Tardive Dyskinesia (TD) has a global mean prevalence of 25%, with slightly lower rates seen in treatment with atypical (or second generation) antipsychotics – 20.7%, as opposed to 30.0% with typical/first generation antipsychotics (Carbon et al, 2017). This case was particularly interesting, given that the patient had no known previous history of treatment with antipsychotic medication. The case highlighted the many other factors that can contribute to the development of TD.
What is Tardive Dyskinesia?
TD is a neurological disorder that is characterised by involuntary movements of the face and jaw (Royal College of Psychiatrists [RCPsych], 2019); described by Waln and Janovic (2013) as any ‘tardive hyperkinetic movement disorder, such as stereotypy, akathisia, dystonia, tremor, tics, chorea, and myoclonus’. It is a recognised side-effect of prolonged use of anti-psychotic medication. TD is a ‘hyperkinetic syndrome’ that occurs later in the treatment journey than extra-pyramidal side-effects (EPSEs), and is persistent (Fann et al, 1976). The prevalence is thought to be 20–50% of all patients treated with neuroleptics (Carbon et al, 2017), although this varies with age.
The most widely accepted hypothesis of the mechanism behind TD is linked to the blockade of dopamine receptors. A chronic blockade by dopamine antagonists (eg antipsychotics) results in a ‘synaptic upregulation’ (Ali et al, 2020). This leads to an exaggerated response of post-synaptic dopamine receptors, particularly in the nigrostriatial dopamine pathway. This region of the brain is highly innervated by dopamine neurons, and is responsible for control of voluntary motor movements. If this area becomes hypersensitised, then hyperkinetic disorders such as tics and chorea may develop. Following chronic dopamine blockade, TD will result (Stahl, 2013).
Other documented mechanisms include ‘perturbation of the delicate balance between dopaminergic and cholinergic systems in the corpus striatum’ (Klawans and Rubovits, 1974). This is where cholinergic neurons in the striatum become damaged or destroyed because of prolonged over-activation, secondary to chronic dopamine inhibition (Margolese et al, 2005).
In the nigrostriatal pathway, dopamine and acetylcholine have a reciprocal relationship. Dopamine neurons here make postsynaptic connections with cholinergic neurons. Dopamine normally inhibits acetylcholine release from cholinergic neurons thereby reducing its activity. If dopamine is blocked, as with the use of antipsychotic drugs, acetylcholine becomes overly active (Stahl, 2013), leading to EPSEs. Anticholinergic agents such as procyclidine, which were commonly prescribed alongside first generation (‘typical’) antipsychotic drugs to combat EPSEs, worsen the symptoms of TD (Yassa, 1988).
Case study
- This is the case of an 80-year-old Caucasian woman (Mrs X) with a long history of anxiety and depression. In January 2020, she was admitted to the acute hospital with constipation (chronic), dehydration and a catheter-associated urine infection. It was also noted by the referring consultant that she displayed some ‘bizarre facial movements’
- On examination, she presented with marked continual involuntary orofacial movements – these included grimacing, movements of the eyebrows, puckering and pouting of her lips, mouth opening and chewing movements, lateral movements of the jaw, repeated protrusion of the tongue. There were occasional choreic movements of her arms and hands observed. These movements are signs of Tardive Dyskinesia
- Her son reported that she had been an inpatient in a psychiatric hospital in the 1970s and 80s but had little knowledge of her full medical and psychiatric history
- It was not possible to access her full medical history prior to 2011 (when Electronic Patient Records [EPR] were introduced), but her GP reported that in 1992 Mrs X had a ‘severe depressive episode’ and in 1993, a ‘non-organic psychosis’. Between the years 1994–2006, she was treated with lithium (it is not known who initiated this). There is no known history of head injury or brain damage, and no known family history of hereditary movement disorders
- From the EPR, it is possible to see that Mrs X was known to the Community Mental Health Team (CMHT) from 2011 to 2015 and was treated for depression and anxiety. During this time, she was on Pregabalin, which was increased to 200 mg twice daily and Clomipramine 250 mg at night. In 2013, Diazepam was introduced by her GP, which was slowly reduced to 2 mg twice daily by the CMHT. In 2015, Mrs X was re-referred with short-term memory problems and subsequently diagnosed with Mild Cognitive Impairment (MCI). In 2018, she was re-referred again; at this time, Diazepam 2 mg twice daily, Pregabalin 200 mg twice daily were tried and Clomipramine 250 mg was replaced with Imipramine 125 mg at night. In November 2018, her GP added sertraline, which was increased to 100 mg twice daily. There is no history of use of anti-emetic medication, such as Metoclopramide. There is no documentation in relation to any movement disorder noted, other than a comment made by a Consultant Psychiatrist in 2015 regarding ‘fine tremor of her hands’ attributed to previous lithium therapy, and ‘general shakiness’ having improved
- At the time of the referral to the Mental Health Liaison Team, Mrs X was treated with Pregabalin 250 mg twice daily, Sertraline 100 mg twice daily and Imipramine 125mg at night. Additionally, Lorazepam 500mcg as required (maximum four times daily) was prescribed. Overall, the Anticholinergic Burden score was 5 (Rudolph et al, 2008). Diazepam had been omitted from her regular prescription for the four days since admission; this was then reinstated
- Her presentation slowly improved as a result of treatment of her infection, as well as improved concordance with medication. Mrs X was amenable to care interventions, and her oral intake improved. The orofacial movements persisted.
