, and shared, stepwise decision-making remain the backbone of care, and for established tardive dystonia, the realistic expected prognosis is partial improvement rather than complete remission [2,21,24,26,47,73]. Across available interventions, published outcomes are inconsistent and overall certainty is limited; therefore, management should be individualized and staged, and expectation-setting should emphasize that improvement is often partial [2,19,21,24,25].

Aligned with evidence-informed, stepwise care, we trialed an anticholinergic (trihexyphenidyl) and a dopaminergic modulator (amantadine) and subsequently transitioned antipsychotic therapy to clozapine, but the patient achieved only partial and fluctuating improvement – mirroring the heterogeneous and generally modest treatment effects reported for tardive dystonia [2,4,20,21,54].

Tardive dystonia commonly follows a chronic, often persistent course, with incomplete remission even after drug cessation, imposing sustained functional and quality-of-life burdens [2,17,41]. Accordingly, clinicians should balance antipsychotic efficacy against tardive risk over the long term, maintain vigilant surveillance for abnormal movements, and intervene promptly to reduce chronicity [74–76]. In established tardive dystonia, optimizing antipsychotic drug exposure, trialing VMAT-2 inhibition, considering clozapine where appropriate, and engaging Neurology and Rehabilitation teams can maximize functional outcomes [21,77–80].

Conclusions

Tardive dystonia can follow exposure to long-acting injectable paliperidone, especially the longer-acting agents like PP3M, and may be prolonged yet partly reversible despite discontinuation. Given therapeutic limits, variable prognosis, and the 3-month formulation’s extended pharmacokinetics, clinicians should maintain high suspicion, minimize dopamine-receptor–blocking exposure, and individualize care, considering timely VMAT-2 inhibitors or clozapine plus structured long-term motor monitoring and shared decision-making.