Tardive Dyskinesia also called TDs is a term referred to as the spontaneous movement of body parts such as the face, lips, and tongue. TDs can also occur in patients experiencing extremities of long-standing use of Dopaminergic Antagonist Drugs. Even though they are linked with constant use of Neuroleptics, people with Neuropsychiatric Conditions and Schizophrenia are also vulnerable to the development of Tardive Dyskinesia since they regularly use Anti-Cholinergics, Orthodox Neuroleptic Drugs, and Toxins.
Tardive Dyskinesia is usually valued due to the polymorphism reaction of Dopamine Receptor D2 Gene, Taql A, Taql B, Haplotypes and Dopamine Receptor D3, Dopamine Transporter Gene as well as manganese Superoxide Dismutase Gene.
Among all these factors, the breakdown of Dopamine Transporters has been calculated to play the most significant role in the growth of Tardive Dyskinesia. This disease is mostly discerned from other movement syndromes. These movement disorders occur in patients as a result of the manifestation of Dopamine Antagonists leading to the development of Acute Dystonia and Akathisia. Dopamine Antagonists are also known to leave some acute effects over a patient’s body such as Parkinson's disease, Pill Rolling Tremors, and Bradykinesia. These movement disorders that occur because of dopamine antagonists are termed as Extrapyramidal Syndromes, i.e. EPSs.
A. Adenosynergic Receptor System
There are multiple shreds of evidence that state that there is significant involvement of the Adenosynergic Receptor System in the prevalence of Tardive Dyskinesia in rodents. Several drugs such as Haloperidol were found to encourage void eating movements, facial stereotypies, and orofacial movements in research animals. These effects were later treated by the help of Caffeine and Adenosine. These two are a main inhibitory neurotransmitter of a central nervous system and so play a major role in the treatment of Tardive Dyskinesia. Moreover, these results strongly recommend the use of Caffeine and Adenosine as therapeutic agents during clinical trials.
B. Extrapyramidal Dysfunction
The pyramidal system of a body is responsible for controlling voluntary movements and embraces specific anatomic trails from cortex to the body muscles. The movements due to the pyramidal system are visible such as a heart attack that leads to paralysis of a body organ.
On the other hand, the extrapyramidal motor activities can cause static as well as automatic movements of posture that are not visible. Classic syndromes due to the extrapyramidal system include Akathisia, Stereotypies, Chorea, Myoclonus, Dyskinesia, Tremor, and Tic, etc. some of these disorders do not take account of lesions in basal ganglia and may also not be involuntary.
C. Bradykinesia and Hyperkinesia
Tardive Dyskinesia is an involuntary, movement syndrome that can be divided into two categories, i.e. Bradykinesia and Hyperkinesia. This dualistic categorization of Tardive Dyskinesia is based on the studied topographies, etiologies, and phenomenology. Different methods towards data analysis, logistic regression, and dynamic cluster analysis have also facilitated this binary classification.
Bradykinesia is described as abnormal slowness like rigidity, problems in terminating actions, difficulty in initiating a new task, and incognito facial expressions. These symptoms are usually seen in patients with Parkinson’s disease. In contrast to this, Hyperkinesia is referred to as an irrational movement of the body, such as Chorea, Dystonia, Tic, Tremors, and Akathisia.