Selective Serotonin Reuptake Inhibitors (SSRIs) can inhibit dopaminergic neurones in the nigrostriatial pathway, increasing the inhibitory effects of serotonin on dopamine production in the basal ganglia (Mander et al, 1994; Stahl, 2013).
There is evidence to suggest that TD and other movement disorders may be an intrinsic feature of schizophrenia, rather than purely an adverse effect of the medication used to treat it (Whitty et al, 2009), as described by Kraeplin in Dementia Praecox (1919). A study of 47 antipsychotic-naïve patients with schizophrenia published in 1982 highlighted that involuntary movement disorders were present in 51%, and the presentation was ‘indistinguishable from TD’ (Owens et al, 1982). A further study of 64 individuals with schizophrenia who were antipsychotic-naive found 10.9% displayed abnormal involuntary movements (Ayelu at al, 2014).
Risk factors for developing TD
- The use of antipsychotic medication (both typical and atypical drugs) (RCPsych, 2019)
- Increased age leads to higher risk of TD, with age-related progression of neurodegenerative conditions (Waln and Jankovic, 2013)
- Vascular-type dementia (Woerner et al, 1998)
- Rates of TD are higher in women, with post-menopausal women being at greater risk (there is some evidence that oestrogen has a modulating effect on dopamine-mediated behaviours) (Waln and Janovic, 2013)
- Those who display EPSEs early in treatment have a higher risk of developing TD in the longer term (Tarsy and Baldessarini, 2006)
- Compared to caucasians, those from African descent are at a greater risk. Interestingly, individuals of Filipino and Asian descent have a lower rate of TD, despite using predominantly typical antipsychotics (Cornett, 2017)
- Previous exposure to lithium, without co-medication with antipsychotics (Fountoulakis et al, 2019).
Involuntary movements during long term lithium treatment were reported in 16% of cases after seven years of treatment, with risk factors being age, high 12hr Li levels, as well as female sex, early onset of affective disorder and low body weight. Prior exposure to neuroleptic medication, and/or lithium may sensitise nigrostriatial dopamine receptors to increased serotonergic activity (Budman and Bruun, 1991).
Antipsychotics and Tardive Dyskinesia
Although treatment with any antipsychotic medication is associated with common or very common movement-related side effects (British National Formulary 80, September 2020–March 2021), second generation antipsychotics (SGA) are known to cause fewer side effects associated with long term use, ie tardive dyskinesia. In four adult studies (n=2088, age 41.2 years, 71.2% male, 62.0% white), TD prevalence rates were 13.1% for second-generation antipsychotics, 15.6% for antipsychotic-free patients, and 32.4% for first-generation antipsychotics (Correll and Schenk, 2008). This review also points to an observation already cited in this paper that TD is also relatively significantly present in the antipsychotic naïve patients suffering from enduring mental illness.
There are also more recent observations that will require further attention from researchers regarding the role of comorbid obsessive-compulsive syndrome in the emergence of tardive movements in patients treated with antipsychotic medication and particularly with SGAs (Ryu et al, 2015).
