Use AIMS to monitor for and assess tardive dyskinesia (TD) symptoms

Andrew Cutler:

Hello, I’m Dr Andrew Cutler, Chief Medical Officer at the Neuroscience Education Institute in Carlsbad, California, and a Clinical Associate Professor of Psychiatry at SUNY Upstate Medical University in Syracuse, New York.

Today, on behalf of Teva Pharmaceuticals, I’ll speak about the importance of differentiating tardive dyskinesia or TD, and drug-induced parkinsonism or DIP. We’ll take a look at how these disorders affect dopamine signaling to better understand why anticholinergics should not be used in patients with TD.

TD and DIP are common movement disorders caused by exposure to antipsychotic drugs.

It is unfortunate that the term extrapyramidal symptoms, or EPS, has historically been used to describe any drug-induced movement disorder, because it is a nonspecific term.

TD and DIP are both included under the umbrella of EPS and are often treated indiscriminately with anticholinergic medications. However, this concept is outdated. Today, we know these disorders are distinct and the use of anticholinergics for all drug-induced movements is inappropriate.

TD and DIP have different underlying causes, opposite clinical presentations, and very different treatments. In fact, treatment for 1 movement disorder may worsen the other.

Treatment guidelines from the American Psychiatric Association or APA and the DSM-5-TR provide recommendations for TD and DIP.

The APA guidelines for the treatment of schizophrenia recommend treating TD with a vesicular monoamine transporter 2, or VMAT2, inhibitor if symptoms have an impact on the patient, regardless of severity.

The DSM-5 cautions that symptoms of TD tend to be worsened by anticholinergic medications, such as benztropine.

Although anticholinergics are indicated for the treatment of DIP, the APA cautions that these agents can result in multiple difficulties for patients, including impaired cognition, diminished quality of life, and significant health complications.

The APA advises that it is important to keep in mind the total anticholinergic burden when selecting a medication for DIP. For this reason, antiparkinsonian medications are not typically administered on a prophylactic basis.

If an anticholinergic is used, it is important to adjust the medication to the lowest dose that can treat the symptoms, in order to minimize side effects. In addition, they should be used for the shortest time necessary.

Despite warnings about anticholinergic use, about 40% of psychiatry providers indicated they would initiate benztropine to treat, as well as to prevent, TD. Clearly the distinction between TD and DIP is misunderstood among the greater healthcare community.

The causes of TD and DIP can help explain their treatment. I hope that after watching this video you will have a better understanding of their biologic mechanisms, clinical symptoms, and appropriate treatments.

Patients with DIP display slowness of movement, or bradykinesia. I’ll demonstrate how this slowness, or as we see here, frozen appearance correlates with decreased dopamine.

In contrast, patients with TD have an excess of abnormal, irregular movements.

I’ll start with a refresher on the neurobiology of normal movement and then explain how signaling is altered in patients with DIP versus TD.

We will also review how anticholinergics resolve symptoms related to the mechanisms of DIP versus TD.

Movement is controlled by dopamine signaling in the basal ganglia. We’ll be discussing a presynaptic neuron that receives the signal to initiate movement and a postsynaptic neuron that transmits the signal to produce movement.

Here we can see that VMAT2 has transported dopamine into vesicles,

…where it waits for the signal to be released.

When the signal is received by the presynaptic neuron to initiate movement, the vesicles fuse with the presynaptic membrane and release dopamine into the synapse.

Dopamine binds to postsynaptic receptors…

and a signal is transmitted to initiate movement.

In DIP, antipsychotic drugs transiently block postsynaptic dopamine receptors.

When dopamine is now released, the antipsychotic drug is bound to dopamine receptors, and the blockade results in reduced dopamine signaling in the post synaptic neuron.

Reduced dopamine signaling results in bradykinesia, or slowness of movement.

Since the mechanism of DIP occurs when antipsychotics are first started, it makes sense that the clinical signs of DIP occur early, within a few weeks to months of starting or increasing the dosage of an antipsychotic.

The exact pathophysiology of TD is not fully known. However, it is thought that chronic blockade of dopamine receptors by antipsychotics results in the upregulation, or a hypersensitivity, of dopamine receptors.

This upregulation results in increased dopamine signaling, which manifests as the excessive movements that are characteristic of TD, which is a possible explanation for why DIP is a risk factor for TD.

In TD, a chronic blockade of dopamine receptors by antipsychotics results in an upregulation, or hypersensitivity, of dopamine receptors. So, TD develops after using an antipsychotic for at least a few months, typically years.

Some elderly or high-risk patients may develop symptoms in a shorter period.

Discontinuing the antipsychotic may improve or resolve the symptoms associated with DIP.

