Extrapyramidal side effects (EPS), commonly referred to as drug-induced movement disorders, are among the most common adverse drug effects patients experience from dopamine-receptor blocking agents. It was first described in 1952 after chlorpromazine-induced symptoms resembling Parkinson disease. A variety of movement phenotypes have since been described along the EPS spectrum, including dystonia, akathisia, and parkinsonism which occur more acutely, as well as more chronic manifestations of tardive akathisia and tardive dyskinesia. The symptoms of EPS are debilitating, interfering with social functioning and communication, motor tasks, and activities of daily living. This is often associated with poor quality of life and abandonment of therapy which may result in disease relapse and re-hospitalization, particularly in schizophrenic patients stopping pharmacologic therapy.
Centrally-acting, dopamine-receptor blocking agents, namely the first-generation antipsychotics haloperidol and phenothiazine neuroleptics, are the most common medications associated with EPS. While EPS occurs less frequently with atypical antipsychotics, the risk of EPS increases with dose escalation. Other agents that block central dopaminergic receptors have also been identified as causative of EPS, including anti-emetics (metoclopramide, droperidol, and prochlorperazine), lithium, serotonin reuptake inhibitors (SSRIs), stimulants, and tricyclic antidepressants (TCAs). In rare situations, antivirals, antiarrhythmics, and valproic acid have also been implicated.
Rates of EPS are dependent on the class of medication administered. First-generation neuroleptics were associated with EPS in 61.6% of patients in a study of institutionalized patients with schizophrenia. Rates of EPS have declined with atypical antipsychotics with clozapine having the lowest risk and risperidone the highest. In terms of antiemetics with a dopamine D2 receptor antagonist effect, EPS incidence is cited to be between 4% to 25% with metoclopramide and between 25% to 67% with prochlorperazine.
Risks factors include a history of prior EPS and high medication dose. Elderly females are more susceptible to drug-induced parkinsonism and tardive dyskinesia, while young males manifest with more dystonic reactions.
The mechanism of EPS is thought to be due to antagonistic binding of dopaminergic D2 receptors within the mesolimbic and mesocortical pathways of the brain. However, the anti-dopaminergic action in the caudate nucleus and other basal ganglia may also contribute significantly to the occurrence of EPS.
Researchers previously hypothesized that the faster dissociation of atypical antipsychotics from the dopamine receptor, compared to typical antipsychotics, explained the reduced incidence of EPS. However, a recent study by Sykes utilized a novel time-resolved fluorescence energy transfer assay to demonstrate that binding kinetics and association rates, not dissociation, correlate more with EPS.
There is a wide spectrum of EPS presentations. Dystonia most often occurs within 48 hours of drug exposure in 50% of cases, and within 5 days in 90% of cases. On physical exam, dystonia manifests with involuntary muscle contractions resulting in abnormal posturing or repetitive movements. It may affect muscles in different body parts including the back and extremities (opisthotonus), neck (torticollis), jaw (trismus), eyes (oculogyric crisis), abdominal wall and pelvic muscles (tortipelvic crisis), and facial and tongue muscles (buccolingual crisis). The provider must evaluate these patients for pain and particularly difficulty in breathing, swallowing, and speech.
Akathisia is characterized by a subjective feeling of internal restlessness and a compelling urge to move, leading to the objective observation of repetitive movements comprising leg crossing, swinging, or shifting from one foot to another. The onset is usually within 4 weeks of starting or increasing the dosage of the offending medication. Due to its often vague and non-specific presentation of nervousness and discomfort, akathisia is often misdiagnosed as anxiety, restless leg syndrome, or agitation. In an attempt to treat these incorrect diagnoses, the provider may subsequently increase anti-psychotic or SSRI medications, further exacerbating akathisia. This failure to correctly diagnose can be detrimental as the severity of akathisia is linked to suicidal ideation, aggression, and violence. The provider must also note that withdrawal akathisia may occur with discontinuation or dose reduction of antipsychotic medication, and is typically self-limited lasting within 6 weeks.
