Extrapyramidal Symptoms Associated with Antipsychotic Use Tamara Pringsheim, MD, FRCPC, FAAN Associate Professor, University of Calgary Department of Clinical Neurosciences, Psychiatry, Pediatrics and Community Health Sciences
Extrapyramidal Symptoms Preferred term now is drug-induced movement disorders Can be seen with many types of drugs Antipsychotics, dopamine-receptor blocking drugs and dopamine depleting drugs are most frequently associated with drug-induced movement disorders
First Generation Antipsychotics (FGAs)
FGAs: Chemical Classification Phenothiazines Non-phenothiazines Butyrophenones Thioxanthenes Dihydroindolones Dibenzepines Diphenylbutylpiperidines
Phenothiazines Share the same three-ring structure Three subclasses: Aliphatic, Piperidine, Piperazine Fluphenazine Very high D2 activity Moderate 5HT2 activity Low muscarinic activity Low alpha 1 adrenergic activity Moderate antihistamine activity
Non-phenothiazines Butyrophenones: Haloperidol Very high D2 activity Moderate 5HT2 activity Low muscarinic, alpha 1 adrenergic and antihistamine activity Diphenylbutylpiperidines: Pimozide Very high D2 activity Moderate 5HT2 activity Low muscarinic, alpha 1 adrenergic and antihistamine activity
Second generation antipsychotics Dopamine-serotonin antagonists Block D2 and 5HT2 receptors Affinity for 5HT2 receptors is higher than D2 receptors Clozapine was the first drug in this class Risperidone, olanzapine, quetiapine, paliperidone, iloperidone, asenapine, lurasidone, ziprasidone Some drugs in this class have fewer extrapyramidal symptoms More metabolic side effects
Receptor Binding Profile Risperidone High D2 activity Very high 5HT2 activity Moderate antihistamine and alpha 1 adrenergic activity Clinically insignificant muscarinic activity
Receptor Binding Profile Ziprasidone High D2 activity Very high 5HT2 activity Moderate alpha 1 adrenergic and antihistamine activity Clinical insignificant muscarinic activity
Receptor Binding Profiles Olanzapine High D2 activity Very high 5HT2 activity Very high antihistamine and muscarinic activity Moderate alpha 1 adrenergic activity
Receptor Binding Profiles Quetiapine Low D2 activity Low 5HT2 activity Very high antihistamine and alpha 1 adrenergic activity Moderate muscarinic activity
Third generation antipsychotics Dopamine partial agonists Aripiprazole Reduces dopaminergic neurotransmission through D2 partial agonism, not D2 antagonism
Antipsychotic Use in Canada FGAs mainly used for psychotic disorders SGAs approved for use in psychosis and bipolar disorder Some SGAs have been approved as adjunctive therapies for major depressive disorder with inadequate response to antidepressants Risperidone approved for use in the elderly with psychotic/aggressive behaviour in the setting of Alzheimer s Disease Black box warning SGAs used in children and youth with behavioural disorders (ADHD, Conduct Disorder) and autism Quetiapine Risperidone Aripiprazole Aripiprazole
Pharmacoepidemiology of Antipsychotic Use in Canada Use of antipsychotics has risen dramatically over the past 20 years in all ages groups Rise almost exclusively in SGAs Most common diagnoses associated with antipsychotic use 1. Mood disorders 2. Psychotic disorders 3. Anxiety disorders 4. Sleep disturbances
Risk of EPS with antipsychotics The development and promotion of SGA use was predicated on indications that SGAs would have a milder EPS profile than FGAs and therefore greater tolerability Comparative efficacy trials in schizophrenia suggest there is no advantage of SGAs over FGAs in effectiveness or tolerability SGAs and FGAs should be seen as lying on a multidimensional continuum rather than as two distinct classes; the tendency to group the drugs this way masks the complexity of side effects associated with individual drugs Very difficult to find adequate data that compares risk across all individual drugs
