Lurasidone‐Induced Tardive Syndrome

ABSTRACT

Introduction

Tardive syndrome (TS) is an often irreversible movement disorder caused by dopamine receptor‐blocking agents (DRBAs). Although TS are well recognized to occur with typical antipsychotics, less well appreciated is that atypical antipsychotics also carry a risk of TS.

Methods

Case series.

Results

We describe 4 patients who developed tardive dystonia, tardive akathisia, and drug‐induced parkinsonism with the use of the atypical antipsychotic, lurasidone, which was U.S. Food and Drug Administration approved in 2013 for use in bipolar disorder and schizophrenia.

Conclusion

Movement disorders are reported as a rare side effect of lurasidone, and, as such, prescribers may perceive a false sense of security regarding this potential complication. Our cases indicate that this relatively new atypical antipsychotic may cause irreversible disabling TS as well as parkinsonism. Caution must be taken when prescribing lurasidone.

View Supplementary Video 1

Introduction

Tardive syndromes (TSs) are defined by Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition criteria as medication‐induced movement disorders which persist despite discontinuation or change of a dopamine receptor‐blocking agent (DRBA). Criteria for diagnosis include persistence of movements for 1 month after discontinuation of the inciting medication. Clinical subtypes of TS include classical orofacial dyskinesia, dystonia, akathisia, stereotypy, and others, collectively referred to as tardive syndromes.1 TSs are usually irreversible, emphasizing the need to reduce the risk of occurrence and recognize the clinical features promptly.2 In contrast to tardive syndromes, drug‐induced parkinsonism is generally considered reversible, but may take up to 1 year.3 More protracted cases have been shown, based on dopamine transporter single‐photon emission computed tomography, to likely have underlying Parkinson's disease.4

TS and drug‐induced parkinsonism are caused by DRBAs (antipsychotics and antiemetics). Although most commonly recognized with typical agents, also known as first‐generation antipsychotics (FGAs), data indicate that atypical agents (second‐generation antipsychotics; SGAs) confer a similar risk,5 yet this is not well appreciated. TS have rarely been reported with the SGA, lurasidone. Here, we describe 4 cases.

Case Series

Case 1

A 36‐year‐old woman presented to the movement disorder clinic for abnormal movements that began 6 months after initiating 40 mg of lurasidone daily for bipolar disorder. Her symptoms started as right hand tremor that progressed to dystonic posturing of her right arm and forearm. She also had abnormal pulling of her head to the left and back. Her symptoms worsened with walking, making mobility difficult. She described these movements as painful muscle spasms, which interfered with all activities of daily living, including eating and writing. Lurasidone was discontinued shortly after the onset of the movement disorder. She had no history of exposure to any other DRBA. There was no family history of a related disorder. On examination (Video 1, Segment 1), there was mild lip pursing at rest; her right shoulder was pulled down and forward, and she had rotation of her head 45 degrees to the left with mild anterior shift and intermittent mild‐to‐moderate retrocollis. She had mild truncal extension while walking. There was sustained pronated dystonic posturing of her right forearm with flexion of her wrist and fingers. She had decreased right finger tapping, and mildly increased tone in the right hand. There was decreased right arm swing while walking as well as dystonic posturing of her right hand. Her diagnosis was tardive dystonia affecting the neck, trunk, and right upper extremity. Treatment with benztropine (1 mg twice a day [bid]), clonazepam (1 mg three times a day), and deutetrabenzine (24‐mg daily dose) was minimally effective. OnabotulinumA injections (six sessions) for cervical dystonia provided moderate relief. Her parkinsonism has remitted.

