Extrapyramidal Symptoms (EPS)

Extrapyramidal Symptoms (EPS) are drug-induced movement disorders that occur due to antipsychotic blockade of the nigrostriatal dopamine tracts. These blockades can lead to increased cholinergic activity, resulting in acute dystonia, acute akathisia, antipsychotic-induced parkinsonism, tardive dyskinesia (TD), tardive dystonia, and tardive akathisia.

Antipsychotic naive individuals, the elderly, and those with intellectual disability are at greater risk for developing EPS.^[1] In particular, elderly females are more likely to develop drug-induced parkinsonism and tardive dyskinesia, while young ethnic males are more likely to develop dystonic reactions.^[2]

• A long time ago, before the introduction of dopamine agonists (e.g. - L-dopa), anticholinergics (e.g. - benztropine) were a very common treatment for Parkinson’s disease.
  • Recall that Parkinson's disease caused by the destruction of dopamine neurons in the nigrostriatal region.
  • Thus, this led to initial theories about Parkinson's that there is a reciprocal relationship between acetylcholine and dopamine in the brain.
    • Anticholinergics were thought to improve Parkinsonian symptoms by increasing endogenous dopamine levels.
• Acute dystonia from antipsychotics is thought to occur through this pathway seen in Parkinson's.
  • Normally, dopaminergic neurons in the nigrostriatal pathway have an inhibitory effect on cholinergic interneurons that regulate motor movements in the body.
  • When dopamine antagonists (i.e. - antipsychotics) are given, this decreases endogenous dopamine.
  • Since antipsychotics reduce dopamine's inhibitory effects, this results in increased firing of cholinergic interneurons, and increased release of acetylcholine.
  • This combination of decreased dopamine (postsynaptic nigrostriatal dopamine blockade) and excessive acetylcholine is thought to create a dopaminergic-cholinergic imbalance that leads to development of extrapyramidal symptoms (including Parkinsonism).^[3]
  • This theory is supported by several observations: acute dystonia usually occurs after initiation of an antipsychotic agent, or an increase in dose. Acute dystonia is also less common in the elderly due to overall lower levels of dopamine (D2) receptor activity.^[4]
• Conversely, when an anticholinergic drug (e.g. - benztropine) is given, this counteracts the excess cholinergic activity, and reduces acute dystonia and Parkinsonism.
  • This is also why antipsychotics that are more anticholinergic (e.g. - clozapine, quetiapine) also have a lower incidence of EPS! They have “built-in” benztropine!

• In rare cases of acute dystonia, the diaphragm can also be involved, and there can be breathing compromise. Patients may also report a tense tongue or throat, another moderate sign of acute dystonia. If untreated, acute dystonia can progress to dysphagia, laryngospasm/pharyngospasm, leading to dyspnea.
• In rare, but severe cases, there can be asphyxia or choking.

• Other rare presentations of acute dystonia include oculogyric crises, which can lead to permanent injury. On physical exam, patients in an oculogyric crisis have prolonged involuntary upwards deviation of the eyes bilaterally.

• The offending antipsychotic should first be stopped. After, an intramuscular or oral anticholinergic such as benztropine can be given. In theory, any drug that blocks cholinergic activity (e.g. - an antiparkinsonian agent) or drugs that increase striatal dopamine function (e.g. - certain atypical antipsychotics) can correct this dopaminergic-cholinergic imbalance and postsynaptic nigrostriatal dopamine blockade.
• Although the emergency use of benztropine for acute dystonia is very effective, benztropine should be prescribe chronically or as a prophylactic measure. This practice is highly questionable and likely to cause more harm to patients than benefit. There are adverse effects from long-term use including cognitive impairment, increased dementia risk,^[5] and worsening of tardive dyskinesia (in individuals who already have TD).^[6][7]
  • In the vast majority of cases, chronic prescriptions of benztropine can be safely discontinued with no worsening of risk for acute dystonia or movement disorders, along with improvements in cognition once benztropine is stopped.^[8]

Akathisia (Greek: “Inability to sit”) is a neuropsychiatric syndrome characterized by the subjective feeling of anxiety, restlessness, and an irresistible urge to move.^[9] Akathisia is an acute reaction, and occurs within hours to days of starting the offending agent. Individuals may feel compelled to pace and do tasks; for some, this can cause severe agitation, irritability, outbursts, and may place individuals at higher suicide risk.^[10]

• The etiology of akathisia is not well understood. It is thought that reduced dopamine transmission in the brain is responsible.^[11] However, akathisia does not respond as as well to anticholinergic agents (compared to acute dystonia and pseudoparkinsonism), which suggests there is an alternative etiology.

• A commonly used rating scale for the measurement of akathisia includes the Barnes Akathisia Rating Scale (BARS) and Extrapyramidal Symptom Rating Scale (ESRS).

• On examination, patients will appear unable to sit, stand, or lie still. When seated, their legs may cross and uncross frequently.
• When walking, the body weight may shift from one foot to another, or they may pace back and forth.

