This meta-analysis was conducted to examine the efficacy of pharmacologic treatments for tardive dyskinesia (TD).

PubMed was searched on December 12th, 2017, for randomized, placebo-controlled trials examining the treatment of TD using the search terms (drug-induced dyskinesia OR tardive dyskinesia) and (psychotic disorders OR schizophrenia). Studies were included if they examined tardive dyskinesia treatment as the primary outcome and were randomized and placebo-controlled trials. The effect size (standard mean difference) of improvement (compared to placebo) stratified by medication class should have been reported for each of the trials included. A meta-analysis was subsequently conducted.

placebo. There was significant evidence of publication bias in vitamin E studies. Shorter duration of treatment and a lower dose of vitamin E was significantly associated with greater measured treatment benefit. Vitamin B₆ was also associated with a significantly greater reduction in TD symptoms compared to placebo in two trials. Vesicular monoamine transporter 2 (VMAT2) inhibitors demonstrated significant benefit on tardive dyskinesia symptoms compared to placebo. Amantadine was associated with significantly greater score reduction compared to placebo. Calcium channel blockers were not associated with significantly greater score reduction compared to placebo.

Data suggests that VMAT2 inhibitors, vitamin E, vitamin B₆, and amantadine may be effective for the treatment of TD. Evidence of publication bias and a significant negative association of dose and duration of treatment with measured efficacy suggests that the benefits of vitamin E in TD may be overstated. Head-to-head trials are needed to compare the efficacy and cost-effectiveness of pharmacologic agents for TD.

This meta-analysis revealed that several agents demonstrated efficacy compared to placebo and are likely to be effective in the treatment of TD. VMAT2 inhibitors, vitamin E, vitamin B6, and amantadine have demonstrated benefit compared to placebo in multiple controlled trials.

The randomized controlled trials of valbenazine and deutetrabenazine have a medium-to-large treatment effect compared to placebo. These trials included large samples and were well designed. These trials had a high Jadad score (rates the quality of the trial). There is strong evidence for the VMAT2 inhibitors.

Vitamin E is the most studied agent with strong evidence of publication bias within the vitamin E trials. Overall modest at best. The vitamin B6 trials had design flaws. 

In summary: In my opinion, several agents have demonstrated efficacy in randomized controlled trials but there are no head to head studies to demonstrate the efficacy of one agent versus another. In the interim, I would use FDA approved agents as they have well-designed trials with large sample size and higher quality. They have also undergone review by the FDA concerning tolerability and there is ongoing monitoring of side-effects.

To add to the limited evidence on the Abnormal Involuntary Movement Scale (AIMS) as a measure of tardive dyskinesia (TD) in clinical practice settings, the characteristics and correlates of AIMS scores were assessed in a Veterans population.

This was a retrospective study.  Veterans with schizophrenia/schizoaffective, bipolar, or major depressive disorders receiving antipsychotics and at least 1 AIMS score from October 1, 2014, to September 30, 2015, were identified. Tardive dyskinesia was determined by the International Classification of Diseases, Ninth Revision, Clinical Modification, codes. Psychiatric and relevant medical comorbidities were recorded. Psychiatric medications were also recorded including if the patient was on two antipsychotics.

Statistical analyses were used to assess AIMS awareness and incapacitation as well as correlation with ethnicity, diagnosis, use of antipsychotics, and benztropine.

7985 veterans were receiving antipsychotics. Only 4706 (58.9%) had at least 1 AIMS examination. Of these, 229 (4.9%) were diagnosed with possible TD. The mean total AIMS scores and AIMS awareness/incapacitation scores were significantly higher for patients with TD. Comparing diagnostic threshold criteria of AIMS ratings, only 17.5% to 37.1% of veterans with TD were successfully identified. Among TD patients, 21.4% had a total score of moderate-severe and 15.3% had ratings of at least mild movements in 2 or more body regions. Older age, African-American, having schizophrenia/schizoaffective disorder, and receiving two antipsychotics or benztropine significantly increased the severity of AIMS scores.

