European Review for Medical and Pharmacological Sciences 2021; 25: 4746-4756 and management of Akathisia 70 years after the introduction of the , the first

N. ZAREIFOPOULOS1, M. KATSARAKI1, P. STRATOS1, V. VILLIOTOU, M. SKALTSA1, A. DIMITRIOU1, M. KARVELI1, P. EFTHIMIOU2, M. LAGADINOU2, D. VELISSARIS3

1Department of , General Hospital of Nikea and Pireus Hagios Panteleimon, Athens, Greece 2Emergency Department, University General Hospital of Patras, Athens, Greece 3Department of Internal Medicine, University of Patras School of Medicine, Athens, Greece

Abstract. – OBJECTIVE: Akathisia is among CONCLUSIONS: Pharmacological manage- the most troubling effects of psychiatric drugs ment may pose a challenge in chronic akathi- as it is associated with significant distress on sia. Rotation between different pharmacologi- behalf of the patients, and it limits treatment ad- cal management strategies may be optimal in re- herence. Though it most commonly presents sistant cases. Discontinuation of the causative during treatment with antipsychotic drugs which drug and use of b-blockers, , benzo- block D2 receptors, Akathisia has al- diazepines or gabapentinoids for symptomatic so been reported during treatment with selec- relief is the basis of management. tive serotonin reuptake inhibitors (SSRIs), se- rotonin reuptake inhibitors (SN- Key Words: RIs), stimulants, mirtazapine, tetrabenazine and , , Haloperi- other drugs. dol, Locus coeruleus, . MATERIALS AND METHODS: This article was designed as a narrative review on akathisia with a focus on its clinical presentation, pathophys- iology and management. A PubMed search for akathisia was conducted which returned 8481 Introduction articles. RESULTS: Akathisia is experienced as severe Akathisia is a common adverse effect of treat- restlessness commonly accompanied by dys- ment with antipsychotic drugs, with incidence phoria and purposeless movement which re- rates ranging from 5-50% depending on the du- lieves subjective tension. It has been attribut- ration of treatment and the drug used1. It is a ed to an imbalance between dopaminergic and common cause of treatment non-adherence and noradrenergic neurotransmission in the bas- 2,3 al ganglia. Acute akathisia commonly resolves has been associated with violence and suicide . upon treatment discontinuation but tardive and Though most commonly observed with dopa- chronic akathisia may persist after the caus- mine D2 receptor antagonists, it may also compli- ative agent is withdrawn and prove resistant to cate treatment with other psychiatric drugs which pharmacological treatment. Even drugs which do not interact with dopamine receptors directly, induce no other extrapyramidal side effects including selective serotonin reuptake inhibitors (such as , quetiapine, aripiprazole and ) may induce akathisia. A high (SSRIs), serotonin norepinephrine reuptake in- index of suspicion should be maintained in hibitors (SNRIs) tricyclic , mir- patients with motor disabilities, drug-induced tazapine and vesicular monoamine transporter and those under mechanical re- 2 (VMAT2) inhibitors which deplete dopamine straint. Propranolol and low-dose mirtazapine and other monoamine neurotransmitters4. Drugs are the most thoroughly studied pharmacolog- of this class include (used as an antipsy- ical interventions for akathisia, though ben- chotic in the 1950s, now prescribed only rarely in zodiazepines, voltage- gated calcium channel blockers (gabapentin, pregabalin) and opioids low doses as an antihypertensive), tetrabenazine may be effective. (indicated for the treatment of Huntington’s dis-

