Ever-Evolving Treatments & Underpinnings in Tardive Dyskinesia

DECEMBER 25, 2018
Krista Rossi
           epilepsy in 2018

Coming in off the heels of the 2017 approval of valbenazine, tardive dyskinesia sped into 2018 with a lineup of evolving treatments, ranging from deeper understandings of the fairly new drug to transcranial magnetic stimulation (TMS). Additionally, investigators made strides in unearthing underlying disease mechanisms, such as in genetics and harmful therapies.

While the rare condition is often caused by long-term use of antipsychotics—which are now being more consciously developed in order to avoid results of tardive dyskinesia—already affected patients exist, making the ever-evolving treatments and discoveries all the more significant.


New & Potential Therapies

Valbenazine blazed into 2018 with positive long-term study results, showing the vesicular monoamine transporter 2 (VMAT2) inhibitor was both effective and safe in patients over extended periods of time.

In the phase 4 KINECT 4 clinical trial, a long-term study of valbenazine, results showed patients taking 40 mg and 80 mg doses experienced improvements based on changes from baseline to week 48 on the Abnormal Voluntary Movement Scale (AIMS) scale.  

Among the patients involved in the study, the most involved body regions with a baseline score of ≥3 included lips (n = 59) and tongue (n = 56), as well as jaw (n = 48), upper extremities (n = 48), and face (n = 38). Lower extremities in 27 patients and trunk in 26 patients were also found in baseline data.

“Tardive dyskinesia is most commonly associated with noticeable symptoms in the face, but this may not be the reality for all patients,” Eiry W. Roberts, MD, the chief medical officer at Neurocrine Biosciences told MD Magazine®.

For lips, jaw, upper extremities, and lower extremities, investigators found that the rate (a score of ≤2, mild to moderate symptoms after 48 weeks) reached 100% for both 40 mg and 80 mg doses. Additionally, the rates of patients shifting to ≤2 score for the remaining body regions varied by dose (40 mg and 80 mg, respectively): face (100%, 97%), tongue (100%, 98%), trunk (88%, 89%).

“These data further highlight that symptoms manifest differently throughout the body for patients suffering from tardive dyskinesia, with valbenazine demonstrating effectiveness regardless of where symptoms are most prominent,” she added.

But the advantages of the long-term use of valbenazine stretch beyond efficacy measurements. Patients with tardive dyskinesia showed improvements after taking once-daily valbenazine and had high satisfaction rates.

Using the Clinical Global Impression of Severity-TD, which measured the severity of the disorder on a scale ranging from 1 (normal or not ill) to 7 (extremely ill), 160 patients assessed themselves. The Patient Satisfaction Questionnaire ranged from 1 (very satisfied) to 5 (very dissatisfied).

Almost all of the patients reported satisfaction with valbenazine at baseline: 100% of the 40 mg patients and 99.1% of the 80 mg patients. Those scores also remained nearly unchanged after 48 weeks of treatment. The 40 mg patients continued to report 100% “very satisfied or somewhat satisfied,” and 97.4% of the 80 mg patients reached that threshold.

“Similar to the KINECT 4 Abnormal Voluntary Movement Scale (AIMS) and Patient Global Impression of Change (PGIC) results, this long-term, extension study confirmed the positive overall perception of valbenazine treatment among participants, suggesting a meaningful benefit to patients’ everyday lives,” continued Roberts.

Improvements in mood disorders were also noted with use valbenazine in 2 long-term phase 3 studies that included patients administered valbenazine 40 mg once-daily without dose escalation to 80 mg, and in patients who were escalated from 40 mg to 80 at Week 4.

Of the patients included in the studies, most of the patients received antidepressants (84%) and/or antipsychotics (76%) in addition to the valbenazine treatment. Other concomitant drugs included antiepileptics, anxiolytics, and anticholinergics.

Based on the Abnormal Involuntary Movement Scale (AIMS) and Clinical Global Impression of Change-Tardive Dyskinesia (CGI-TD) measures, investigators reported meaningful and sustained tardive dyskinesia improvements after 48 weeks as patients’ mood symptoms remained generally stable during the studies.

Approximately 70% of all mood disorder patients achieved an AIMS response of greater than 50% improvement, and three-quarters achieved CGI-TD response. There was some return toward baseline levels after 52 weeks; however, that followed a 4-week washout.

The patients’ mood symptoms also remained generally stable during the investigation, the investigators observed. There were minimal changes from baseline in mean total Montgomery-Asberg Depression Rating Scale (MADRS) and Young Mania Rating Scale (YMRS). After 48 and 52 weeks, there were no worsening specific mood symptoms.