Drug-induced parkinsonism presents as tremor, rigidity, and slowing of motor function in the truncal region and extremities. The classic appearance is an individual with masked facies, stooped posture, and a slow shuffling gait. Gait imbalance and difficulty rising from a seated position are often noted.
Finally, tardive dyskinesia manifests as involuntary choreoathetoid movements affecting orofacial and tongue muscles, and less commonly the truncal region and extremities. While symptoms are typically not painful, they may impede social interaction and cause difficulty in chewing, swallowing, and talking.
In most cases, laboratory and imaging tests are not required. The diagnosis is apparent from an accurate history and physical exam, especially noting a history of medication exposure.
If a patient is experiencing acute onset of EPS, particularly dystonia, the provider must assess if an emergency airway intervention is necessary as laryngeal and pharyngeal dystonic reactions may increase the risk of imminent respiratory arrest. Dystonic reactions are rarely life-threatening, and the provider should discontinue the offending agent and manage pain if present. If the causative medication is a typical first-generation antipsychotic, switching to an atypical antipsychotic may be trialed. Administration of an antimuscarinic agent (benztropine, trihexyphenidyl) or diphenhydramine may relieve dystonia within minutes. In cases of tardive dystonia, additional therapeutic strategies include administration of benzodiazepine, injection of botulinum toxin for facial dystonia, trial of muscle relaxant (e.g., baclofen), trial of dopamine-depleting agents (e.g. tetrabenazine), and consideration of deep-brain stimulation or pallidotomy for refractory cases.
For treatment of akathisia, strategies similar to managing dystonia are employed including stopping or reducing the dosage of offending medication, switching to an atypical antipsychotic if a typical first-generation antipsychotic was the offending drug, and administering anti-muscarinic agents. Additional therapeutic strategies more specific to akathisia include administration of a beta-blocker (most commonly propranolol), amantadine, clonidine, benzodiazepines, mirtazapine, mianserin (tetracyclic antidepressant), cyproheptadine, and propoxyphene.
Tardive dyskinesia is treated by withdrawal or dose reduction of the causative medication, switching to an atypical antipsychotic, withdrawal of concurrent antimuscarinic medications (although trihexyphenidyl has been reported to be therapeutic), injection of botulinum toxin for facial dyskinesia, benzodiazepines, amantadine, and trial of dopamine-depleting medications (e.g. tetrabenazine). Interestingly, the trial of levetiracetam, zonisamide, pregabalin, vitamin B6, and vitamin E have also been reported as therapeutic.
Drug-induced parkinsonism is treated with discontinuation or dose reduction of the causative medication, switching to an atypical antipsychotic, and administration of medications used for Parkinson disease including amantadine, antimuscarinic agents, dopamine agonists, and levodopa.
EPS may be challenging to distinguish from other idiopathic movement disorders. Muscle rigidity and tension are nonspecific symptoms that may be observed in neuroleptic malignant syndrome, serotonin syndrome, and other movement disorders. Chorea and athetosis are also present in Huntington’s disease (distinguished based on family history and genetic testing), Sydenham’s chorea (identified with a history of streptococcal infection), Wilson disease (adolescent-onset with a defect in copper metabolism), and cerebrovascular lesions. The flat facial expression, psychomotor slowing, and low energy level in akathisia may mimic the negative symptoms of schizophrenia. In addition, restlessness in akathisia may also appear similar to anxiety and psychotic agitation. If dementia accompanies parkinsonian signs and other motor abnormalities, the provider should evaluate the patient for Parkinson disease, Lewy body dementia, vascular dementia, and frontotemporal dementia. Interestingly, up to a third of new-onset schizophrenic patients who have never been medicated may present with parkinsonian signs.