The differential diagnosis for akathisia is broad and includes:

• Agitation secondary to psychotic symptoms
• Non-akathisia antipsychotic dysphoria
• Restless legs syndrome
• Anxiety
• Agitation related to affective disorder
• Drug-withdrawal states
• Organic disorders (e.g. - delirium, head injury, hypoglycemia, encephalitis lethargica)
• Neurologic disorders (e.g. - Parkinson’s disease, Huntington’s disease)
• Tardive dyskinesia (commonly coexists with akathisia)
• Insomnia

• Prior to starting antipsychotics, prescribers should systematically assess for symptoms and signs of akathisia using a validated scale. Using a scale can allow providers to monitor for any emergent symptoms of akathisia.^[12]

• Treatment of akathisia includes reducing the dose of the offending agent, or treatment with benzodiazepines. Benzodiazepines (clonazepam, lorazepam, diazepam) can also be given prophylactically to reduce the incidence of akathisia.
• Other treatments include propranolol or mirtazapine.^[13][14][15]
• The use of anticholinergic medications such as benztropine should not be routinely used due to poor evidence and risk of side effects.^[16]
• There is also limited evidence that Vitamin D6 can be used in persistent akathisia.^[17]

Parkinsonism is a clinical syndrome comprised primarily of rigidity, tremor, and bradykinesia. The most common cause of parkinsonism is Parkinson disease, but parkinsonism also can occur because of the use of antipsychotics (more accurately referred to as medication-induced Parkinsonism, or pseudoparkinsonism, since the symptoms are not from a true Parkinson's Disease). It usually appears within a few days of starting treatment, or may evolve slowly over several weeks. Other causes of parkinsonism include Lewy Body Dementia, Wilson's disease, substance abuse, or Huntington disease, and must be ruled out.

Symptoms are similar to Parkinson's Disease, including bradykinesia, mask-like face, cogwheel rigidity, and tremors. Tremors are considered a cardinal sign of antipsychotic-induced Parkinsonism.^[18] Other features of drug-induced parkinsonism include increased salivation, drooling, seborrhea, and postural instability. Approximately 40% of older patients treated with typical antipsychotics can develop drug-induced parkinsonism even at low doses.^[19] Atypical antipsychotics have a lower incidence of causing parkinsonism.

The blockage of D2 receptors by antipsychotic drugs in the striatum is thought to lead to disinhibition of GABA and encephalin-containing striatal neurons in the indirect pathway without affecting the direct pathway in the basal ganglia, along with by disinhibition of the subthalamic nucleus. The change in the output of the indirect pathway of the basal ganglia-thalamocortical motor loop, is similar to changes seen in Parkinson disease.^[20]

Benztropine is commonly prescribed, but its use should be limited to short-term use, as there are significant adverse effect associated with long-term anticholinergic use, including: tachycardia, memory loss, blurred vision, urinary retention, and constipation. This is especially common in older patients. In general, the evidence is poor for the use of benztropine, though it is commonly used.

• Abruptly stopping an antipsychotic drug in any patient may cause a withdrawal-emergent dyskinesia (W-ED)!

Chronic blockade of dopamine receptors (in the nigrostriatal pathway) by antipsychotics results in dopamine receptor hypersensitivity and up-regulation of postsynaptic dopamine receptors.^[25][26] The increase in dopamine receptors means there is hyperinhibition of the stop signal, in conjunction with unopposed go signals in the post-synaptic receptor. This is thought to generate the hyperkinetic movements observed in TD. Of note, this remains a theory and research is still ongoing. However, it remains a useful pathophysiological explanation for the development of tardive dyskinesias.

Tardive dyskinesia movements can often be revealed or amplified by an activation technique since many patients need to be distracted before the disorder will visually manifest. For example, ask the patient to keep their mouth open for 20 to 30 seconds, then ask them hold up their hand while tapping each finger to the thumb in sequence. Another clinical exam is to ask the patient to open and close each hand while the mouth is open. This allows one to observe any curling or writhing movements of the tongue.^[27] TD can persist even after discontinuing treatment, hence, it is very important to monitor for early signs of TD using the Abnormal Involuntary Movement Scale (AIMS).

The Abnormal Involuntary Movement Scale (AIMS) is a rating scale that was designed in the 1970s to measure involuntary movements known as tardive dyskinesia (TD).

• The first approach to treatment of tardive dyskinesia is either to stop the offending antipsychotic, reduce the dose, switch to a lower potency second-generation antipsychotic (such as olanzapine, quetiapine, clozapine, or asenapine).^[29] Clozapine remains largely under-utilized, despite evidence of its superiority over other antipsychotics, and the lower risk of TD.^[30]
• Adjunctive treatments can be added, such as tetrabenazine,^[31] and with newer agents like the VMAT-2 inhibitor valbenazine.^[32]
• Vitamin E may have minor beneficial effects on reducing the severity of TD.^[33]

The figure below (figure 1) shows the timeline of EPS over time.

Fig. 1

• University of British Columbia Therapeutics Initiative: How well do you know your dopamine antagonists? (2022)
• Saltz, B. L., Robinson, D. G., & Woerner, M. G. (2004). Recognizing and managing antipsychotic drug treatment side effects in the elderly. Primary care companion to the Journal of clinical psychiatry, 6(suppl 2), 14.
• Tulane Psychopharmacology - EPS and Mechanisms