4746 Corresponding Author: Nicholas Zareifopoulos, MD; email: [email protected] Pathophysiology and management of Akathisia ease) and valbenazine, the only drug indicated treatment initiation or dose adjustment11. Acute for the treatment of antipsychotic-induced tardive akathisia after a single dose of has dyskinesia5. also been described by physicians who took the It is difficult to comprehend the concept of drug to understand its action12. akathisia as it is not a normal component of hu- Objective of this article is to review the pre- man experience. It is typically encountered as sentation, pathophysiology and management of a side effect of psychiatric drugs but may also akathisia. A comprehensive review would be occur during opioid or stimulant withdrawal and valuable for clinicians and researchers alike due rarely as a result of traumatic brain injury6. It to its distressing nature, high prevalence and can be described as an intense sensation of inner lack of high-quality clinical trials regarding its restlessness accompanied by an urge to remain management. constantly in motion. It is typically accompanied by intense which worsens when will- ingly remaining still. It was initially classified as Materials and Methods part of the extrapyramidal syndrome (EPS) in- duced by antipsychotic drugs, but some evidence A review of the literature was conducted on suggests that akathisia is fundamentally distinct PubMed using akathisia as a search term. The from other EPS manifestations7. The underlying search returned 8481 articles. This work was mechanism is the inhibition of dopaminergic conceived as a narrative review with added neurotransmission in the nigostriatal pathway for emphasis placed on uncommon presentations of acute events, whereas tardive has been akathisia and management options. All articles attributed to D2 receptor upregulation and sub- were however screened for relevance (by title sequent hypersensitivity to dopamine following and abstract) and the full text of those consid- prolonged exposure to D2 antagonists5. Patients ered likely to be relevant was retrieved. A hand are characteristically indifferent to EPS and the search of the references of these articles was presentation is far more distressing to observers also conducted. All recommendations regarding of the movement disorders than to those actually management of akathisia were made based on experiencing them8. the available empirical evidence (clinical trials Akathisia by definition has a strong subjective and naturalistic studies) and on the pharmaco- component and may cause significant distress logical properties of the drugs if no other evi- in patients even in the absence of typical motor dence was available. A meta-analysis of clinical symptoms (pacing, adjusting position constantly trials regarding the management of akathisia in bed). This is indicative of cortical involvement may not be feasible as relatively few studies in the pathogenesis of the condition, whereas the have been conducted which are characterized by indifference typical of EPS suggests that only high heterogeneity and small sample sizes. As subcortical structures are involved1. The contro- this work is a narrative review we did not strictly versial entity of pseudoakathisia is defined as the adhere to a systematic review methodology as presence of behavior typical of akathisia in the dictated by the PRISMA guidelines. absence of the subjective component. This may be encountered in chronic schizophrenic patients with prominent negative symptoms9. Akathisia Results is considered acute if its duration is less than 3 months, chronic if its duration is greater than 3 Presentation and months and tardive if it presents after long-term of Akathisia treatment. Historically it was assumed that it The presentation of akathisia is distinct from presents some time (2 weeks or more) after ini- restless leg syndrome (RLS), though the patho- tiation of neuroleptic treatment or dose increase, physiological underpinnings may be similar. Pa- but recent evidence10 suggests that this is accurate tients with RLS complain of an uncomfortable only for drugs with a long half-life (aripirpazole, sensation in the legs and an insurmountable cariprazine) which require weeks to reach their urge to move them13,14. It is worse during the therapeutic steady state concentration. Drugs night and the discomfort associated with it is which attain therapeutic concentrations follow- primarily due to its disruptive effect on sleep. ing administration of a single dose (haloperidol, Patients may have a history of substance abuse, ) can induce akathisia within hours of as RLS is commonly present in the post-acute

4747 N. Zareifopoulos, M. Katsaraki, P. Stratos, V. Villiotou, M. Skaltsa, et al. withdrawal syndrome of many illicit drugs. It is of haloperidol to reliably induce akathisia even also associated with iron deficiency15. Akathisia in restrained individuals may explain why it on the other hand affects the entire body, is as- was used as a pharmacological torture agent24. sociated with intense dysphoria and symptoms Restrained patients should be frequently evalu- are constant throughout the day. It may dissi- ated for akathisia. It is recommended to inquire pate entirely when the patient is asleep, though directly about the nature of the patient’s discom- it is not uncommon for patients to experience fort (whether he feels as if he needs to move, if frequent awakenings (every 15-30 minutes) in it is localised to a particular limb, whether it order to pace for a few moments prior to going started after a drug was administered) and offer back to bed16. This is especially common when to provide symptomatic relief neuroleptics with a high propensity for causing if the diagnosis is confirmed. akathisia (aripiprazole, haloperidol, ) It should be noted that all neuroleptics and are prescribed as monotherapy in high doses17. It any other substance which acts as a D2 receptor is important to differentiate RLS from akathisia antagonist can cause akathisia. That said, some as the first line treatment is different. are more likely to cause it than others. Haloperi- Akathisia may rarely present after traumatic dol causes akathisia alongside the full spectrum brain injury or as a consequence of a cerebrovas- of EPS, a property it shares with most high po- cular event18,19. In elderly patients with multiple tency typical (fluphenazine, tri- cardiovascular risk factors imaging studies (CT fluoperazine, , benperidol, ), or MRI of the brain) are recommended to rule out whereas low potency typical antipsychotics are focal lesions as a cause of akathisia. far more likely to cause akathisia than other EPS A common clinical pitfall is the misdiagnosis when used at low doses2,21; this is particularly of akathisia as agitation due to the underlying important for , which is used psychiatric condition (, manic and almost exclusively in low doses (12.5-50 mg) as mixed episodes of bipolar disorder) for which a sedative. It is also preferred in the palliative a drug was initially prescribed. The dysphoria care setting for the potentiation of opioid an- which accompanies akathisia is similar to that algesics and to prevent opioid-induced nausea encountered in mixed episodes of bipolar disor- and vomiting. Despite its potent , der, but the recommended management strate- antiadrenergic and antisertotonergic properties gies are clearly distinct: acute akathisia usually it frequently causes akathisia which may be mis- resolves upon antipsychotic discontinuation or diagnosed as delirium25. It is important for cli- dose reduction, whereas a mixed state may nicians who routinely use levomepromazine in respond to an increase in the dose of the anti- their practice to be aware of this, as haloperidol psychotic9. and mechanical restraint (commonly used for The physical manifestations of akathisia (con- the management of delirium) may cause unnec- stant movement) in patients chronically exposed essary suffering and contribute to deterioration to neuroleptics may be masked by EPS (rigidity of the patient’s condition. Even clozapine and and bradykinesia due to Parkinsonism)20 so it is quetiapine, the two antipsychotic drugs consid- important to maintain a high index of suspicion ered to have an EPS liability low enough so as to and inquire about the subjective component21. be used safely in Parkinson’s disease can cause An atypical presentation of akathisia can be akathisia, though the risk is lower compared to observed in patients who experience intense other drugs26. Interestingly, the antipsychotic restlessness while being physically unable to least likely to induce akathisia is iloperidone, move (because of a pre-existing disability or which has an extremely high affinity for a1 as a consequence of mechanical restraint)22. adrenergic receptors, approximately 50 times Restrained patients may ask to be released and higher than its affinity for D2 and 5-HT2A re- tend to negotiate removal of the restraints from ceptors27. The development of akathisia appears 1 or 2 limbs if the initial request is refused. to be independent of other EPS and it does not The experience of akathisia while restrained predict the occurrence of parkinsonism during has been described as a state of unfathomable the first few months of treatment. Likewise, the torment and is typically encountered when a emergence of acute akathisia early in the course high potency (usually hal- of treatment has not been identified as a risk operidol) is administered as monotherapy for the factor for the development of management of acute agitation23. The propensity or other tardive syndromes2,5,6.