The AIMS is essential for TD research. There is still a need for increased monitoring of TD and AIMS is still not being used often enough in the clinical setting. There is a need for training and oversight for it to be valuable in clinical practice. Efforts to adapt screening procedures to clinical needs may be worth considering.

This is a retrospective study in a Veterans population and has important findings as listed below.

In an organized medical system like the VA, TD is still being missed or not being assessed despite prompts in the EMR. This raises the question of monitoring in the “real world”.

This study also revealed that patients with TD had a higher likelihood of having the AIMS done. The AIMS may be perceived as time-consuming although extra time spent with a patient for side-effect monitoring is important and a billable service.

Those on anticholinergic agents had higher AIMS scores. Benztropine and trihexyphenidyl are commonly used anticholinergic agents. Patients with schizophrenia and those on first-generation antipsychotics (FGAs) are more likely to be prescribed anticholinergic agents for drug-induced parkinsonism. Second-generation antipsychotics should be used preferentially (SGA) and use anticholinergic drugs only if needed for the shortest time duration. There is a proposed balance in the striatum between dopamine and acetylcholine Klawans HL and Rubovits R.  Journal of Neurology, Neurosurgery, and Psychiatry 1974, 27; 941-947.

We should avoid using two antipsychotics in patients as this practice increases TD risk. Consider clozapine a highly underutilized drug that is efficacious as well as may be beneficial if TD is present.

This study raises important questions like can we mandate our clinicians to do the AIMS as a possible quality measure or other avenues need to be explored to detect TD early in the interest of patient care.

Summary:

In my clinical opinion, daily routine practice is fast-paced and the AIMS gets skipped. Clinicians in those 15-20 minutes have now a lot more to do including eprescribe medications and EMR entries. More time should be set aside for AIMS visits to be completed and coordinated with the EMR prompt. Training nursing staff as well as other health care workers to look for TD movements would be beneficial. Therapists and case managers spend a lot of time with the patient and may be able to pick up the abnormal movements and bring them to the attention of the clinician for confirmation (patient is also more relaxed with them). Front office staff and medical assistants can be trained to observe patients in the waiting area and bring to our attention if they notice abnormal movements. This training can be done periodically using videos. Bottom line is that we should not give up on monitoring for TD.

There are differences in the diagnosis, screening, and monitoring of TD. This study aimed to survey expert opinions on best practices to screen, diagnose, and treat TD.

A steering committee of 11 TD experts met to prioritize questions to be addressed and identify core bibliographic materials and criteria for survey panelists. Of 60 invited experts, 29 (23 psychiatrists and six neurologists) agreed to participate. This was a modified Delphi consensus study.

A targeted literature search of PubMed (search term: tardive dyskinesia) and recommendations of the steering committee were used to generate core bibliographic material. Inclusion criteria were as follows: (1) review articles, meta-analyses, guidelines, or clinical trials; (2) publication in English between 2007 and 2017; and (4) publication in key clinical journals with impact factors ≥ 2.0. Of 29 references that met these criteria, 18 achieved a score ≥ 5 (calculated as the number of steering committee votes multiplied by journal impact factor and number of citations divided by years since publication) and were included.

Consensus process: Two survey rounds were conducted anonymously through electronic media from November 2017 to January 2018; responses were collected, collated, and analyzed. The respondent agreement was defined a priori as unanimous (100%), consensus (75%-99%), or majority (50%-74%). For questions using a 5-point Likert scale, an agreement was based on the percentage of respondents choosing ≥ 4 ("agree completely" or "agree"). Round 1 survey included questions on TD screening, diagnosis, and treatment. Round 2 questions were refined per panelist feedback and excluded Round 1 questions with < 25% agreement and > 75% agreement (unless feedback suggested further investigation).

The consensus was reached that (1) a brief, clinical assessment for TD should be performed at every clinical encounter in patients taking antipsychotics; (2) even mild movements in one body area may represent possible TD; (3) management requires an overall evaluation of treatment, including a reassessment of antipsychotics and anticholinergics as well as consideration of vesicular monoamine transporter 2 (VMAT2) inhibitors; and (4) informed discussions with patients/caregivers are essential.

