1Department of Neurology, Osaka Neurological Institute, Osaka, Japan
2Center for Drug Discovery and Development Sciences, Research Organization of Science and Technology, Ritsumeikan University, Kyoto, Japan
3Department of Clinical Neuroscience, Institute of Biomedical Sciences, Tokushima University, Tokushima, Japan
Corresponding author: Satoshi Goto, MD, PhD Center for Drug Discovery and Development Sciences, Research Organization of Science and Technology, Ritsumeikan University, Kyoto 603-8577, Japan / Tel: +81-77-561-2631 / E-mail: sgoto0326@outlook.jp
• Received: November 15, 2024 • Accepted: December 8, 2024
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
The long-term use of antipsychotics (neuroleptics) can lead to tardive dystonia (TD), which is part of tardive syndrome that encompasses various motor and psychiatric symptoms [1,2]. According to the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) [3], TD is characterized by its late onset during treatment and persistence, even after cessation or dose reduction of antipsychotic drugs. This drug-induced dystonia is a significant concern in clinical practice because of its iatrogenic nature and potentially preceding a life-threatening condition [1,2]. Since all antipsychotics are capable of blocking the dopamine D2-type receptors (D2Rs), which are highly expressed in the striatum, TD is thought to be due to prolonged striatal D2R inactivation [1,2]. Increasing evidence suggests that balanced activities between the D1Rs and D2Rs in the striatal striosome-matrix system are crucial for understanding dystonia pathology and treatment [4-6]. This case report highlights the striking impact of a low dose of levodopa/carbidopa on tardive truncal dystonia caused by chronic exposure to sulpiride, a D2R antagonist.
A 58-year-old man was diagnosed with major depression by a psychiatrist at the age of 55 and was prescribed sulpiride (initially, at 50 mg/day). Over 2 years, the sulpiride dosage was increased to 100 mg/day as his depressive symptoms worsened. He then experienced a gradual onset and worsening of focal dystonia, causing his trunk to bend to the left. Therefore, the daily dose of sulpiride was reduced to 50 mg, but his truncal dystonia remained unchanged until his first visit to our hospital 1 year later. He had no family history of dystonia and no history of alcohol consumption or smoking. He underwent endoscopic treatment for bladder cancer at the age of 53.
Upon admission, the patient exhibited involuntary and patterned leftward trunk flexion. His dystonia symptoms appeared when he was standing or walking but not when sitting or lying down. Physical examinations revealed no cranial nerve abnormalities or overt parkinsonism. Magnetic resonance imaging revealed no abnormalities in the brain. Laboratory testing did not reveal abnormalities, and pathogenic variants in the known dystonia genes were not identified by whole-exome sequencing (OMIM phenotypic series PS128100). According to the DSM-5 criteria [3], the patient was diagnosed with tardive truncal dystonia (Figure 1A). His Burke-Fahn-Marsden Dystonia Movement Scale (BFMDMS) [7] score was 16 (maximum 120). He refused to take anticholinergics because of concerns about the potential for cognitive decline. Therefore, we prescribed a daily dose of levodopa (50 mg)/carbidopa (5 mg). He noted a significant improvement in truncal dystonia within a few weeks after levodopa/carbidopa initiation. At 4-week (Figure 1B) and 1-year (Figure 1C) follow-up assessments, his BFMDMS scores were 6 and 0, respectively. His truncal dystonia was completely resolved with levodopa/carbidopa treatment within a few months, as shown in the video image (Supplementary Video 1 in the online-only Data Supplement). To date, the re-emergence of TD has not been observed for more than 2 years. He has been taking 50 mg of sulpiride daily for major depression.
Sulpiride, a substituted benzamide antipsychotic drug, was responsible for causing TD in the patient described herein. Sulpiride has been used to treat major depressive disorder [8] on the basis of the consensus that it acts as an atypical antidepressant at “low” doses by activating striatal dopamine transmission presynaptically through the blockade of D2R autoreceptors on the nigrostriatal dopaminergic axon terminals [9]. However, as shown in this report, long-term exposure to antipsychotics (e.g., sulpiride), even at low doses, can lead to TD by reducing striatal postsynaptic D2R signaling. When antipsychotics (D2R antagonists) are used, the optimal occupancy of presynaptic and postsynaptic D2Rs in the striatum is crucial for balancing therapeutic efficacy and adverse effects [9].
TD can develop gradually, often as focal or segmental dystonia, and then spread over time to other body parts [1]. Once the causative drug is identified, it should be changed or discontinued, if possible [1]. However, cessation of antipsychotics can sometimes temporarily worsen dystonia symptoms (known as “neuroleptic-withdrawal dystonia”) [1,2]. Depending on the severity of underlying psychiatric conditions, it is often difficult to discontinue an antipsychotic medication. It is challenging to balance the management of psychiatric symptoms with the prevention and treatment of TD. TD can be permanent even after the discontinuation of the offending drugs [1-3]. This irreversible feature of TD may be due to neuronal degeneration caused by oxidative stress in the basal ganglia circuits [2]. Fortunately, TD in our patient was reversible and responded perfectly to levodopa/carbidopa treatment.
