October 2001
D E Nelson
The Orchard Clinic
Royal Edinburgh Hospital
Morningside Terrace
Edinburgh
SMJ 2001;46: 133-134
Akathisia is a common and unpleasant side effect of many psychotropic medications. Junior doctors are often slow to recognise it with consequences for the patient which include reduced compliance, exacerbation of psychotic symptoms and an increased risk of suicide and violence. The word akathisia comes from the Greek meaning literally “not to sit’ and was initially used by Haskovec in 19021 to refer to restless patients with hysteria and neurasthenia. Akathisia is a relatively common side effect of antipsychotic medication, although other drugs including antidepressants, metoclopramide, some calcium channel blockers, dopamine agonists, amphetamine and buspirone have all been shown to cause it. The symptoms consist of objective and subjective components. Subjectively there are symptoms of dysphoria including tension, panic, irritability and impatience2 and objectively there are movements usually taking the form of shuffling of feet while sitting and pacing or rocking while standing. Fidgety leg movements may occur while lying down.3 The differential diagnosis includes agitation secondary to psychotic symptoms, the restless legs syndrome, anxiety, drug withdrawal states and a number of neurological disorders.
Clinical implications
Non-compliance is likely to be increased in patients suffering from the unpleasant symptoms of akathisia. Associated severe anxiety may exacerbate psychosis and there is an increased risk of suicide and violence.4,5 Patients may not be able to distinguish akathisia from the ongoing symptoms of illness leading to despair.6 Patients are also at increased risk of developing tardive dyskinesia.7
It is important that akathisia is recognised and treated appropriately as misdiagnosis and a further increase in antipsychotic medication dosage may further exacerbate the condition.
Epidemiology
Studies have reported incidences ranging between 20 and 75%.1,3 Varying diagnostic approaches and differences in study populations account for much of the difference in incidence quoted.
Gender does not seem to influence occurrence8 however it appears that acute akathisia and pseudoakathisia are more common in men and chronic akathisia is more common in women.2 There is no evidence any one race is particularly vulnerable.8
The risk is increased with higher potency drugs, higher dose, increased rate of dose escalation, the presence of extrapyramidal side effects (EPSEs), and parenteral administration.8,9 Age does not have a significant influence on the occurrence of acute akathisia.10
Pathophysiology
The underlying cause of akathisia is still far from clear.4 There appears to be dopamine receptor blockade in the mesocortical dopamine system. PET studies show D2 receptor occupancy in the striatum plays a role12 and noradrenergic and serotonergic systems also appear to he involved.13 Antipsychotics with potent 5HT receptor antagonism show a lower incidence of akathisia and some 5HT2 antagonists eg cyproheptadine, have therapeutic efficacy.
There is a possible association between low iron status and akathisia which was initially described by Ekbom in his investigation of patients with restless legs syndrome.4,11
Classification
There have been a number of subtypes of akathisia proposed, although a lack of consensus in the use of the terms is evident. Most authors refer to acute, tardive, chronic, withdrawal and pseudoakathisia.
Acute akathisia has an onset within hours or days, however some authors suggest the onset may be up to six months after an increase in dosage.7
Tardive akathisia is generally taken to mean akathisia of delayed onset (usually three months), not related to a recent change in drug or dose.10,11 It has been found to be significantly associated with tardive dyskinesia3 and some have proposed it to be a variant where the trunk and limbs are most affected. Activation procedures may help distiniguish between the two, for example finger tapping may increase symptoms in tardive dyskinesia but decrease the compulsion to move in akathisia.
Chronic akathisia usually refers to a persistence of symptoms for three months irrespective of the type of onset. 10,11
Withdrawal akathisia starts within six weeks of discontinuation or a significant dose decrease10 and pseudoakathisia refers to a variant where there are objective symptoms but no subjective awareness or distress. These individuals tend to display more negative symptoms of psychotic illness.
Assessment
There are a number of rating scales available. The most commonly used is the Barnes Akathisia Scale.15 This has objective, subjective and global clinical assessment components. It has good reliability and inter-rater reliability and takes less than five minutes to complete.4
Newer antipsychotics
The newer or 'atypical’ antipsychotics have a much lower propensity to cause movement disorders. They have however been shown to cause akathisia and some studies have shown the incidence may be as high as that for chlorpromazine.13,16 Sandoz pharmaceuticals have criticised the methodology in these trials and quote an incidence of akathisia with clozapine of 3% in their large trial.17 Some other studies have suggested clozapine may permit recovery from chronic akathisia.18
In a study looking at risperidone, a point prevalence of akathisia of 13% was calculated19 and in an open study of amisulpiride, 3 of 14 patients developed akathisia.8
Treatment
Optimal management is to prevent akathisia in the first instance. Patients should be forewarned of possible side effects and educated and reassured regarding these. Drugs which have been found to have some efficacy in the treatment of akathisia are outlined below.
Anticholinergics
These are probably most useful when akathisia is accompanied by parkinsonian side effects and are usually only partially efficacious.4,10 Studies have shown response rates between 39 and 73%.3
Beta blockers.
(B2 blockers). These are the most useful group of drugs in the treatment of akathisia.10 The mechanism is thought to be antagonism of the adrenergic system which is overactive due to neuroleptic blockade of presynaptic dopamine receptors. The initial use of propranalol is suggested, starting at 10mg three times a day and increasing every few days to a maximum of 90-120 mg. The onset of action is usually fairly rapid (4-40 hours) and it is well tolerated.4
Benzodiazepines
These may be effective in acute and chronic akathisia. Clonazepam is preferable due to its long half life. Tolerance and dependence are issues which limit their use and withdrawal should be slow and begin after 2-4 weeks.20
Cyproheptadine
This is an anti 5HT agent which has been shown to be efficacious in some studies.4,21 Continuing its administration for more than a few months is not recommended due to potential adverse effects.20
Clonidine
This is a centrally acting alpha 2 agonist which decreases central noradrenergic neurotransmission. Studies have shown some improvement but adverse effects such as sedation and hypotension can limit its use.10 If tolerated it may be continued although its withdrawal should be gradual.
Mianserin
This is a 5HT2A antagonist. One trial showed a response to treatment of 40% compared with 9.1 % in a placebo group.22
A number of other treatments have been proposed. Iron has been discussed above although the rationale for its use remains weak and there is the possibility of adverse effects. Some efficacy has been described for both nicotine patches4,23 and amantadine10 although the studies were small and not methodologically sound. Piracetam is structurally similar to GABA, induces neuronal metabolism and possibly alters membrane permeability in the central nervous system. One study showed a beneficial effect compared with placebo although more research into its use is required.10
A proposed plan of treatment
Initially reduce the dose or the potency of the drug, perhaps considering a newer (atypical) antipsychotic. If this is of no benefit consider an anticholinergic drug and if this fails to help, a beta blocker. Next a trial of a benzodiazepine (diazepam up to 15mg or clonazepam, 0.5-3mg) should be considered. Where there is still no improvement a trial of cyproheptadine, 16mg, followed by clonidine 0.2 to 0.8 mg is suggested.20
The other treatments listed above may be considered in treatment resistant cases however the evidence for their efficacy is as yet weak.