The opinions of the expert panel were a cross-sectional view on best clinical practices for screening, diagnosis, and treatment of TD.

There was a unanimous consensus:

All patients on dopamine receptor blocking agents must be screened for TD.

High-risk individuals included older adults, longer cumulative antipsychotic exposure, and acute extrapyramidal symptoms.

As little as one month exposure to the antipsychotic was considered an adequate time frame for the development of TD. 

Screening at every encounter was suggested (does not mean that the AIMS has to be done every time).

A mild in one body area in a clinical practice setting should be considered a diagnosis of TD. Recognition of mild TD may be critical for early intervention.

Choreoathetoid movements were important in determining the TD diagnosis.

The role of continuing the offending antipsychotic, switching to a second-generation agent, or clozapine was to be made on a case by case basis.

The panel agreed that VMAT2 (vesicular monoamine transporter 2 inhibitors) were agents of choice to treat TD.

The use of anticholinergic medications needs to be stopped or minimized.  

Summary:

In my clinical opinion we do need to do a rapid screen for TD at every clinical visit but a more detailed AIMS periodically, every 6 months to a year. Please follow the guidelines of the agency where you practice. I do start one of the two VMAT2 inhibitors (valbenazine is the first choice due to simplicity of use as well as easy titration, once a day dosing, and not needing to be taken with food).

Long-term treatment with dopamine D2 receptor antagonists such as antipsychotic drugs has been thought to lead to dopamine receptor supersensitivity leading to TD. It has been conceptualized as changes in the structure or function of the post-synaptic D2 receptor. However, the measured 1.4-fold increase in D2 receptor density and the lack of actual receptor supersensitivity is probably inadequate to explain outcomes such as tardive dyskinesia (TD) and dopamine supersensitivity psychosis.

Hypothesis: Recent data suggests that TD may result from a combination of presynaptic, synaptic, and postsynaptic changes.

Presynaptic increase in dopamine release occurs when a super-therapeutic blockade of postsynaptic D2 receptors results in excess synaptic unbound dopamine which ultimately ends up being reuptaken by the presynaptic neuron through the dopamine transporter. The increased availability of recycled dopamine results in higher vesicular dopamine concentrations. Since the quantity of neurotransmitter released (known as quanta) is determined by the number of presynaptic neurotransmitter vesicles, the increase in the number (concentration) of dopamine molecules in the vesicles results in a higher concentration of synaptic dopamine with successive depolarization events. Synaptic changes such as the appearance of perforated synapses which is an early step in new synapse formation have been shown in animal models of TD. Finally, postsynaptic increases in D2 receptor expression without demonstration of increased sensitivity or potency has been demonstrated.

TD likely develops due to changes across the synapse and terminology such as 'dopamine receptor supersensitivity' can be misleading. 'Synaptic upregulation' may be a more correct term.

Psychiatry and psychopharmacology are branches of medicine in which we are never sure of how medications work. There is always the line after a mechanism statement “the exact mechanism of action is unknown”. This applies to multiple medications, their side-effects, as well as diagnostic classifications. Electroconvulsive therapy (ECT) is a highly efficacious treatment and we are unable to pinpoint exactly the mechanism of efficacy. In the past, the mechanism of action of antidepressants and ECT was also proposed as the downregulation of the beta receptors.  We don’t hear of this explanation in current times.

Postsynaptic dopamine receptor supersensitivity

The prevailing theory is that of the upregulation of the postsynaptic D2 receptors and their supersensitivity. In support of this theory is the suggestion that antipsychotic agents increase the density of striatal D2 receptors in rodents. In humans, there is PET scan evidence of increased D2 receptor binding in those exposed to long-term antipsychotic drugs. Increased D2 receptors can result due to increased synthesis or through an increase in the number of synapses or both. This process was called maladaptive synaptic plasticity by Teo et al. It should be noted that there is no evidence to suggest D2 receptor supersensitivity.