Emerging evidence suggests that imbalanced activities between D1R- and D2R-expressing medium spiny neurons (D1- and D2-MSNs, respectively) in the striatal striosome-matrix system may cause dystonia symptoms [2,4-6]. It is also hypothesized that striosomal D1-MSN activity might participate in motor learning (value updating) and performance (action selection) and that its deregulation could cause repetitive and stereotyped motor symptoms, the key clinical features of dystonia syndrome [2-5]. This hypothesis can be applied to TD, as we recently reported that neuroleptic medications could reduce striosomal D1-MSN activity by increasing the striatal cholinergic activity and collateral inhibitory action of D2-MSNs on neighboring D1-MSNs within the striosome subfields [2]. It is thus plausible that the reduced striosomal D1-MSN activity could lead to the emergence of TD. In this context, we showed that idiopathic dystonia could be attenuated through dopaminergic modulation with a low dose of levodopa and chlorpromazine (a D2R antagonist), which increases striosomal D1R signaling [2,4-6]. Since D1Rs are heavily enriched in the striosomes of the human striatum, a low dose of levodopa can exert D1R-agonistic effects primarily on striosomal D1-MSNs [2,4-6]. Overall, we consider that in our patient with major depression, a low dose of levodopa/carbidopa could increasingly normalize striosomal D1R activity, thereby resulting in complete relief of tardive truncal dystonia caused by sulpiride.
In conclusion, once TD symptoms are properly identified, it is crucial to treat them promptly because TD can potentially precede irreversible or life-threatening conditions. Because of its ability to increase striosomal D1-MSN activity [2,4-6], a low dose of levodopa/carbidopa may help to treat reversible TD symptoms. Given that TD is an iatrogenic disorder that is caused by chronic inactivation of striatal D2Rs, it is also advisable to reconsider the appropriateness of using antipsychotics (e.g., sulpiride) for treating major depressive disorder in this era of selective serotonin reuptake inhibitors.
Therapeutic effects of levodopa/carbidopa on tardive truncal dystonia in a patient treated with sulpiride (50 mg/day) for major depression. The patient’s condition was recorded before treatment (Segment 1), at 3 months (Segment 2), and 1 year (Segment 3) after treatment with a daily dose of levodopa (50 mg)/carbidopa (5 mg). Before treatment (Segment 1), he manifested focal dystonia, causing his trunk to bend to the left while standing or walking. His dystonia symptoms fully disappeared at 3 months (Segment 2) and 1 year (Segment 3) after levodopa/carbidopa initiation.
Notes
Ethics Statement
This clinical study was approved by the institutional ethics committee of Osaka Neurological Institute (reference number: OR01-4). Informed consent from the patient was obtained. The study was registered with an International Committee of Medical Journal Editors-recognized registry, the UMIN Clinical Trials Registry (UMIN000054201).
Conflicts of Interest
The authors have no financial conflicts of interest.
Therapeutic effects of levodopa/carbidopa on tardive truncal dystonia in a patient treated with sulpiride (50 mg/day) for major depression. Rear views of the patient before treatment (A) and at 4 weeks (B) and 1 year (C) after treatment with a daily dose of levodopa (50 mg)/carbidopa (5 mg).
REFERENCES
1. Perju-Dumbrava L, Kempster P. Movement disorders in psychiatric patients. BMJ Neurol Open 2020;2:e000057.ArticlePubMedPMC
2. Goto S. Functional pathology of neuroleptic-induced dystonia based on the striatal striosome-matrix dopamine system in humans. J Neurol Neurosurg Psychiatry 2024 Dec 3 [Epub]. Available from: https://doi.org/10.1136/jnnp-2024-334545. Article
3. American Psychiatric Association. Diagnostic and statistical manual of mental disorders, fifth edition, text revision (DSM-5-TR). Washington, DC: American Psychiatric Association, 2022;712.
4. Matsumoto S, Koizumi H, Shimazu H, Kaji R, Goto S. A dual dopaminergic therapy with L-3,4-dihydroxyphenylalanine and chlorpromazine for the treatment of blepharospasm, a focal dystonia: possible implications for striosomal D1 signaling. Front Neurol 2022;13:922333.Article
5. Matsumoto S, Koizumi H, Shimazu H, Goto S. Therapeutic effects of dual dopaminergic modulation with L-DOPA and chlorpromazine in patients with idiopathic cervical dystonia. Neurol Clin Pract 2024;14:e200254.PubMed
6. Matsumoto S, Goto S. Meige syndrome as a craniofacial type of dystonia treatable by dual dopaminergic modulation using L-DOPA/chlorpromazine: a case report. J Mov Disord 2024;17:233–235.ArticlePubMedPMCPDF
7. Burke RE, Fahn S, Marsden CD, Bressman SB, Moskowitz C, Friedman J. Validity and reliability of a rating scale for the primary torsion dystonias. Neurology 1985;35:73–77.ArticlePubMed
8. Kishimoto T, Hagi K, Kurokawa S, Kane JM, Correll CU. Efficacy and safety/tolerability of antipsychotics in the treatment of adult patients with major depressive disorder: a systematic review and meta-analysis. Psychol Med 2023;53:4064–4082.ArticlePubMed
9. Chakroun K, Wiehler A, Wagner B, Mathar D, Ganzer F, van Eimeren T, et al. Dopamine regulates decision thresholds in human reinforcement learning in males. Nat Commun 2023;14:5369.ArticlePubMedPMCPDF
Complete Relief of Tardive Truncal Dystonia With a Low Dose of Levodopa/Carbidopa: A Case Report
Figure 1. Therapeutic effects of levodopa/carbidopa on tardive truncal dystonia in a patient treated with sulpiride (50 mg/day) for major depression. Rear views of the patient before treatment (A) and at 4 weeks (B) and 1 year (C) after treatment with a daily dose of levodopa (50 mg)/carbidopa (5 mg).
Figure 1.
Complete Relief of Tardive Truncal Dystonia With a Low Dose of Levodopa/Carbidopa: A Case Report