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Home , Akathisia, Dystonia

Graylands Hospital

Drug Bulletin

Extrapyramidal Side Effects (EPSE) – forgotten but not gone

North Metropolitan Health Service – Mental Health March 2014 Vol 21 No.1 ISSN 1323–1251 Introduction limited efficacy in the treatment of and are not at all effective in alleviating TD.² In fact Are movement disorders (commonly known as can sometimes worsen the extrapyramidal side effects, EPSE) ‘yesterday’s’ side movements of TD, and when discontinued a modest effect? One would think so looking at the plethora improvement may be seen.² Other hazards of medical literature that appears to focus almost associated with these drugs include: exclusively on the metabolic adverse consequences adverse effects (dry mouth, blurred vision, of treatment. Certainly, given the , tachycardia and urinary retention), ubiquitous use of drugs, risk of abuse (they can cause euphoria), toxic clinicians are less likely to observe EPSE in clinical confusional states and cholinergic rebound on 1 practice. withdrawal.²

However, EPSE are not restricted solely to the Box 1: Extrapyramidal side-effects ² agents, they are also an unwelcome adverse effect of certain atypicals, 1 especially when used at high doses and in • Acute : involuntary muscular contraction combination. Given that EPSE cause considerable which results in abnormal posture or movement. subjective distress, may lead to physical disability Typically involve muscles of the head and . and poor compliance with , 1 EPSE should Occurs more commonly in young adults and may remain at the forefront of side-effect monitoring. appear after only a few doses. These are acute and

This Bulletin provides an overview of the current painful and need immediate treatment sometimes knowledge of antipsychotic induced EPSE, with an with Intramuscular anticholinergics. emphasis upon clinical features, prevalence, , treatment and monitoring. • : , rigidity, bradykinesia. Symptoms generally emerge within a few days of Hopefully, this information will serve to remind starting the offending drug but may emerge slowly health professionals not to forget the importance of monitoring the occurrence of these highly over several weeks. Anticholinergic drugs are distressing and often preventable adverse effects. usually effective.

• Akathisia: sensation of inner restlessness, a Definitions compulsion to keep moving. Patients may be observed repeating purposeless movements. Acute EPSE is an umbrella term used to describe a wide akathisia is often associated with irritability, variety of movement disorders. They can be divided agitation and violent outbursts. Responds to into acute syndromes (those that develop generally treatment with . within hours or days of treatment) and chronic or tardive syndromes (those that develop after a 1 • Tardive : rhythmic involuntary sustained period of exposure). Acute EPSE include movements of face and jaw. Develops acute dystonia, akathisia and parkinsonism, whereas following long-term use of . May be is perhaps the most common late irreversible. has been shown to be an occurring . 1 effective treatment.

Anticholinergic drugs and EPSE Acute dystonia Anticholinergic drugs, such as benztropine, benzhexol, and orphenadrine, are often Acute dystonia (AD) is a sustained or repeated prescribed to counteract EPSE caused by involuntary muscular contraction which results in antipsychotic drugs. 1 Although there is little abnormal posture or movement.³ AD is often difference between them, benztropine is used most frightening, painful, debilitating and may negatively commonly in clinical practice. Anticholinergics are impact the therapeutic relationship between the generally effective, but not all EPSE are equally doctor and patient.³ responsive to these drugs. 1 For example, they have

muscles induces stridor. Intramuscular administration Clinical features of anticholinergic drugs (e.g. 1-2 mg of benztropine) is usually effective within 20 minutes. Occasionally, Symptoms may begin immediately, or can be repeated injections are necessary; they should be delayed by hours or days, after starting treatment administered at half hour intervals. Intravenous or increasing the dose of an antipsychotic.² administration of an anticholinergic is only necessary Symptoms typically involve muscles of the head and in cases of highly dangerous forms of AD such as neck. Involvement of the laryngeal and pharyngeal stridor.³ muscles may lead to serious problems, such as respiratory distress, asphyxia, dysphagia and choking.³ A tense tongue or throat may indicate a Akathisia moderate form of AD. Sometimes only the hands or just a few fingers may be affected. Frequently, Akathisia is a word of Greek origin meaning ‘not to sit’. It usually begins to appear within days of however, AD worsens when one or more muscle 5 groups are activated, such as while walking.³ beginning an antipsychotic or increasing its dose. The condition frequently becomes chronic if untreated and 5 Table 1: Acute dystonia – symptoms 4 may worsen and persist on . Akathisia may then exist in acute, chronic and tardive forms. The prevalence of tardive akathisia is not known but is Sustained eye closure an extremely unpleasant and difficult to treat Oculogyric Eye rotation condition when it occurs. Grimacing Trismus Jaw Clinical features Dysarthria Speaking difficulties