Only 1 patient experienced suicidal ideation, which did not worsen throughout the course of the study.

“For tardive dyskinesia patients who are managing an underlying mood disorder, such as bipolar or severe depression, this analysis showed that valbenazine is an effective, long-term treatment option that does not interfere with other psychiatric medications or the stability of underlying psychiatric symptoms,” Roberts said.

Despite valbenazine’s proven efficacy in multiple long-term studies, it was not the only treatment that made headway in 2018. Investigational therapies like transcranial magnetic stimulation (TMS) also showed potential across its own set of studies.

Upon therapeutic repetitive transcranial magnetic stimulation (rTMS) to treat a 24-year-old female patient with severe neuroleptic malignant syndrome as a last resort, a team of investigators from Aswan University Hospital in Egypt found that the patient regained normal gait after 5 sessions per week for 4 weeks.

When performed in a larger group of patients, the team found patients treated with rTMS improved (decreased) in AIMS scores by a mean of 8.3 ± 1.7 points, while the sham group saw an improvement of 1.2 ± 3.3 points (P = .001). They also showed greater improvements in other measures as well, such as in overall severity, incapacitation, and awareness.


Unearthed Causes

Amidst all the leaps forward with treatment innovations, tardive dyskinesia also took steps in unearthing disease causes. Specifically, underlying genetics and harmful therapies were discovered.

One such treatment investigators found to be harmful was reducing antipsychotic doses in patients.      

“In treating patients who develop tardive dyskinesia, physicians should understand that antipsychotic dose reduction may not be effective for tardive dyskinesia but may increase risk of relapse in some patients,” study author Stanley Caroff, MD, told MD Magazine®.

In a study conducted by University of Pennsylvania investigators, the team found that dose reduction in antipsychotics correlated with an increase in hospital admissions and emergency room visits. Specifically, dose reduction of more than 30% led to an increase in admission for all causes of 1.23, and for emergency room visits for all causes the risk increased to 1.31 compared to controls.
 
While the team noted that the dose reductions had no significant effect on claims for tardive dyskinesia since the number of tardive dyskinesia claims was too small for interpretation from the study population, the data from patients schizophrenia and other psychiatric disorders suggest dosing reductions may cause trouble.

“The decision to reduce the dose should be individualized to the needs of each patient,” Caroff said. “More work needs to be done to educate physicians to recognize, diagnose, document, and treat tardive dyskinesia using effective alternative strategies.”

Another therapy investigators found to be harmful to patients with tardive dyskinesia was lithium therapy.
 
When treating a 68-year-old female with bipolar disorder with lithium monotherapy and documenting her progress in order to explain the development of her tardive dyskinesia-like syndrome, investigators from Aristotle University in Thessaloniki, Greece, found the tardive dyskinesia-like symptom appeared in correlation with the treatment—in the absence of other antipsychotics.

Investigators also pointed to another UK-based study, in which higher rates of Alzheimer’s disease in lithium-treated patients were reported—highlighting the neurotoxic potential of the treatment.

Meanwhile in genetics, investigators found a link between tardive dyskinesia and the HSPG2 gene, proving the significant role that genetic factors play in causing the rare disorder.

By showing the HSPG2 gene to be significantly associated with tardive dyskinesia in Japanese patients with schizophrenia—which was later replicated by an independent research group—the team showed that more than antipsychotics may be at play in the disease’s underpinnings and cause.

In a separate study on the HSPG2 gene—also called perlecan since it codes for the production of the protein perlecan—investigators also found that the G allele was significantly linked to tardive dyskinesia.

When adding additional filters to the data, such as sex, ethnicity, etc., the team found they affected the findings, suggesting tardive dyskinesia risk reflects multiple genetic factors and that more research is needed.

While the rare nervous system disorder made a number of strides in 2018, Jeffrey A. Lieberman, MD, also told MD Magazine® that a narrowing patient population may be contributive to future research and treatment developments, especially in the area of genetics. However, he also noted that the increasing use of preventative measures may help diminish the disorder in general, which would be most favorable across all areas.

“It’s unlikely that there will be new effort placed on developing newer, better, medications because fewer people will be affected by this,” he said. “On the other hand, there may be things that may be useful in a preventative way… the problem is the population frequency of the gene is not high, so it will only pertain to a small proportion of the patients who are being treated and it may not be cost effective to do screenings.”

Regardless of what next steps lie ahead for tardive dyskinesia, the ones that have already been made have catapulted the field forward, moving it closer to treating and diminishing its patient population.

This article is part of MD Magazine's This Year In Medicine 2018 series. To read more from the series, check out the links below and follow us on Twitter at @MDMagazine.

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