CATIE trial 2005 1493 patients with schizophrenia in the US randomly assigned to receive olanzapine, perphenazine, quetiapine, risperidone, or ziprasidone for up to 18 months Primary aim was to delineate differences in overall effectiveness of these 5 treatments
CATIE trial 2005 No difference between the 5 drugs in prevalence of EPS Tardive dyskinesia Akathisia Drug-induced parkinsonism High rate of discontinuation across all 5 drugs (74%) More patients discontinued olanzapine due to metabolic side effects (9% vs 1-4% with other drugs); more patients discontinued perphenazine due to EPS (8% vs 2-4% with other drugs)
Risk of EPS with Antipsychotics Comparative efficacy and tolerability of 15 antipsychotic drugs in schizophrenia Multiple treatments meta-analysis of 212 clinical trials EPS measured as use of anti-parkinson drugs Leucht et al, Lancet 2013
Risk of Tardive Dyskinesia Correll 2008 Systematic review of studies of at least 1 year duration reporting the incidence of TD Compared SGAs (risperidone, olanzapine, quetiapine, clozapine and ziprasidone) as a group to FGAs (haloperidol and perphenazine)
Annual Tardive Dyskinesia Incidence Rates Children SGAs 0.35% (95% CI 0.1-1.2) Adults SGAs 2.98% (95% CI 2.59-3.43) FGAs 7.7% (95% CI 6.2-9.6) Elderly SGAs 5.2% (95% CI 4.7-5.8) FGAs 5.2% (95% CI 4.7-5.8)
Tardive dyskinesia prevalence rates SGAs 13.1% (95% CI 11.1-15.2) FGAs 32.4% (95%CI 29.0-35.9)
Risk of Akathisia Miller 1997 Prospective study of 73 patients admitted to psychiatry and started on antipsychotics (mostly haloperidol and other FGAs) Calculated incidence rates for akathisia over a 4 week period 22.4% (95% CI 12.6-32.1) All cases occurred within the first 2 weeks with a peak on day 3 Development of akathisia strongly associated with rapid dose escalation in the first days of treatment
Risk of Akathisia Meta-analysis of RCTs of new antipsychotic drugs for schizophrenia Prevalence of treatment emergent akathisia Medication Prevalence % (95%CI) I 2 Aripiprazole 8.5% (7.2-10.1) I 2 0 Clozapine 7.9% (2.7-20.7) I 2 43.9 Olanzapine 8.7% (6.9-10.9) I 2 18.5 Paliperidone 3.3% (1.8-6.0) I 2 0 Quetiapine 5.2% (4.0-6.7) I 2 0 Risperidone 14.2% (11.4-17.6) I 2 6.9 Ziprasidone 8.3% (5.6-12.2) I 2 1
Risk of Drug-Induced Parkinsonism Medication Prevalence % (95%CI) I 2 Aripiprazole 7.2% (4.7-10.9) I 2 0 Asenapine 2.4% (0.2-25.6) I 2 0 Clozapine 3.7% (0.3-35.3) I 2 0 Olanzapine 8.1% (5.5-11.8) I 2 37.5 Quetiapine 8.8% (4.6-16.3) I 2 23.6 Risperidone 12.1% (6.9-20.3) I 2 51.2 Ziprasidone 10% (4.6-20.5) I 2 0
Summary: Risk of EPS Clozapine and quetiapine appear to have a lower risk of EPS than other antipsychotics Haloperidol has a higher risk of EPS Risk is not zero for any of the antipsychotics Vigilance for EPS should be high in patients on any antipsychotic
Antipsychotic Induced Movement Disorders: Several Types Acute dystonia reactions Acute akathisia Parkinsonism Tardive dyskinesia Withdrawal dyskinesia Tardive dystonia Tardive akathisia
Neuroleptic Malignant Syndrome Rare adverse effect of antipsychotic medication Incidence 0.01-0.02% Onset occurs within hours to days after drug initiation Most occur within the first week; virtually all cases within 30 days
Neuroleptic Malignant Syndrome Hyperthermia (oral temperature >38C) Profuse diaphoresis Generalized rigidity Other abnormal movements can be present Changes in mental status delirium, stupor, coma Tachycardia, elevated blood pressure, tachypnea High CK
Neuroleptic Malignant Syndrome Once antipsychotic treatment is stopped, NMS is self-limited in most cases Mean recovery time after drug discontinuation is 7-10 days Most individuals recover within 1 week and nearly all by 30 days Fatality rates of 10-20% when not recognized early All dopamine antagonists have been associated with NMS High potency antipsychotics pose a greater risk than lowpotency agents and newer antipsychotics