Dysphagia Swallowing difficulties The symptoms of akathisia are divided into subjective Neck distortion and objective. Subjective symptoms include a Opisthotonos Neck, head & trunk sensation of inner restlessness, a compulsion to keep distortion moving, unease, , discomfort, , Abnormal gait e.g. Pisa syndrome nervousness and apprehension. Patients with akathisia

are usually physically unable to maintain a fixed Prevalence posture when seated or standing but may be able to lie still and sleep. 5 AD is seen in up to 10% of those receiving conventional antipsychotics. ² It is most common Box 2: Brief clinical assessment for akathisia 6 with high-potency conventional antipsychotics (e.g. ) and less common with low-potency conventional drugs (e.g. ) and is Ask about: particularly prevalent in younger patients.³ Other • Feeling of inner restlessness risk factors include male gender and a prior dystonic • Desire to walk or pace • reaction. Clozapine is the only antipsychotic not to Difficulty sitting or standing still induce AD; ² other atypicals all have the potential • Related distress to induce AD at certain specific doses.³ Dystonia Observe for restless movements, such as: may also occur as a persistent, or tardive, disorder • Fidgety movements in patients receiving long-term antipsychotic • Leg swinging while sitting treatment, with a prevalence of around 1.5-4%.³ • Rocking from foot to foot The motor presentations are similar to those seen in • pacing AD, and are distinguishable from them only by their duration.³ Objective symptoms usually involve the lower limbs and feet. Patients may be observed repeating Pathophysiology purposeless movements, such as rocking from foot to foot, pacing, crossing legs, toe-tapping and face- Since all antipsychotics bind to D receptors, it has 2 rubbing. A coarse tremor and myoclonic jerks may been suggested that blockage of these receptors in 5 also be observed. Akathisia caused by high-potency the caudate, putamen and globus pallidus is partly conventional antipsychotics such as haloperidol, have responsible for causing AD.³ This would also explain been shown to provoke suicidal, homicidal and violent the diminished propensity of these drugs to cause behaviour. 4 More recently, suicidality has been linked AD in elderly patients, since D 2 activity decreases to the subjective aspect of akathisia. 7 with age.³

Prevalence Treatment The prevalence of akathisia varies according to AD usually presents suddenly and requires urgent definitions used and, perhaps more markedly, with treatment, especially where spasm of laryngeal antipsychotics prescribed. Generally, akathisia is

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much less commonly seen with newer atypical gradual onset over days or, more usually weeks. 9 antipsychotics than with conventional drugs, and is Table 2: Parkinsonism - symptoms 4 rare indeed with clozapine and quetiapine in particular. 2 Studies with conventional drugs Bradykinesia Slow movements (shuffling gait, reported prevalence rates as high as 68%, whereas soft/weak voice) studies undertaken on patients receiving atypicals 5 Absence of purposeful movements, reveal prevalence rates of between 11-15%. reduced arm swing, mask-like In the Clinical Antipsychotic Trial of Intervention expression Effectiveness (CATIE) study, it was estimated that Tremor Usually coarse or fine hand tremor 26-35% of people taking an atypical antipsychotic seen when arms outstretched experienced akathisia each year, compared with Rigidity Often co gwheel, less often leadpipe 8 35% taking the typical antipsychotic perphenazine. rigidity

Others Drooling, constipation Pathophysiology

The pathological basis for drug-induced akathisia Prevalence has never been precisely defined but the condition The prevalence of parkinsonism in those receiving seems inexorably to be associated with central, conventional antipsychotics may reach 75%. In those postsynaptic D antagonism. 5 2 taking atypical drugs the prevalence of such symptoms 9 Treatment is generally less than 20%. Interestingly, the baseline for parkinsonism in is not zero and

symptoms of parkinsonism are seen in around 15% of Akathisia may resolve following dose reduction, or 10 by switching to an alternative antipsychotic.² If this never-medicated people with schizophrenia. is not possible or desirable then the mainstay of treatment is propranolol, which has been shown to Pathophysiology be effective in reducing both subjective and The parkinsonism seems to occur as a result of the objective features of akathisia.² Doses range from relative balance of influences of dopamine and 30 to 80 mg/day and response seems to occur in the in the . 9 In Parkinson’s first few days of treatment. Other beta-blockers are disease dopaminergic neurones are destroyed and not effective, either because they do not enter the cholinergic innervation is allowed relative in sufficient concentration or because they prominence. In antipsychotic-related parkinsonism, lack propranolol’s unique action on serotonin dopaminergic transmission is blocked by the systems.² Other potential treatments include antagonistic actions of these drugs at postsynaptic anticholinergic drugs (which seem to be effective dopamine receptors. 9 where akathisia occurs alongside parkinsonism) & such as and Treatment .²