Synaptic multiplication theory

There is evidence to suggest that there is an increase in the actual number of synapses in the dopamine system. This is also seen as an increase in the dendritic spines and there is evidence to suggest synaptic remodeling.

Presynaptic dopamine release theory

In 1987 Bowers and Glazer raised a question if TD has presynaptic pathophysiology based on observations that cerebrospinal fluid (CSF) homovanillic acid (HVA), a metabolite of dopamine is higher in patients with TD compared to those without.

The Vesicular Monoamine Transporter 2 (VMAT2) is expressed in monoaminergic neurons. Normally it packages monoamines into presynaptic vesicles for release into the synaptic cleft. The VMAT2 inhibition leads to blockage of the vesicular uptake of monoamines and hence the dopamine released with each neuronal firing is decreased.

Unifying theory

In discussing the pathophysiology of TD one can surmise that TD occurs due to presynaptic, synaptic, and postsynaptic changes. Postsynaptic changes represent the current dominant model of the "behavioral supersensitivity” of the dopamine receptors. There is also an increase in the actual number of synapses and hence the potency of the dopamine signal. Finally, there is an increase in the presynaptic dopamine due to the excessive availability of dopamine due to unbound dopamine in the synapse due to postsynaptic dopamine 2 receptor blockade.

Summary:

The currently proposed hypothesis of TD may be overthrown by the unifying theory as explained above. Stay tuned. Meanwhile, treatment of TD includes prevention followed by the use of VMAT2 inhibitors.

Tardive dyskinesia (TD) is a serious neurological movement disorder. This is a side effect of antipsychotic medications used to treat bipolar disorder (BD), major depressive disorder (MDD), and schizophrenia (SZ). This study aimed to evaluate health-related quality of life (HRQoL) in patients with diagnoses for BD, MDD, or SZ by comparing patients with TD with those without TD and the general population.

The TD group included 197 patients and those without TD included 219 patients. The study recruited patients between May and December 2017. This study employed a cross-sectional web-based survey. HRQoL was assessed by four instruments: the SF-12 Health Survey, Version 2 (SF-12v2), the Quality of Life Enjoyment and Satisfaction Questionnaire, Short Form (Q-LES-Q-SF), the Social Withdrawal subscale of the Internalized Stigma of Mental Illness Scale (SW-ISMI); and two questions on movement disorders.

Patients with TD had a significantly worse HRQoL and social withdrawal than those without. The differences were more pronounced for physical HRQoL domains than for mental health domains. Patients with more severe TD, assessed through either self-rating or clinician rating, experienced significantly worse HRQoL than did those with less-severe TD. The impact of TD was substantially greater in patients with SZ than in those with BD or MDD. Compared with the general population, patients with BD, MDD, or SZ experienced significantly worse HRQoL regardless of TD status, although this deficit in HRQoL was greater among those with TD.

The presence of TD is associated with worse HRQoL and social withdrawal. The most severe impact of TD is on the physical aspects of patients' HRQoL.

This is an important study that informs us about the issues not often thought about in the clinical setting. These findings are important for clinicians to take note of, hence prevent, screen, and treat TD.

The patients with psychiatric disorders had deficits in quality of life compared with those who did not have a psychiatric illness.

Patients with TD had lower scores on the quality of life measures compared to those without TD. The physical limitations caused by TD had an even greater effect on the quality of life measures and social withdrawal. When the patient with bipolar disorder, schizophrenia, and major depression were examined separately the results were similar (those with TD had worse quality of life measures and social withdrawal).

The severity of TD in general (disease burden) had a greater effect on quality of life deficits as well as social withdrawal.  

Summary:

In my clinical opinion, the most important lesson from this study is to prevent TD by using antipsychotics judiciously, using second-generation agents (SGAs) preferentially, and trying other augmentations of antidepressants before augmenting with an antipsychotic. Also, avoid/minimize anticholinergic drug use and screen to detect TD early. Treat upon detection with FDA approved agents Valbenazine and Deutetrabenazine.