Medication induced acute dystonia Seen within days of starting or increasing dose of antipsychotic, or after reducing the dosage of a medication used to treat extrapyramidal symptoms Dystonia= sustained muscle contractions causing twisting, repetitive movements and abnormal postures Cranial, neck and trunk muscles preferentially affected Retrocollis or torticollis Extension of trunk Deviation of eyes (oculogyric crisis) Forced jaw opening and tongue protrusion
Medication Induced Acute Akathisia Akathisia= state of excessive restlessness with a need to move Subjective complaints of inner tension and restlessness Observed excessive movements Shaking or rocking legs and trunk, pacing, marching in place, rubbing face, moaning to relieve discomfort, inability to sit or stand still Young children may not be able to articulate symptoms of akathisia May describe vague sensations of internal restlessness, discomfort, or anxiety; parents may state child appears anxious, more irritable/agitated Develops within a few weeks of starting or raising the dosage of a medication, or after reducing the dosage of a medication used to treat EPS
Neuroleptic induced parkinsonism Dose dependent adverse effect Develops within a few weeks of starting or raising the dosage of medication, or reducing the dosage of a medication for EPS Can be indistinguishable from idiopathic Parkinson s disease Classic resting tremor, rigidity, slowness of movement, shuffling gait, unilateral symptoms Fine, rhythmic perioral tremor may occur (rabbit syndrome) Can take months to resolve after withdrawal of offending agent
Neuroleptic Induced Tardive Dyskinesia Dyskinesia= abnormal movements Tardive dyskinesia refers to stereotypic, repetitive, choreiform movements of the mouth, lips and tongue, in a pattern that resembles chewing, sucking or lip pursing Occurs after using of a neuroleptic medication for at least a few months; can occur after a shorter period in the elderly Involvement of trunk, diaphragm, pelvis and distal limbs can occur Patients may be unaware of movements
Neuroleptic Induced Tardive Dyskinesia Movements of this type may appear after discontinuation, or after change or reduction in dosage of neuroleptic medication In these cases the condition is called neuroleptic withdrawal-emergent dyskinesia Withdrawal-emergent dyskinesia is usually time limited, lasting less than 4-8 weeks Dyskinesias persisting beyond this window is considered tardive dyskinesia
Neuroleptic induced tardive dystonia Subtype of tardive dyskinesia Sustained, slow, involuntary twisting movements affecting the limbs, trunk, neck or face Can be generalized, segmental or focal Common manifestations include retrocollis, facial grimacing, opisthotonic trunk extension, and hyperpronation of the arms Younger patients more likely to have generalized dystonia
Neuroleptic-induced tardive akathisia Persistent akathisia may occur as a subtype of tardive dyskinesia Defined as being present for at least one month when the patient is on a constant dose of a neuroleptic May occur in association with typical orolingual tardive dyskinesia or tardive dystonia Movements affecting the legs most common- marching in place while standing, while sitting crossing/uncrossing legs, rapidly abducting/adducting legs, pumping legs up and down
Neuroleptic-induced tardive akathisia Rocking of trunk while sitting Arm movements including smoothing hair with palms, rubbing face, folding/unfolding arms, repetitive rubbing anterior surface of the thighs Simple vocalizations such as grunting or moaning
Tardive dystonia and tardive akathisia Both of these movement disorders can persist for months to years, even after neuroleptic discontinuation or dosage reduction Can be very difficult to treat
Clinical Pearls When using an antipsychotic, try to use the lowest effective dose Medications should be gradually tapered when stopping Parkinsonism almost always begins with rigidity and cogwheeling- examine for these signs at every visit Acute dystonia is terrifying for patients Always counsel when first prescribing and advise to have benadryl on hand in case of an acute dystonic reaction
How do I examine for EPS?