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Tardive dyskinesia is a medication-induced movement disorder characterized by repetitive, uncontrollable bodily movements, primarily in the tongue, lips, face (most notably the jaw), and occasionally the periorbital area.

Sometimes, these movements are evident in the neck, shoulder, trunk, and limbs, as well.

Symptoms can be severe enough to interfere with breathing, speaking, eating, and ambulation.

Despite the effects of psychotic disorders on self-awareness, it has been estimated that 80% of patients with tardive dyskinesia are in fact aware of their abnormal movements. For some people, this can substantially impact their ability to interact with others and engage in daily activities.

Pathophysiology

Dopamine blockade by medications with dopamine antagonist properties are believed to play a central role in the pathophysiology of tardive dyskinesia.

Dopamine plays a critical role in regulating reward and movement.

In the motor pathway, dopamine is produced in the substantia nigra cell bodies and discharged into the striatum. These areas are involved in the control of bodily movement.

Reductions in dopaminergic function in the striatum lead to a compensatory increase in the sensitivity of the D2 receptors on the postsynaptic neuron.

Tardive dyskinesia occurs most frequently with the use of antipsychotic medications. As use of antipsychotics for mood disorders is increasing, we can expect to see more cases of TD being reported.

A meta-analysis of 41 clinical trials showed an overall prevalence of 25% in patients receiving antipsychotic medications – 30% with first generation, or typical, antipsychotic agents, and 21% with second-generation, or atypical agents. However, in patients treated with an atypical without prior exposure to a typical agent, the prevalence rate was only 7.2%.

Atypical antipsychotics bind less tightly to the D2 receptors compared with first-generation agents, and it is believed that more rapid D2 dissociation decreases the risk of tardive dyskinesia.

However, the dopamine hypothesis is unlikely to represent the complete picture.

If it did, discontinuation of a dopamine antagonist might be expected to result in symptom resolution, but tardive dyskinesia is often irreversible.

GABAergic dysfunction, oxidative stress, and the accumulation of certain metals during antipsychotic treatment are among the mechanisms implicated as causes.

Diagnosis

Although symptoms of tardive dyskinesia can be very noticeable, diagnosis can be challenging. The most common obstacle to prompt diagnosis is that tardive dyskinesia is easily confused with drug-induced parkinsonism, which has a similar presentation and may co-occur in the same patient, complicating both diagnosis and treatment.

However, tardive dyskinesia and drug-induced parkinsonism differ in important ways.

Tardive dyskinesia onset is usually after 3 months or more, but it can begin years after treatment initiation (“tardive” means delay).

Drug-induced parkinsonism and other acute movement disorders, such as acute dystonia, emerge earlier, typically during the first month after treatment initiation, and in 90% of cases within 3 months.

Tardive dyskinesia movements are arrhythmic, whereas tremors in parkinsonism are rhythmic, more rapid (3-6 cycles/sec), and often accompanied by rigidity and/or shuffling gait.

Tardive dyskinesia symptoms can either improve or worsen (perhaps transiently) after an antipsychotic dose increase or dose reduction, whereas drug-induced parkinsonism would be expected to improve or resolve after a dose reduction or discontinuation. Anticholinergic drugs would tend to relieve drug-induced parkinsonism, but not tardive dyskinesia.

Arriving at the correct diagnosis promptly is essential for effective management. To that end, dyskinetic movements evident in tardive dyskinesia can be assessed using the Abnormal Involuntary Movement Scale (AIMS). This scale rates the severity of movements in individual body areas on a 5-point scale, with zero meaning no movements, and 4 or 5 meaning severe movements. The scale also rates the overall severity of dyskinesia, the functional impairments it causes, and the patient’s awareness of it.

The Schooler-Kane diagnostic criteria for tardive dyskinesia requires at least 3 months of cumulative exposure to a dopamine receptor blocking agent; at least moderate dyskinetic movement in 1 body area, or mild dyskinetic movements in 2 body areas, as measured using the AIMS; and absence of other conditions that might cause abnormal movements.

Inhibitors of the vesicular monoamine transporter type 2, or VMAT-2, are recommended as first-line treatment of tardive dyskinesia based on strong evidence of efficacy.

Under normal circumstances, VMAT-2 transports monoamines including dopamine into synaptic vesicles for release into the synaptic cleft.

VMAT-2 inhibitors block this transport, reducing dopamine release into the synapse and decreasing dyskinetic movements.

Valbenazine and deutetrabenazine, both approved in 2017, are reversible inhibitors of VMAT-2 that have shown similar efficacy but differ in terms of dosing interval, titration schedule, instructions for use, drug interactions, and contraindications.

Talk to your patients!

All patients for whom antidopaminergic medication is indicated should be educated about the risk and symptoms of tardive dyskinesia before initiating treatment.

Tardive dyskinesia can be prevented by only using antipsychotic medication when clearly indicated. Risk can further be reduced by using a second-generation antipsychotic medication, using the minimum effective dose, and for the shortest duration of time that is clinically indicated.

During treatment with an antidopaminergic medication, monitoring for movement disorders should take place at every follow-up visit.

Keep in mind that patients may be reluctant to discuss symptoms of tardive dyskinesia out of embarrassment or fear that their medication might be discontinued, or they may lack the insight or knowledge necessary to recognize and report tardive dyskinesia-related symptoms.

Finally, upon diagnosis of tardive dyskinesia, treatment should be initiated promptly with an approved VMAT-2 inhibitor to help stop the progression of tardive dyskinesia and to have the best chance of improving symptoms.