In contrast, reducing the dose or discontinuing an antipsychotic may fail to improve the symptoms of TD or might even induce withdrawal dyskinesia.

Anticholinergic agents like benztropine act to promote dopamine signaling. This can help alleviate the bradykinesia associated with DIP, but it is the exact opposite of what we want to do with TD.

If we add more dopamine to the postsynaptic neuron in TD, the already upregulated receptors may transmit an even greater number of signals. This could result in an even further increase in abnormal movements.

As mentioned previously, guidelines recommend VMAT2 inhibitors for adults with TD.

It is believed that VMAT2 inhibitors reduce the amount of dopamine packaged into presynaptic vesicles, which may reduce the amount of dopamine released at the synapse and reduce TD movements.

If we use a VMAT2 inhibitor in a patient with DIP, it could worsen symptoms, as reduced levels of dopamine being released into the synapse can reduce the already decreased dopamine signaling and further slow the patient’s movement.

Recognizing the different neurobiology and clinical presentation between TD and DIP can help clinicians choose appropriate treatment.

I hope this video helped you understand these differences and will encourage you to apply this knowledge to help your patients

Rajeev Kumar:

Hello. I’m Dr Rajeev Kumar, the medical director of the Rocky Mountain Movement Disorders Center and the Huntington’s Disease Society of America, Center of Excellence in Englewood, CO. I’ve been working with patients with tardive dyskinesia, or TD, for more than 20 years.

Today, on behalf of Teva, I'll be speaking about clinical symptoms and treatment of TD and its differentiation from drug-induced parkinsonism, or DIP. Movement disorders in patients taking antipsychotics are common and up to one-third of them will develop either TD, DIP, or both.

I’ll be focusing on how these 2 disorders may be misdiagnosed, and how treating a patient with TD for DIP could have adverse consequences for the patient. I’ll also speak about how the opposite is true as well.

Tardive dyskinesia and drug-induced parkinsonism are both very common movement disorders, and both are caused by dopamine receptor blocking medications, like antipsychotics.

However, they present differently, differ in their pathophysiology with respect to dopaminergic signaling, and have different treatments. In fact, treatment for one disorder may worsen the other.

The term EPS, or extrapyramidal symptoms, has been used in psychiatry for many years, and this term has been propagated by the labeling of medications by the FDA.

Historically, EPS has been used to describe all drug-induced movement disorders experienced by patients taking antipsychotic medications. As a result, there’s been the indiscriminate treatment of both disorders with anticholinergic medications.

We now know that the term EPS is outdated. It’s very important to differentiate between the disorders because they merit different treatments.

The use of antipsychotics has markedly increased over the past 2 decades due to expanded indications for use in mood disorders, such as depression and bipolar disorder.

The data suggests that in 2022, 8.7 million Americans received prescriptions for an antipsychotic and, as a result, we estimate there are at least 785,000 individuals who have TD in the United States.

Now that's a shocking number, and even more surprisingly, at least 85% of patients have been misdiagnosed or remain undiagnosed.

Many of these individuals, who have been misdiagnosed, have been labeled as having EPS, and many of them, in fact, have DIP.

So, this means that about 15% of patients have been diagnosed and only 6% of individuals have been treated with a VMAT2 inhibitor.

If we look at US healthcare claims data of those individuals who have been diagnosed with TD, about 36% of individuals are receiving benztropine with about three-quarters of these individuals having received benztropine for more than 3 months, and about a-third having been treated for greater than a year.

And if we look at online surveys of psychiatry providers, about 40% of individuals indicate that they would actually initiate benztropine to treat TD, which is an unfortunate failure of our ability to educate these providers.

So, for patients suffering from TD, the lack of an accurate diagnosis can lead to mistrust and frustration. And of course, for patients that have been misdiagnosed, the wrong therapy can result in a worsening of their symptoms.

As a result, patients can fail to seek care because of their frustration and may not follow instructions correctly.

Let's talk a little bit about the underlying mechanisms of disease for both TD and DIP, and then we'll review some videos that could help one make appropriate diagnostic and treatment decisions when seeing patients with drug-induced movement disorders.

First, let's talk about the time course of TD and DIP. DIP occurs due to acute blockade of predominately dopamine D2 receptors.

Now, because of this blockade, we get a reduction in postsynaptic dopamine signaling.

Tremor, bradykinesia, rigidity, and impairment of gait may become apparent within the first few weeks or first few months of starting or increasing the dose of the antipsychotic.

In tardive dyskinesia, the term “tardive” means delayed. Chronic blockade of dopamine receptors by antipsychotics results in delayed upregulation, or super sensitivity, of these postsynaptic dopamine receptors. So, TD usually develops after months or years of exposure to antipsychotic medications.

Let's review the clinical features of DIP and TD and see how they're differentiated when we examine patients.