Case 2

A 70‐year‐old man with a long history of bipolar illness was seen for involuntary movements of the tongue and jaw, making it difficult to speak. He was treated with lithium for 35 years, which was discontinued 6 months earlier because of renal dysfunction. He was then started on lurasidone 80 mg per day, and within 1 month, the tongue and jaw movements began. Lurasidone was discontinued 3 months later, and he was off it for 1 month before his initial appointment. His only previous exposure to a DRBA was a brief trial of aripiprazole 2 years before being seen; it caused reversible drug‐induced parkinsonism. There was a no family history of a movement disorder. Medications at the time of the visit included bupropion 200 mg, valproic acid 500 mg, escitalopram 20 mg, losartan 50 mg, tamsulosin 0.4 mg, and trazodone 50 mg.

The neurological examination (Video 1, Segment 2) was normal, except for slight slowing of rapid repetitive movements of all limbs, mildly stooped posture, diminished stride length while walking without shuffling, and diminished arm swing. There were continuous, slow, stereotyped movements of the tongue with elevation of the soft palate, which significantly affected speech. There was occasional puckering of the lips as well as slow sustained lateral dystonic movements of the jaw to the right more than left side. He was diagnosed with tardive oro‐lingual‐mandibular dystonia and treated with repeated injections of onabotulinumA. Symptoms improved to the point where toxin therapy could be suspended. Parkinsonism remitted.

Case 3

A 68‐year‐old man was started on lurasidone 20 mg per day for bipolar disorder and titrated to 80 mg per day. After 3 months, he experienced restlessness with an urge to move his hands and feet. The sensations were severe enough to affect his work. Lurasidone was decreased to 20 mg within a month of symptom onset, which exacerbated his motor restlessness. He was tapered off lurasidone over the next few weeks. He has no history of exposure to other DRBA and no family history of movement disorders. On examination, he had motor restlessness with stereotyped movements of hands and feet consistent with a diagnosis of tardive akathisia. Additionally, he had rest tremor in his left hand with cogwheel rigidity indicative of drug‐induced parkinsonism. His symptoms are well controlled with propranolol ER 120 mg daily and trazodone 150 mg at night. Symptoms were resolving when the patient was lost to follow‐up.

Case 4

A 66‐year‐old woman was seen in April 2019 for involuntary movements of the mouth and jaw first noticed 12 to 15 months earlier. She has a long‐standing history of bipolar illness and, because of side effects, was switched from lithium to lurasidone 80 mg in 2015. During this time, she was not treated with any other antipsychotics. In January 2019, the lurasidone was decreased to 60 mg and she noticed that the movements lessened. She was started on benztropine 0.5 mg bid. The movements interfered to a mild degree with talking and were embarrassing. On examination (Video 1, Segment 3), there was intermittent, brief, sustained, stereotyped retraction of the corners of the mouth and simultaneously jaw closure as well as contraction of the platysma; some of the movements were associated with blepharospasm.

Discussion

We report on 4 cases (Table 1) of TS caused by lurasidone: 3 with tardive dystonia and 1 with tardive akathisia. All patients also had drug‐induced parkinsonism. One of the cases had previous brief treatment with aripiprazole 2 years before being seen.

Table 1.

Case summary

	Age at Presentation	Sex	Tardive Syndrome	Parkinsonism	Duration of Symptom at Time of Presentation (Months)	Dose of Lurasidone	Duration of Medication Exposure	Past Exposure to DRBA	Psychiatric Condition	Treatment of TS
Case 1	36	Female	Tardive dystonia	Yes	1	40 mg	6 months	No	Bipolar	Onabotulinum A injections for cervical dystonia
Case 2	70	Male	Tardive oromandibular dystonia	Yes	4	80 mg	1 month	Yes	Bipolar	Onabotulinum toxin A
Case 3	68	Male	Tardive akathisia	Yes	2	20 mg titrated to 80 mg in 1 month	3 months	No	Bipolar	Propranolol ER 120 mg and trazodone 120 mg QHS
Case 4	66	Female	Tardive oromandibular dystonia	No	6	80 mg	4 years	No	Bipolar	Benztropine

