Abstract
Background
Long-term use of antipsychotics or other dopamine antagonists can result in the extrapyramidal side effect of tardive dyskinesia (TD).
Case presentation: An 18-year-old female patient experienced abnormal speech and behavior and because of an equivocal diagnosis, she was given daily doses of 300 mg of quetiapine and 60 mg of ziprasidone. She had used these medications for 2 years before the appearance of involuntary abnormal movements. These movements, which were classified as TD, steadily worsened and markedly interfered with her daily life. Following a trial-and-error course of therapy with vitamin E, vitamin B6, amantadine, valproic acid sodium, lorazepam, and diazepam, the drugs were gradually reduced and stopped, yet the aberrant movements persisted. Finally, the patient was given olanzapine, clonazepam, baclofen, and gabapentin. The Abnormal Involuntary Movement Scale was used to assess changes in the patient's condition. Her TD was efficiently managed through co-administration of olanzapine, clonazepam, baclofen, and gabapentin.
Conclusions
The possibility of TD inducing by antipsychotic use is a clinical concern, even though atypical antipsychotics decrease the incidence of extrapyramidal side effects, and it cannot be entirely excluded. This report provides useful insights into the management of TD and will help clinicians manage similar cases.
Background
Tardive dyskinesia (TD) is characterized by involuntary spasms or dance-like movements of the tongue, lower face, jaw, and limbs, which sometimes involve the muscles of the pharynx, diaphragm, or trunk. These symptoms last for at least several weeks and typically occur several months after the use of dopamine receptor blockers. 1 Symptoms may appear within a relatively short period of time after older adults use these drugs. TD is an iatrogenic condition that encompasses a wide phenomenological spectrum of movement disorders caused by exposure to dopamine receptor blocking agents, according to the Fifth Edition of the Diagnostic and Statistical Manual of Mental Disorders. 1 These movements disappear during sleep and lessen during conversation.
The pathophysiological mechanism of TD is unclear and controversial. However, the prevailing hypothesis is that TD is caused by D2 receptor blockade in the motor striatum. 2 Furthermore, genetic factors and insufficiency of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA) 3 might be involved.
Data on TD treatment are limited, and the best management strategy remains prevention. Additional long-term safety and efficacy data are needed for the drugs deutetrabenazine and valbenazine, and their routine availability to patients outside of the USA remains in question. Here, we present a case report of a patient with neuroleptic-induced severe TD who benefitted from concurrent administration of olanzapine, clonazepam, baclofen, and gabapentin. This report will provide useful insights into the management of TD and will help clinicians manage similar cases.
Case presentation
On December 24, 2020, an 18-year-old female patient was admitted to our psychiatry inpatient facility with reports of unusual behavior and uncontrollable movements. The patient, suffering from auditory hallucinations and abnormal behavior, with an undetermined diagnosis, was admitted to a local psychiatric hospital for inpatient treatment 3 years prior. She was given a prescription for 300 mg of quetiapine and a 60 mg capsule of ziprasidone once per day, which helped regulate her symptoms and eventually resulted in full remission of her condition. She continued using the same dosage for 2 years. She experienced an upward extrapyramidal reaction in both of her eyes during this time. Benzhexol hydrochloride tablets (6 mg/day) were administered for 6 months before being discontinued. Her hands began to spread out uncontrollably one day, and the symptoms worsened when she walked. The symptoms were thought to be caused by the antipsychotic drug when she returned to the local psychiatric hospital. Her symptoms increased as her medication was tapered and stopped, and if she continued to walk for a short distance, her entire body would tumble backwards. The patient was moved to another psychiatric hospital for inpatient and outpatient care, and her condition was identified as TD. She was given prescriptions for quetiapine, amantadine, Ginkgo biloba, and baclofen, and her symptoms began to improve slightly. The patient's aberrant posture and uncontrollable body movements started to worsen 1 week before admission to our facility. She was unable to walk normally, which greatly hampered her everyday activities. According to a thorough analysis of her medical history, the patient exhibited a depressed mood, decreased interest, slow mental processing of responses, trouble concentrating, negative thoughts, and recurrent negative behaviors. The most serious incident occurred when she locked all windows and doors and attempted to suffocate herself with gas, but her family was alert and stopped her in time. The illness had at least a 2-week course. For 1 month, the patient experienced excitement, talkative behavior, excessive spending beyond her means, lack of sleep but with high energy levels, and increased activity.
The patient’s father had died of a brain infarction 2 years earlier. She had an undefined history of mental illnesses. When the patient was 8 years old, her mother died from an unknown cause. The patient had never used alcohol or drugs. A physical examination did not reveal any evident abnormalities, and a psychological evaluation revealed a mild depressive episode and a reduction in volitional needs.