The degree of movements is one of the first things I look for.

This patient with DIP has a masked face with reduced facial expression and reduced blink rate, which is different from the typical normal level or increased level of facial movement we see in TD.

This patient also has mildly flexed posture, reduced arm swing, reduced stride length, reduced speed, and multi-step turns, all of which are characteristic of parkinsonism.

The nature of movements in DIP and TD are also different. When patients with DIP have abnormal movements, it is rhythmic.

This elderly gentleman has typical 4 to 5 Hertz resting tremor in the left hand, and it is not uncommon for the tremor to improve during sustained action and posture, but it may persist.

You can see this with the postural tremor in this gentleman's right hand.

And in fact, if we allow the jaw to hang down, he has synchronous tremor of his jaw.

TD is characterized by excessive movement or hyperkinesia.

This patient has continuous movements of the neck, jaw, and face. We can see she has quivering movements of the lips. In addition, she has excessive right shoulder elevation and right head tilt.

This patient has undulating movements of the lips, occasional tongue protrusion, and excessive blinking.

This younger woman has excessive lip pursing, platysma contraction, frontalis activation, and eyebrow elevation.

This patient has tongue movements that are unique. They go back and forth and then to one side of his mouth. He has very severe back and forth movements of his tongue, which are unpredictable, and, in fact, you can see that he has involuntary jaw closing and briefly bites his tongue.

This patient’s TD movements are irregular, jerky, and unpredictable. This patient has severe generalized choreiform movements, with piano playing movements in the fingers and the toes, body rocking, and facial dyskinesias with grimacing, and we can see the protrusion of his tongue within the mouth.

Let's look at the upper extremity muscle tone, which is a component of the AIMS examination.

First, we examine rigidity at the level of the wrist by isolating the wrist and passively moving it. Then we examine the tone at the level of the elbow.

Now, if you do not detect increased tone at rest, have the patient open and close the other hand, while we examine the tone again at the level of the wrist and the elbow.

We should do this for each side of the body independently. As you can see, I can easily move this TD patient’s arm at the level of the wrist and the elbow without resistance, both with and without activation of the contralateral hand.

Performing the same maneuvers on this man with parkinsonism, you can see that I don't have difficulty moving his wrist, but there is a resistance that occurs when I attempt to flex and extend his elbow.

Now, this is something you predominantly feel, but here you can almost see that I'm having some difficulty extending his elbow.

To make an accurate diagnosis of TD, it is essential that we are able to carefully assess and differentiate TD from DIP.

Because if one makes a misdiagnosis and prescribes an anticholinergic to a patient with TD, you may exacerbate the hyperkinetic movements by increasing dopaminergic signaling.

On the other hand, if you prescribe a dopamine-depleting VMAT2 inhibitor to a patient with DIP, you further reduce the patients already low level of dopamine, and this can worsen the patients’ features of parkinsonism.

So, it's important to differentiate TD and DIP by careful observation and examination of the patient. With the correct diagnosis, we can render the correct treatment.

Thank you for watching, and I hope what I’ve shared today will help you in the assessment of your patients with movement disorders who are taking antipsychotic medications.

Craig Chepke:

Hi, I’m Dr. Craig Chepke, adjunct professor of psychiatry for Atrium Health and medical director of Excel Psychiatric Associates in Huntersville, North Carolina.

Today, on behalf of Teva, I’ll talk about the importance of differentiating tardive dyskinesia, or TD, and drug-induced parkinsonism, or DIP. The American Psychiatric Association, or APA, and the DSM-5-TR, provide distinct treatment recommendations for TD and DIP, but there is a disconnect between the guidelines and how patients are being managed in the real world. Data indicate that anticholinergics are being used to treat TD, but this is not an effective treatment strategy and can have a number of detrimental consequences for patients.

Approximately one-third of patients taking antipsychotic drugs, or APDs, will experience TD, DIP, or both.

In the past, TD and DIP were both described by the term “EPS,” or extrapyramidal symptoms, and as such, patients with both disorders were managed with anticholinergics.

However, the concept of EPS is outdated. We now understand that TD and DIP have different underlying causes, opposite clinical presentations and, therefore, very different treatments.

Unfortunately, the concept of EPS is so well entrenched in psychiatry, and many providers still don’t recognize that TD is distinct from DIP.

It’s critical to differentiate patients with TD from patients with DIP, because treatment for one disorder may exacerbate the other disorder.

The APA Practice Guideline for the Treatment of Schizophrenia and the DSM-5-TR guidelines provide guidance for the treatment of each disorder, as well as several precautions that should be made when considering anticholinergic medications.

VMAT2 inhibitors, which are approved for TD, are recommended if symptoms have an impact on the patient.

