Tardive Dyskinesia – Examination and Management

Time to read: 5 minutes

Tardive dyskinesias (TDs) are involuntary movements of the tongue, lips, face, trunk, and extremities that occur in patients with long-term exposure to antipsychotics.

Tardive dyskinesia occurs due to supersensitivity of dopamine (D2) receptors after long-term exposure to antipsychotics resulting in downregulation of D2 receptors. Read more on the dopamine hypothesis of schizophrenia.

The Abnormal Involuntary Movement Scale (AIMS) is commonly used to quantify the severity of TD and should be considered as a regular and routine part of clinical management. See below.

Tardive dyskinesia is also known to occur in neuroleptic-naive individuals which may indicate the underlying pathophysiology of the illness.

Risk Factors: [Solmi M et al., 2018]

Non-modifiable patient-related and illness-related and risk factors:

  • Older age, female sex
  • white and African descent
  • longer illness duration
  • intellectual disability and brain damage
  • negative symptoms in schizophrenia
  • mood disorders
  • cognitive symptoms in mood disorders
  • gene polymorphisms involving antipsychotic metabolism and dopamine functioning.

Modifiable comorbidity-related and treatment-related factors:

  • Diabetes
  • Smoking
  • Alcohol and substance abuse
  • First-generation APs
  • Higher cumulative and current antipsychotic dose or antipsychotic plasma levels
  • Early parkinsonian side effects
  • Anticholinergic co-treatment
  • Akathisia
  • Emergent dyskinesia.

Pathophysiology of Tardive dyskinesia: 

  • In Tardive dyskinesia, long-standing D2 antagonism leads to supersensitivity of D2 receptors (reduced inhibition of indirect pathways).
  • The balance thus is shifted towards the overactivation of the D1 excitatory loop.
  • This combined effect leads to an overactivation of the direct pathway (excitatory) out of proportion to the indirect pathway (inhibitory) leading to pathologic overactivity of striatal (movement regions).



Prevention is paramount: Select an antipsychotic with lower propensity for TD

  • Stop anticholinergic
  • Address smoking (A risk factor for TD)
  • Reduce the dose of antipsychotic. (In some cases this can worsen dyskinetic movements)
  • Change to an atypical drug if on a typical antipsychotic.
  • If untreated; consider a switch to Clozapine

Other strategies include:

  • Tetrabenazine – depressogenic, useful in Huntington’s
  • Benzodiazepine
  • Vitamin E
  • There are case reports on the use of Botulinum Toxin in Tardive Dyskinesia and single-blind study showing benefits. [van Harten , 2006, [Slotema et al., 2008]
  • Botulinum toxin has greater evidence in a range of other movement disorders e.g Tics, myoclonus, dystonia, and tremor. [Anandan et al, 2021]


VMAT-2 inhibitors :

  • Given that vesicular monoamine transporter type 2 (VMAT-2) transports serotonin, norepinephrine, and dopamine for storage and future neurotransmission, the inhibition of VMAT-2 increases cytosolic dopamine levels and decreases postsynaptic receptor stimulation, thereby decreasing dyskinesia.
  • VMAT2 inhibition reduces dopamine stimulation without blocking D2 receptors.
  • It, thus, relieves the inhibition of the indirect D2 pathway allowing for greater GABAergic output from the striatum to the (Globus pallidus externa) GPe resulting in a net inhibitory effect on excitation of striatum and cortex.
  • This,then, rebalances the relationship between the indirect inhibitory D2 and D1 excitatory direct pathway.

Valbenazine is a novel, highly selective vesicular monoamine transporter 2 inhibitor that has been approved by the FDA for the treatment of Tardive Dyskinesia. Once-daily valbenazine significantly improved tardive dyskinesia in participants with underlying schizophrenia, schizoaffective disorder, or mood disorder at doses of 80 mg/day.

The other VMAT-2 inhibitor approved for TD is deutetrabenazine. The starting dose if 12 mg/day increasing to 24 mg and a maximum of 36 mg/day.

In contrast to tetrabenazine, deutetrabenazine utilizes the nontoxic deuterium isotope rather than hydrogen, which is hypothesized to lead to slower metabolism and therefore fewer plasma fluctuations and adverse effects. [Touma K and Scarff J, 2018]

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