Lurasidone is an SGA which was U.S. Food and Drug Administration approved in 2010 for treatment of schizophrenia and in 2013 for bipolar disorder. It is an antagonist of D2 (Ki [ligand binding affinity] = 0.994 mM) and 5HT2A receptors (Ki = 0.47 nM). Additionally, it has activity on 5‐HT₇ (Ki = 0.495 nM, antagonist), 5‐HT_1A (Ki = 6.38 nM, partial agonist), α_2C‐adrenergic (Ki = 10.8 nM, antagonist), and D₃ (Ki = 15.7 nM) receptors. There is reduced affinity for human D4 (Ki = 29.7 nM), α₁ (Ki = 35.7 nM), and α_2A‐adrenergic (Ki = 40.7 nM) receptors.6, 7, 8 A meta‐analysis by Leucht et al. of 212 trials involving 43,049 participants on lurasidone showed an odds ratio of 2.46 (1.55–3.72) for causing extrapyramidal side effects compared to placebo.6 It was initially presumed that the incidence and prevalence of TS would be significantly lower with SGA compared to FGA. A meta‐analysis of 41 studies (n = 11,493) by Carbon et al.9 demonstrated a global mean TS prevalence of 20.7% (95% confidence interval [CI]: 16.6–25.4) with SGA versus 30% (95% CI: 26.4–33.8; P = 0.002) with FGA treatment. In 20 studies which directly compared FGA and SGA treatment groups, TS prevalence was 30.1% in FGA versus 25.3% in SGA (P = 0.011). Furthermore, the meta‐analysis reported lower prevalence of TS (7.2%; number of studies = 4) in subjects that had no previous exposure to FGA compared to SGA‐treated cohorts that had previous FGA exposure (23.4%; P < 0.001; 28 studies). Such trends may be a result of relatively recent utilization of SGA compared to FGA. There are very little data in these studies on the effect of lurasidone.

Our cases show that lurasidone has the potential to cause a TS and parkinsonism. When prescribing a SGA, including lurasidone, physicians and patients should be aware of the risk of a TS, which may be irreversible and significantly impact quality of life.

Author Roles

(1) Review of Clinical Cases; (2) Video Editing; (3) Manuscript Preparation: A. Writing of the First Draft, B. Final Revision.

R.T.: 1, 2 3A, 3B

S.G.R.: 1, 2, 3A, 3B

L.S.: 1, 3A, 3B

E.G.: 1, 2, 3A, 3B

S.A.F.: 1, 2, 3A, 3B

Disclosures

Ethical Compliance Statement: The authors confirm that the approval of an institutional review board was not required for this work. Informed consent was obtained from the patients for using their clinical video for manuscript submission. We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this work is consistent with those guidelines.

Funding Sources and Conflicts of Interest: Dr. Factor is supported by the Sartain Lanier Family Foundation. The authors report no conflicts of interest.

Financial Disclosures for previous 12 months: Stephen G Reich reports the following: NINDS (grant support); Informa (Royalty for Reich S. Movement Disorders: 100 Instructive Cases); Enterin (Data Safety Monitoring Board); UpToDate (reviewer). Stewart A. Factor reports the following: honoraria from Neurocrine, Lundbeck, Teva, Sunovion, Biogen, and Acadia; grants from Ipsen, Medtronics, Teva, US World Meds, Sunovion Therapeutics, Vaccinex, Voyager, Jazz Pharmaceuticals, CHDI Foundation, Michael J. Fox Foundation, and NIH; royalties from Demos, Blackwell Futura for textbooks, and UpToDate; Other: Bracket Global LLC.

Supporting information

Video S1. Case 1: A 36‐year‐old woman with cervical dystonia with chin tilt to the left side and mild retrocollis. She has trace bradykinesia on finger tapping and mild dystonic posturing of her hands on arm extension bilaterally. There is mild truncal tilt to the left. Case 2: A 68‐year‐old gentleman with lateral dystonic movements of the jaw and mild lip puckering. He has slow stereotyped movements of the tongue as well. Case 4: A 66‐year‐old woman with mild blepharospasm and stereotyped jaw movements including jaw deviation along with platysma contractions.