In contrast, symptoms of TD tend to be worsened by anticholinergic medications, such as benztropine.

Anticholinergics are indicated for the treatment of DIP; however, their use has been linked to impaired quality of life, impaired cognition, and significant health complications.

Guidelines recommend considering the anticholinergic burden before prescribing a medication in this class. Many medications have anticholinergic properties, and for this reason, anticholinergics are not typically administered prophylactically when starting an antipsychotic.

If an anticholinergic is used, it should be adjusted to the lowest dose possible for the shortest time necessary.

Despite the recommendations regarding the use of anticholinergics, a survey of providers indicated that fewer than 40% are familiar with the 2020 APA Practice Guideline for the Treatment of Schizophrenia.

In the United States, TD affects approximately 785,000 patients.

However, only about 15% of these patients have received a formal diagnosis…

and less than 6% have been treated with a VMAT2 inhibitor.

So, this leaves as many as 85% of patients with TD either being missed, or possibly, misdiagnosed with DIP.

In addition, approximately 40% of psychiatric providers stated they use benztropine to prevent or treat TD.

In a separate analysis of patients who were diagnosed with TD, 36% were receiving benztropine. Additional analyses from the same data set indicated that, of those patients with TD who were taking benztropine, about 75% of them remained on treatment for over 3 months, and 35% were treated for over a year.

Training and education to reduce use of benztropine in TD is needed because clinical symptoms can be tied to the relative changes in dopamine signaling that can occur. I’ll be reviewing the mechanisms underlying TD and DIP to explain why treating patients for TD with anticholinergics can worsen symptoms of TD. Recognizing the unique symptoms and neurobiology of both disorders may help clinicians align with the treatment guidelines.

The time that it takes for symptoms of these disorders to present after use of antipsychotic drugs differs along with their clinical presentations.

Parkinsonian symptoms generally begin within a few weeks to a few months of starting or increasing the dosage of an antipsychotic drug.

DIP occurs due to an acute blockade of dopamine receptors, which leads to a reduction in postsynaptic dopamine signaling.

On the other hand, in TD, the chronic blockade of dopamine D2 receptors by antipsychotics result in an upregulation and hypersensitivity of dopamine receptors.

As such, TD develops after using an antipsychotic drug for at least a few months, but more typically over a few years. By DSM-5-TR criteria, a diagnosis of TD requires at least 3 months of exposure to antipsychotics for adults, but as little as 1 month for elderly patients.

The symptoms of DIP are correlated with a decrease in dopamine signaling, whereas the symptoms of TD are correlated with a relative increase in dopamine signaling. We generally see reduced movement in patients with DIP vs excessive movement in TD.

DIP is characterized by a paucity or slowness of movement. The person in this video demonstrates a masked face consistent with DIP; she appears to be staring and rarely blinks.

In contrast, a person with TD has movements that are excessive and often continuous.

This patient has an increased rate of blinking. Instead of a frozen look, she is puckering her lips repeatedly.

The nature of movements, whether hyperkinetic or hypokinetic, is one of the most important features to help me differentiate TD from DIP.

While DIP is generally associated with a paucity of movement, patients with DIP may sometimes have a tremor; however, the nature of that tremor is different from the movements of TD.

The patient has a parkinsonian tremor in his left hand, which occurs in a predictable and rhythmic fashion.

In contrast, the movements of TD are unpredictable, irregular, and sometimes even jerky. This patient has frequent involuntary movements, especially notable in his fingers and toes.

Evaluating the patient’s muscle tone is also helpful in differentiating TD from DIP.

DIP may be accompanied by rigidity that can be felt and confirmed in a physical exam.

In contrast, patients with TD have normal muscle tone.

Discontinuing the APD may improve or resolve the symptoms associated with DIP.

But if left untreated, TD is typically persistent and irreversible. APD reduction or withdrawal may fail to improve the symptoms of TD or might even induce withdrawal dyskinesia.

Based on the differences between TD and DIP, we must consider which treatment approach can best address this specific condition.

Anticholinergics are indicated for the treatment of DIP. However, the guidelines and the label for benztropine, which is a commonly used anticholinergic, warn that these agents do not alleviate the symptoms of TD and in some cases, may even aggravate them.

VMAT2 inhibitors are recommended for adults with TD but they do have the potential to worsen DIP.

Contrary to recommendations made in treatment guidelines, anticholinergics are being overprescribed in patients with TD, and only a fraction of patients with TD are being treated with a VMAT2 inhibitor.

The APA and DSM-5-TR guidelines reinforce that TD and DIP are 2 very different disorders with different proposed pathophysiologies. As such, it’s critical that we make the right diagnosis so we can select the right treatment approaches for our patients.

I hope this video has provided a helpful overview of these two disorders and will be useful in the clinical management of your patients.