Drug-induced parkinsonism is usually treated by Newer treatment options switching to a drug less likely to be associated with such effects. Where switching antipsychotics is not The high rate of non-response to conventional anti- practical, anticholinergic drugs such as benztropine akathisic agents led clinicians to search in new are effective, but not without their own adverse directions. It was suggested that 5-HT 2 receptor antagonism, by counteracting dopamine D blockade effects.² 2 may prevent the severity of akathisia. As such, there is now evidence to support the use of a Tardive dyskinesia variety of 5HT 2 antagonists in akathisia: mianserin, ritanserin, and trazadone. 8 TD generally occurs after long-term antipsychotic therapy.TD is a complex neurological syndrome that Parkinsonism consists of hyperkinetic, involuntary movements, which are mainly choreoathetoid (but also dystonic) in 11 Antipsychotic-induced parkinsonism resembles nature. idiopathic Parkinson’s disease in many respects. Symptoms of drug-induced parkinsonism usually Clinical features emerge within a few days of starting the offending TD is commonly characterised by lip smacking and drug but may emerge slowly over several weeks. 9 chewing, often with episodic tongue protrusion (‘fly-

Clinical features catching’) or pushing the tongue into the inner cheek or lip. Grimacing and other facial muscle movements

The core features of drug-induced parkinsonism can occur forming the buccolingual masticatory include bradykinesia, rigidity and tremor with a syndrome. Other abnormal movements which can appear include choreiform movements of the hands 3

(‘piano -playing’), pelvic -thrusting or rocking of the withdrawing antipsychotics is not always legs. In severe TD, there may be problems with effective and so additional agents are often speaking and eating as well as difficulty in breathing used. As anticholinergics may exacerbate TD, 11 11 and swallowing. Once developed, symptoms may be they should also be discontinued. partly, or sometimes wholly, irreversible. 11 Although a person who develops TD is usually unaware of the Table 3: Possible treatments for TD ² movements, they are clearly noticed by others, and the condition has long been recognised as a severe Drug Comments social handicap. Tetrabenazine Only licensed treatment for TD in Australia. May cause Box 3: TD – symptoms 4 depression, drowsiness & akathisia. 25-200mg/day. General Benzodiazepines Widely used. Considered Choreiform movements: rapid, jerking contractions effective. Clonazepam 1-4 Athetoid movements: slow, sinuous muscular spasm mg/day & 6- Rhythmic movements: repeated, purposeless 25mg/day movements Propranalol Open label studies only.40 - Specific examples 120mg/day Tongue protrusion Vitamin E Many studies but efficacy Lip-smacking, lip-licking inconclusive. Dose range 400- Grimacing 1600IU/day Blepharospasm Piano-playing or guitar finger Neck-twisting (torticollis, retrocolis) Detecting and Monitoring of

Shoulder-twisting Rating scales available for evaluating drug- Trunk deformat ions (opisthotonos) induced movement disorders include: Barnes Akathisia Scale, 6 Simpson-Angus Scale (for Prevalence Parkinsonism), 13 Abnormal Involuntary Movement Scale 14 for TD. Although these scales For patients receiving extended treatment with are specific to EPSE, they were devised to serve conventional antipsychotics, about 20% will be found the needs of research, and whether they to have TD at any time, and the probability per year automatically transfer to routine practice has of developing TD is about 5%. 12 A recent systematic never been evaluated. The Glasgow review of 11 studies comparing the risk of TD between Antipsychotics Side-Effect Scale (GASS),15 5 different second generation antipsychotics with although not specific to EPSE, may be a more haloperidol, found the mean annual incidence of practical option. It is patient-completed, emergent TD in adults treated with atypical relatively short (21 items for men and women), antipsychotics to be 0.8% compared with an incidence global in its coverage, and rates both the of 5.4% with haloperidol. 13 frequency and distress of each item. Pathophysiology Conclusion A number of theories have been proposed to explain the development of TD with antipsychotics. One of The aim of this bulletin is to remind health the most prevailing hypotheses is that long-term professionals that EPSE remain a significant dopamine blockade in the striatum by antipsychotic concern with the use of antipsychotic drugs. drugs leads to dopamine receptor hypersensitivity, Although the risk of EPSE with atypical drugs is which in turn leads to a loss of voluntary control over reduced compared with conventional various aspects of motor movement. 11 It has also been antipsychotics, EPSE still occur with atypicals at proposed that TD may result from decreased Gamma- specific doses. Clinicians should remain mindful aminobutyric acid (GABA) function in the striatum for the possible development of EPSE when induced by dopamine hypersensitivity in inhibitory choosing an antipsychotic, and to ensure that dopaminergic neurones. It has also been postulated patients are systematically monitored, that TD arises as a result of over-stimulation of preferably with the use of one of the recognised encephalin receptors or because of high activity of rating scales developed for this purpose. free radicals. 11 This Drug Bulletin was written by Barrat Luft & was Treatment reviewed by the Graylands Pharmacy Department and Dr Natalie Pyszora: For references or any It is common practice to withdraw the offending Psychiatric Drug Information enquiries contact the antipsychotic and to substitute with another drug. The Statewide Psychiatric Drug Information Service on use of clozapine is best supported in this regard, but (08) 9347 6400 or email: there is also evidence for quetiapine, , [email protected] and . 11 Switching or 4