What are the concerns of Extrapyramidal Symptoms (EPS) with Tardive Dyskinesia?

From the Guidelines

Extrapyramidal symptoms (EPS) and tardive dyskinesia (TD) are significant concerns in patients taking antipsychotic medications, with EPS often serving as an early warning sign for the potential development of TD, a more serious and potentially irreversible condition. The primary concern is that patients who experience EPS have a higher risk of developing TD later 1. EPS typically appears early in treatment and includes symptoms like muscle stiffness, tremors, akathisia (restlessness), and dystonia (muscle spasms). These symptoms usually respond to dose reduction, medication changes, or anticholinergic medications like benztropine (1-2mg twice daily) or diphenhydramine (25-50mg as needed) 1. In contrast, tardive dyskinesia involves involuntary, repetitive movements, particularly of the face, mouth, and tongue, and typically develops after prolonged antipsychotic use (months to years).

Key Considerations

• The risk of TD is higher with typical antipsychotic agents, with up to 50% of elderly patients developing TD after continuous use for 2 years 1.
• Second-generation antipsychotics, such as quetiapine or aripiprazole, have lower risk profiles for EPS and TD compared to typical antipsychotic agents 1.
• Regular monitoring using the Abnormal Involuntary Movement Scale (AIMS) is essential for early detection of TD 1.
• VMAT2 inhibitors like valbenazine (40-80mg daily) or deutetrabenazine (6-48mg daily) may be considered for treatment of TD if it develops 1.

Management Strategies

• Use the lowest effective dose of antipsychotics to minimize the risk of EPS and TD.
• Prefer second-generation antipsychotics due to their lower risk profiles.
• Regularly monitor patients for EPS and TD using AIMS.
• Consider VMAT2 inhibitors for treatment of TD if it develops.
• Be aware of the potential for weight gain and metabolic problems associated with atypical antipsychotics, and monitor patients accordingly 1.

From the FDA Drug Label

The syndrome consists of potentially irreversible, involuntary, dyskinetic movements. The risk of TD and the likelihood that it will become irreversible are believed to increase with greater durations of treatment and higher total cumulative doses However, the syndrome can develop after relatively brief treatment periods at low doses. Tardive dyskinesia (TD) has occurred in patients treated with antipsychotic drugs, including clozapine. Extrapyramidal Symptoms:(EPS) Dystonia Class Effect: Symptoms of dystonia, prolonged abnormal contractions of muscle groups, may occur in susceptible individuals during the first few days of treatment Dyskinetic event included tardive dyskinesia, dyskinesia, choreoathetosis;

The main concerns of EPS with tardive dyskinesia are:

• Potentially irreversible, involuntary, dyskinetic movements
• Increased risk with greater durations of treatment and higher total cumulative doses
• Development after relatively brief treatment periods at low doses
• Association with antipsychotic drugs, including clozapine and quetiapine
• Symptoms of dystonia, prolonged abnormal contractions of muscle groups
• Tardive dyskinesia, dyskinesia, choreoathetosis 2 3

From the Research

Concerns of EPS with Tardive Dyskinesia

• The concerns of Extrapyramidal Symptoms (EPS) with tardive dyskinesia include the risk of developing chronic motor problems such as tardive dyskinesia, which can cause considerable subjective discomfort and distress 4.
• EPS can also confound clinical assessment of mental-state phenomena because of symptom overlap with the psychotic illness being treated 4.
• The risk of tardive dyskinesia in patients taking atypical antipsychotics is less than that for those taking typical antipsychotics 5.

Mechanisms of EPS and Tardive Dyskinesia

• Neuroleptic-induced EPS are thought to be caused by blockade of nigrostriatal dopamine tracts resulting in a relative increase in cholinergic activity 5.
• Tardive dyskinesia is less well understood but is thought to be a supersensitivity response to chronic dopamine blockade 5.
• The leading hypothesis for the mechanism of action of the newer generation of atypical antipsychotics is the presence of a high serotonin-to-dopamine receptor blockade ratio in the brain 5.

Treatment and Management

• Atypical antipsychotics such as clozapine, olanzapine, and quetiapine may have a beneficial effect on pre-existing symptoms of tardive dyskinesia 6, 7.
• The olanzapine-clozapine-quetiapine rank order of increasing effectiveness against tardive dyskinesia symptoms suggests that this property, although shared by the atypical antipsychotics, is to some degree drug-specific 7.
• Patient- and/or drug-dependent mechanisms may be involved in this gradient of effect 7.

Risk Factors

• Age is significantly associated with the subtype of EPS experienced, such that those patients with akathisia and dystonia tend to be younger, whereas those with tardive dyskinesia tend to be older 8.
• Body mass index (BMI) category is also negatively correlated with the incidence of dystonia 8.
• Exposure to specific DRBAs, classes, and routes of administration significantly affects the risk of developing different subtypes of EPS or OMDs 8.