After admission, the results of blood tests (including routine blood evaluations, a complete biochemical set, thyroid function, hepatitis, syphilis, and human immunodeficiency virus), head computed tomography, electroencephalography, and other associated procedures were all negative. Before starting treatment, the patient had a total score of 22 on the Abnormal Involuntary Movement Scale (AIMS).
The patient had no obvious physical disease, and no obvious abnormalities were found in laboratory examinations, which excluded organic mental disorders and mental disorders associated with somatic diseases. She had no history of psychoactive substance use, which excluded psychoactive substance-related mental disorders. The patient had auditory hallucinations when she had an extremely depressed or manic mood, which excluded schizophrenia and other delusional disorders. Although the patient had an unusual posture, she had no obvious internal conflict before the onset of the disease, and she did not have a dramatic personality, which excluded conversion disorder. TD and tardive dystonia can be difficult to distinguish clinically. Tardive dystonia may respond to high-dose anticholinergic therapy, but TD may not respond or worsen. Huntington's disease is an autosomal dominant inherited neurodegenerative disorder that, in addition to psychiatric symptoms and cognitive changes, is accompanied by involuntary movements, primarily dance-like movements. The patient had no family history of such a disease. The patient took dopamine receptor blockers for 2 years and developed involuntary spastic movements of the limbs and trunk for 1 year. She had a total score of 22 on the AIMS. According to the Fifth Edition of the Diagnostic and Statistical Manual of Mental Disorders, she was identified as having TD and bipolar I disorder (current or most recent depressive episode). The institutional review board (Zhejiang Tongde Lun Review 2023 Approval No. 099-JY) approved the study protocol. The patient participated voluntarily and provided written informed consent prior to treatment. Signed patient consent has been obtained for the publication of this case. The reporting of this study conforms to the CARE guidelines. 4
As shown in Table 1, the patient's daily intake of 400 mg of quetiapine was gradually decreased and eventually stopped. However, the patient's TD symptoms did not lessen. Additionally, a trial-and-error course of therapy was conducted with vitamin E, vitamin B6, amantadine, valproic acid sodium, lorazepam, and diazepam. The uncontrollable movement became markedly worse with the reduction of baclofen. Her AIMS score was 29 at that point. The TD movements were constant and vigorous throughout the day, and these symptoms disappeared as she went to sleep. The patient perspired as a result of her muscle contractions. When she was awake, she frequently experienced fatigue and dehydration. We started by gradually decreasing the quetiapine dosage. According to the neurologist's recommendation, the baclofen dose was gradually decreased, but the patient's uncontrollable movements suddenly became more severe. As a result, the treatment plan was changed to include olanzapine, which was gradually increased to 10 mg per day, baclofen, which was gradually increased to 30 mg per day, and clonazepam, which was gradually increased to 6 mg per day. During the course of the illness, the patient experienced discomfort in both knees. Celecoxib (400 mg/day) was administered for 1 week to manage the pain, but there was no noticeable improvement. Gabapentin (900 mg/day) was then administered. Slightly more than 2 weeks later, the patient's aberrant movements had greatly improved, and she was able to eat and sit on a stool by herself. Her AIMS score decreased to 13. The patient's TD movements were greatly improved 3 weeks later, and her AIMS score had decreased to 5. The dyskinetic movements nearly disappeared and had become hardly perceptible 6 months later, and her AIMS score decreased to 0. Olanzapine, baclofen, clonazepam, and gabapentin were prescribed as treatments. The abnormal movements were completely absent at her 6-month follow-up visit. The patient used 10 mg olanzapine, 2.5 mg clonazepam, 10 mg baclofen, and 900 mg gabapentin daily as part of her maintenance medication. Her overall AIMS score was 0. At the 17-month follow-up visit, the patient lived alone and had a job. She continues to take 5 mg olanzapine, 1 mg clonazepam, 10 mg baclofen, and 900 mg gabapentin daily. To date, the patient is satisfied with the treatment that she received.
AIMS score and doses of the drugs administered (mg).
AIMS, Abnormal Involuntary Movement Scale.
Discussion
Because there is currently no proven cure for TD, it is typically advised to stop using the medication that induces the condition. However, many individuals with severe mental illness cannot stop taking antipsychotics because of relapsing illness. Hence, additional atypical antipsychotics should be considered for this population. Atypical antipsychotics are thus the first option for people who require antipsychotic therapy.