EPS symptoms typically resolve spontaneously or improve with pharmacologic interventions. Acute dystonic reactions are often transient, but late-onset and persistent tardive dystonia have been described in the literature where symptoms persisted for years. A study of 107 cases of tardive dystonia reported that only 14% of patients achieved remission over a mean follow-up period of 8.5 years. Similarly, while acute akathisia may spontaneously resolve or improve with appropriate medication, studies have reported cases of tardive akathisia persisting over many years. Tardive dyskinesia also persists chronically with a cumulative persistence rate as high as 82% in a study of patients with schizophrenia.
Antipsychotic-induced and metoclopramide-induced laryngeal dystonia has been reported predominantly in young males. Rhabdomyolysis is a rare complication of drug-induced dystonia, especially if prolonged dystonia is present. While dystonic storm typically occurs in patients with primary known dystonia (e.g., Wilson disease, DYT1 dystonia), triggers typically include infection and medication adjustment in a significant number of cases. A dystonic storm is a life-threatening situation that manifests with fever, tachycardia, tachypnea, hypertensive crisis, diaphoresis, dysphagia, and respiratory failure. The manifestation of EPS in schizophrenic patients is associated with poor compliance with other atypical antipsychotic medications, which may subsequently lead to a relapse of schizophrenia and hospitalization. Failure to correctly diagnose and treat EPS is linked to suicidal ideation, aggression, and violence.
While some drug-induced movement disorders may last a few minutes, others may last long-term for weeks to years, and may potentially lead to contractures, bony deformities, or significant motor impairment. Physical medicine and rehabilitation consultation may provide useful treatment modalities that have shown efficacy in alleviating dystonia including relaxation training, biofeedback, transcutaneous electrical nerve stimulation (TENS), and percutaneous dorsal column stimulation. Physical and occupational therapy is paramount, leading to improvement in gait and mobility. In patients with oromandibular or laryngeal involvement, speech therapy may assist with dysphagia and communication barriers. In presentations of EPS refractory to pharmacologic management, neurosurgical consultation may be beneficial to explore deep brain stimulation, thalamotomy, and pallidotomy.
The spectrum of acute symptoms in EPS is distressing, especially with painful torticollis, oculogyric crisis, and bulbar type of speech, and if left untreated, it may cause dehydration, infection, pulmonary embolism, rhabdomyolysis, respiratory stridor, and obstruction. To this end, studies investigating the administration of prophylactic anticholinergic medications to prevent or reduce EPS have been performed. Authors have cautioned that prophylactic anticholinergic medications have distressing peripheral side-effects including dry mouth, urinary disturbances, and constipation, as well as undesirable central effects comprising cognitive dysfunction and delirium. This long-term prophylactic administration of anticholinergic medications in schizophrenia patients taking antipsychotics may worsen underlying cognitive impairment and subsequently worsen quality of life. Thus, while current guidelines generally do not recommend the prophylactic or long-term use of anticholinergics in schizophrenic patients taking antipsychotics, this decision should be made on a case-by-case basis with a meticulous risk-benefit analysis. In the emergency medicine realm, a meta-analysis demonstrated that prophylactic diphenhydramine reduces EPS in patients receiving bolus administration of antiemetic (with a dopamine D2 antagonist effect), but not when the antiemetic was given as an infusion; thus, this meta-analysis concluded that the most effective strategy would be to administer the antiemetic as an infusion without anti-cholinergic prophylaxis.
While typical, first-generation antipsychotics are used less frequently today, the provider must also be cognizant that even second-generation atypical antipsychotics may lead to EPS although at a lower incidence. Abouzaid and colleagues recently assessed the economic burden of EPS due to atypical antipsychotics in schizophrenia patients. During a 12-month, follow-up period, 12.6% of patients experienced EPS. Compared to those without EPS, patients who did experience EPS had more schizophrenia-related and all-cause hospitalizations, schizophrenia-related emergency room visits, and higher schizophrenia-related and all-cause total healthcare, inpatient, and prescription medication costs.