Dopamine antagonists are considered to be the major culprit behind Tardive Dyskinesia. Other than this, low potency and high potency neuroleptics, long-term use of depot drugs such as Enanthate and Deaconate are also among the main causative agents of TDs. Some other etiologies of Tardive Dyskinesia are:
- Blockade of D2 dopamine receptor at channeling points of neuroleptics
- Association of Amisulpride with the bloodstream
- Atypical antipsychotic agents such as Olanzapine and Risperidone
- Effects of D2 dopamine receptor antagonist
- Use of Antihistamines
List of medications that can lead to Tardive Dyskinesia is:
- Butyrophenones (Loxapine, Haloperidol, Droperidol, and Dibenzodiazepines)
- Diphenylbutylpiperidines (Pimozide)
- Indolones (Molindone)
- Phenothiazines (Mesoridazine, Perphenazine, Chlorpromazine, Fluphenazine, Trifluoperazine, and Thioridazine)
- Thioxanthenes (Thiothixene)
- These include Risperidone, Paliperidone, Olanzapine, Quetiapine, and Amisulpride
- Anticholinergics (Benzhexol, Ethopropazine, Biperiden, Procyclidine, and Orphenadrine)
- Antidepressants (TCAs: Amoxapine, Amitriptyline, Doxepin, Imipramine, and Amitriptyline-Perphenazine MAOIs: Phenelzine, SSRIs: Trazodone, Fluoxetine, and Sertraline)
- Antiemetic (Prochlorperazine and Metoclopramide)
- Antiepileptic drugs (Ethosuximide, Phenobarbital, Carbamazepine, and Phenytoin)
- Antihistaminic decongestants
- Antimalarials (Chloroquine)
- Antiparkinsonian agents (Levodopa and Bromocriptine)
- Anxiolytics (Alprazolam and Carbidopa-levodopa)
- Biogenic amines (Dopamine)
- Mood stabilizers (Lithium)
- Oral contraceptives (Estrogens)
- Stimulants (Amphetamine, Caffeine, and Methylphenidate)
2. Atypical Antipsychotic Drugs
3. Non-neuroleptic Compounds
A genetic basis has not been discovered as a cause of Tardive Dyskinesia. The scientists are still studying the functional polymorphism process of the gene coding related to human glutathione S-transferase P1 (GSTP1) and its association with the occurrence of human glutathione S-transferase P1 (GSTP1) and its association with Tardive Dyskinesia. Many types of research have also stated that TDs is not associated with functional polymorphism of CYP3A4 and CYP2D6 genes, superoxide dismutase 2 (SOD2) genes, quinine oxidoreductase 1 (NQO1) genes, and nicotinamide adenine dinucleotide phosphate (NADPH) genes but is somewhat linked with the polymorphism of serotonin 2A and 2C receptor genes along with dopamine D3 receptor.
A. Rate of recurrence
- Multiple studies have shown that approximately fifteen-thirty percent of people who are given constantly given neuroleptic drugs may develop Tardive Dyskinesia at some point in their lives. This disease is more likely to prevail in those individuals who experience adverse effects of dopamine antagonists. Different types of TDs such as buccolingual, masticatory dyskinesia, and orofacial disorders may vary widely in terms of its frequency, and only one or two people out of a hundred develop this condition.
- Tardive Dyskinesia can easily prevail in all age groups, but older people are at more risk. Among older adults, females are more likely to develop Tardive Dyskinesia in comparison to males. Young men are not susceptible to develop Tardive Dystonia and Blepharospasm. Tardive Dyskinesia can occur in people from every race and ethnicity, but African-Americans are more likely to have this condition than others if they are constantly exposed to neuroleptic drugs.
B. Race, Age, and Sex
Patients who deal with movement syndromes usually display a combination of multiple dyskinesia disorders. People who have been taking neuroleptics for a long period may show acute or chronic or both symptoms at once. When the doctor attends a patient for the first time, it may be very hard to diagnose acute or chronic Tardive Dyskinesia without carefully knowing the history of prevalence. Brief documentation should be done that inclusively indicates a patient’s movement issues as well as medication charts so the doctor can accurately delineate the problems.
Even thigh Tardive Dyskinesia can be observed after continuous exposure to specific materials such as Metoclopramide, Levodopa, and Amphetamines but the prototypical form of Tardive Dyskinesia can be induced through Antipsychotic Dopamine D2 Receptor Blockers. TDs induced though neuroleptic drugs can be characterized by rhythmic movements of jaw, tongue, trunk, choreiform and athetoid. For diagnostic purposes, exposure to neuroleptics for at least three months is required for young people and one month for people above 60 years.
During the initial examination, a history of neurologic disorders that includes cerebrovascular disorders, basal ganglia, neoplasms, and head trauma should also be made. The doctor should also inform about the family history of hereditary dyskinesia linked to Huntington’s Diseases, Torsion Dystonia, and Wilson Disease.
Basic characterization of Tardive Dyskinesia is irregular movements of low frequency as well as movable amplitudes that can easily be expressed in perioral areas, cheeks, mandibles, tongue and other areas of toes, fingers, and face. During the physical examination, Tardive Dyskinesia should be observed in the upper face of the patient with brow wrinkling and excessive blinking.