With the aging population and the increase in the use of antipsychotic medication in patients who are over 65 years old, one needs to be aware of yet another factor contributing to the effects of treatment with antipsychotics in this age group. In elderly patients, age-related changes in pharmacokinetics and pharmacodynamics because of age–induced epigenetic alterations (chemical and environmental modifications to certain proteins, ie histones that affect expression of the genes) impact on antipsychotic function ie efficacy and side effects, including tardive movements disorder (McClarty et al, 2018).
Antidepressants and Tardive Dyskinesia
In general, antidepressants work by increasing or stabilising the levels of serotonin, dopamine and norepinephrine in the brain. TD related to antidepressant therapy is less prevalent than that related to antipsychotics, but is thought to be more common in older adults (Cornett, 2017). This is likely because of physiological changes in the ability to absorb, distribute, metabolise and excrete the drugs, which may lead to their accumulation in the body and more severe side effects. Trazadone, doxepin, clomipramine and amitriptyline have been reported to induce TD in patients who have had no previous exposure to antipsychotics (Clayton, 1995). Fluoxetine and sertraline are also both associated with TD; increasing age is a significant risk factor for a patient when prescribed sertraline (Mander et al, 1994; Cornett, 2017). Tricyclic antidepressants are highly anticholinergic agents, and this is likely the key to their link to TD (Vandel, 1997).
A review of the literature related to non-dopamine blocking agents and TD (D'Abreu and Friedman, 2018) suggests that antidepressants may increase the risk of TD in those who have previously taken drugs such as antipsychotics, even in the distant past. It is discussed that the dopamine-blocking drugs may somehow ‘prime’ the brain – make it more vulnerable, and the addition of, for example, an antidepressant may ‘unmask a latent TD’.
Tricyclic Antidepressants
The tricyclic antidepressants (TCAs) were originally trialled as antipsychotics (Stahl, 2013) in the mid-twentieth century. They were ineffective in treating psychosis, however they were noted to have antidepressant effects (Pereira and Hiroaki-Sato, 2018). They work by selectively inhibiting the reuptake of norepinephrine and serotonin, to a greater or lesser extent, in the post-synaptic cleft. TCAs are structurally similar to typical antipsychotics. They only have a weak action in altering central dopamine metabolism, but are potent anticholinergic agents. They are antihistamine (causing sedation), and they block alpha 1 adrenergic receptors, leading to orthostatic hypotension. They also weakly block sodium ion channels in the heart and the brain, and it is this action that, in overdose, will lead to arrhythmias, seizures, coma and death.
A reduction in central cholinergic activity can exacerbate idiopathic or drug-induced dyskinesia, and there is evidence that there is a hypocholinergic state in TD, which is likely secondary to chronic exposure to anticholinergic effects of neuroleptic drugs (Fann, 1974). A study involving long-term administration of haloperidol to rodents demonstrated a reduction of cholinergic neurons in specific areas of the striatum, which regulates oral movements (Grimm et al, 2001).
Treatment and prognosis for patients with Tardive Dyskinesia
There is currently no specific treatment for TD. As it is largely triggered by medications, prevention of the onset of the disorder is the best method of combatting it (Waln and Janokovic, 2013).
A small trial by Bergman et al (2005) showed that it is possible that Donepezil may lead to a balance in the dopamine-acetylcholine interactions and give some benefit, however further evidence is needed. Tetrabenazine (a dopamine-depleting drug used in Huntington's disease) has been shown to give a marked reduction in amplitude and intensity of abnormal movements in TD (Kenney et al, 2006).
Discussion
The case of Mrs X was an interesting study, as she presented with a rare case of TD triggered by many factors, with the likely exception of what is commonly regarded as the main causative factor, antipsychotics. The author's opinion is that Mrs X developed TD as a consequence of multiple factors, primarily her prolonged treatment with tricyclic antidepressants (a minimum of 9 years). This was compounded by her gender, being post-menopausal, her history of treatment with lithium and concomitant use of SSRI antidepressants.
The authors felt that this report may offer readers a description of a relatively rare case of multifactorial tardive dyskinesia, as well as practical synopsis of this rare clinical presentation in modern times. The authors hope that by presenting this case, it will help to balance out the view that the wider medical audience may have on the causative mechanisms of TD. This in turn will aid understanding of the disorder for the patients and families in their care through dissemination of information.
There are weaknesses to this paper: the authors were unable to determine whether Mrs X has ever been prescribed antipsychotic treatment as historical paper medical records were sadly inaccessible. It is also unknown if at any stage sporadic Huntington's Disease has been excluded.