TD is still a clinical concern; even though atypical antipsychotics decrease the incidence of extrapyramidal side effects, TD can never be completely ruled out. 5 According to a recent comprehensive analysis, switching to clozapine may decrease the likelihood of developing TD and/or could be used to treat existing TD. 6 If required, management techniques for TD can be implemented in the following order: 1) discontinuing anticholinergic treatment, 2) transferring to clozapine treatment, 3) beginning suppressive treatment with tetrabenazine or a conventional antipsychotic medication, 4) increasing an experimental treatment while decreasing medications such as donepezil, melatonin, branched chain amino acids, vitamin E, or vitamin B6. 7 However, after we informed the patient and her family about clozapine, they decided against its use because they were concerned about its side effects, particularly neutropenia/agranulocytosis, myocarditis/cardiomyopathy, 8 pneumonia, 9 and seizures. Deutetrabenazine and valbenazine are Food and Drug Administration-approved vesicular monoamine transporter 2 inhibitors for the treatment of TD, 10 but these drugs were not taken because they were not readily available at that time.
Quetiapine, a second-generation antipsychotic with a low D2 affinity, was maintained in this case, and the dosage was gradually decreased, but the TD symptoms did not appreciably improve. Meanwhile, we gradually reduced the baclofen dose in accordance with the neurologist's advice before admission, but the patient's uncontrollable movements sharply intensified. When the dose was decreased to 5 mg per day, the patient’s AIMS score increased to 29; therefore, we changed the regimen to increase the baclofen dose to 25 to 30 mg per day. Quetiapine was gradually replaced by olanzapine, and the dose was titrated to 10 mg per day and combined with 900 mg per day of gabapentin. The patient's involuntary movements markedly improved.
Olanzapine, as an active therapeutic agent, would presumably alter neural transmission within specific brain neurocircuits in a manner that promotes restoration of motor control. 11 Many pathophysiological mechanisms of TD have been considered including 1) the dopamine receptor hypersensitivity hypothesis, in which olanzapine may reduce dopamine receptor hypersensitivity by balancing intermittent receptor blockade and increasing dopamine neurotransmission; 12 2) the GABA insufficiency hypothesis, in which olanzapine may facilitate increased motor control through changes in GABAergic neurotransmission; 13 and 3) others, in which olanzapine could facilitate neuroprotective mechanisms, an effect that could counteract neurodegenerative changes involved in the etiology of TD. 14
Clonazepam is advised for TD treatment. Clonazepam is a benzodiazepine, and its mechanism of action involves completing specific binding to the gamma-aminobutyric acid (GABA) A receptor by increasing the affinity of the inhibitory neurotransmitter to the receptor, rather than directly activating the receptor, which indirectly causes GABA excitation via GABA-mediated transmitters. 15 Drugs that act as GABA agonists have been used to treat TD; however, they have strong sedative effects and could exacerbate mental health or psychotic symptoms. 16 Baclofen, as a GABA agonist, is a skeletal muscle relaxant and works mainly at the spinal cord level to inhibit monosynaptic and polysynaptic reflexes by interfering with the release of excitatory neurotransmitters. 17 Gabapentin is structurally similar to the neurotransmitter GABA, but it does not act directly through the GABA mechanism. It is not metabolized into GABA or GABA agonists, nor does it inhibit GABA uptake and degradation. 18 The exact mechanism by which gabapentin acts on TD is unknown, but in this case, it also acted as a mood stabilizer for bipolar disorder. The pathophysiology of neuroleptic-induced TD involves D2 receptor supersensitivity and GABA insufficiency, which may likely explain why co-administering olanzapine, clonazepam, baclofen, and gabapentin to the patient was useful for successfully controlling the illness.
Conclusion
Understanding the potential advantages of the use of olanzapine, other atypical antipsychotics, and non-antipsychotics to treat TD symptoms requires further research. The ideal treatment method for TD is preventive measures because there is no effective and safe medication for the condition. Early detection and routine monitoring are necessary for patients who develop TD. Therefore, careful evaluation is required when using these medications for routine and maintenance treatment of patients with mental disorders. Deutetrabenazine and valbenazine have been approved by the Food and Drug Administration for the treatment of TD, with high-level evidence from key clinical studies. 10 Although the data are limited, additional therapeutic options should be explored for individuals who cannot tolerate or do not respond to vesicular monoamine transporter 2 inhibitors or when these drugs are not readily available. This report provides useful insights into the management of TD and will help clinicians manage similar cases.
Footnotes
Acknowledgements
We are grateful to the patient, who provided informed consent for publication of this case.
Authors’ contributions
The patient was diagnosed by JC and BJ. JC created the treatment plans for the patient. The data were evaluated and statistical calculations were performed by WW, BL, and XG. The initial draft of the document was written by XG and BL. The final text was approved after being revised by all authors.
Availability of data and materials
The datasets generated and/or analyzed during the current study are available from the corresponding author upon reasonable request.
Declaration of conflicting interests
The authors declare that they have no competing interests.
Ethics statement
Written informed consent was obtained from the patient before the case details were published. This case report was approved by the Institutional Ethics Committee of Tongde Hospital of Zhejiang Province.
Funding
The authors declare no funding.