The doctor must inquire about the use of dentures. He must know if the patient is knowledgeable about the movements in his mouth, feet, hands, and face and if their teeth bother them when used. This disorder is mainly linked with involuntary movements, slow and snakelike writhing, wiggling, bending, and tapping of body extremities. All these movements should be assessed and observed. Other movements that can be observed include guitar-playing hand movements, extension, and flexion of wrists and fingers, jerking of diaphragm and abdomen, neck and trunk movements, use of ankle and toes and dyskinesia movements of the pelvic region. In addition to this, investigate any distress during movement, the presence of any inner restlessness, problems in maintaining posture, and overall feelings to conclude the assessment section properly.
Generally, doctors use the following parameters to diagnose if the patient has Tardive Dyskinesia:
- If the patient is consuming neuroleptics for over three months (if young) or one month (if older than 60 years) and exhibit at least two abnormal movements of minor intensity.
- If the patient is consuming neuroleptics for over three months (if young) or one month (if older than 60 years) and exhibit at least one abnormal movements of moderate intensity.
- If the patient is consuming neuroleptics for over three months (if young) or one month (if older than 60 years) and exhibit at least two abnormal movements of minor intensity within four weeks of discontinuing the drugs.
- If the patient is consuming neuroleptics for over three months (if young) or one month (if older than 60 years) and exhibit at least one abnormal movements of moderate-intensity within eight weeks of discontinuing the drugs.
- If the patient shows signs of Toxicity, Compulsions, Convulsion Disorder, Fahr Syndrome, Factitious Disorder, Hypothyroidism, Hyperthyroidism, Malingering, Munchausen Syndrome, Meige Syndrome, Poor Dentures, Spontaneous Dyskinesia, Syphilis, Dementia, Supranuclear Palsy, Zaghrouta, Sydenham Syndrome, Lupus Erythematous, Wilson Disease, Parkinson disease, Somatization Disorder and Polycythemia Rubra Vera.
For the diagnosis and treatment of Tardive Dyskinesia, analysis of resembling disorders such as syphilis, thyroid disease, and seizure disorders is very important. At times, designated laboratory readings, computed tomography, positron emission tomography, magnetic resonance imaging, and single-photon emissions computed tomography are done to evaluate the disease in detail.
- Identification of scarcity of serum ceruloplasmin due to abnormal copper transporter gene
- Urine copper collection
- Liver function test and analyzation of liver transaminases
- Thyroid function test
- Serum biochemistry
- Serum ceruloplasmin
- Serum copper
- Syphilis serology
- Screening tests for connective tissue disease
- Tests for vasculitides
- Red blood cell count
- Checking of serum calcium level
A. Lab Studies
For laboratory studies, the following tests are performed:
B. CT, MRI, SPECT, PET
Patients dealing with Tardive Dyskinesia, the results of CT and MRI are usually under normal ranges. But, these tests are very helpful is supplementing differential diagnosis. CT scan and MRI can show atrophy of the caudate nucleus for Huntington’s disease and calcification of basal ganglia during Fahr syndrome. To check the enhanced metabolism of glucose in precentral gyrus and Globus pallidus, SPECT and PET analysis can be done. PET is very helpful in differentiating Tardive Dyskinesia from other similar disorders while SPECT can assist with amelioration of Tardive Dyskinesia.
Management and Treatment
FDA has approved many drugs for the treatment and management of Tardive Dyskinesia. These drugs are:
This drug is now approved for the treatment of Huntington’s disease and Tardive Dyskinesia. This drug is a VMAT2 inhibitor that can help with the release of dopamine in synapse and can reverse the movement-related side effects of antipsychotics and dopaminergic blockers.
It is also a VMAT2 inhibitor used for the treatment of Tardive Dyskinesia. This drug can manage the involuntary movements in patients dealing with TDs due to over-consumption of placebo and Deutetrabenazine.
This drug was successfully tested and verified to alleviate the signs and symptoms of Tardive Dyskinesia as well as spontaneous oral dyskinesia. 1-4.5 mg of this drug every day in patients with clinical trials showed a legit reduction in Tardive Dyskinesia symptoms by 30 percent in comparison to the placebo.
D. Anecdotal support
Various other therapeutic agents such as Levodopa, Carbidopa, Vitamin E, Benzodiazepines, Propranolol, Reserpine, Dopamine Depleting Agents, Ondansetron, Botulinum Toxin, and Tetrabenazine have helped patients dealing with Tardive Dyskinesia. Discontinuing anti-cholinergic therapies and increasing the overall dose of dopamine antagonists in the body has also provided relief to some extent in patients with TDs.