4748 Pathophysiology and management of Akathisia

Not Just a Dopamine Deficiency: which explains why 5-HT2A and 5-HT2C antag- Remarks on the Pathophysiology onists induce dopamine release in the mesocor- of Akathisia ticolimbic pathway. This may be the mechanism The mechanisms underlying akathisia are more underlying akathisia induced by serotonergic complex than the simple inhibition of D2 mediat- drugs such as SSRIs, which may be distinct from ed nigostriatial signaling that has been implicated the akathisia induced by D2 antagonists1,32. In a in the other forms of EPS. The cell bodies of preclinical study in rodents in which the dopaminergic neurons involved are located was compared with amphetamine it was observed in the ventral tegmental area, not the substantia that the behavioral effects of the 2 drugs were nigra8. Focal lesions of this nucleus give rise to distinct. Specifically, fluoxetine induced direc- a syndrome reminiscent of akathisia in rodents, tionless movement whereas amphetamine caused and pontine infarcts in man have also led to the the subjects to forward along a straight line, in development of akathisia and RLS which has accordance with the tendency of stimulants to responded to treatment with dopamine agonists19. promote goal-directed behavior33. The ventral tegmental area projects to the limbic These findings of an underlying mechanism for system via the nucleus accumbens, the core of the akathisia are also supported by clinical studies brain’s reward circuit. in healthy volunteers, neuroleptic naive psychot- Animal models of akathisia had been proposed ic patients and even psychiatrists themselves: during the 1990s, although their validity and akathisia may be ubiquitous during acute neuro- clinical relevance may not be ideal. The most leptic exposure; it is in fact the principal subjec- common model is that of emotional defecation in tive effect of the drugs. In one study in healthy rats. In this model rats habituated to a particular volunteers almost all subjects developed akathisia environment tend to defecate more frequently after exposure to haloperidol 3 mg per day and if exposed to dopamine antagonists. Increased aripiprazole 15 mg per day by mouth34. Haloperi- frequency of defecation is widely recognized as a dol even at this low dose had a higher rate of dis- sign of dysphoria in rodents28. This response is at- continuation. Reserpine which is a monoamine tenuated by b-blockers such as propranolol, sup- depleting agent did not have such a high inci- porting the hypothesis that antipsychotics induce dence of akathisia, but symptoms of depression an imbalance between noradranergic and dopa- were more common. Though the incidence of minergic neurotransmission29. Overactivation of acute akathisia appears to be ubiquitous with cer- noradranergic neurons leads to b1 adrenergic tain drugs, the intensity of the symptoms appears receptor mediated activation of the amygdala and to lessen over time as the condition becomes the nucleus accumbens shell, resulting in pur- chronic. This may also explain the relatively low poseless movements and intense dysphoria. Un- incidence of akathisia in crossover studies, as der normal conditions both the shell and the core patients with constant exposure to antipsychotics of the nucleus accumbens are innervated by the may have stable chronic akathisia which is not dopaminergic neurons of the ventral tegmental significantly affected by switching to another area to control goal directed behavior by inhib- drug35,36. These insights may be useful for clini- iting inhibitory gabaergic neurons which project cians to better understand the pharmacological to the limbic system and the cortex, but in the treatment of akathisia and to re-evaluate the use presence of antipsychotics the shell becomes hy- of antipsychotic drugs, especially for off label peractive due to its noradranergic innervation30. indications. This response can be attenuated by either b1 an- tagonists or a2 agonists such as clonidine, which Clinical Management of Akathisia reduce norepinephrine release by activating the The first step in the management of akathisia inhibitory autoreceptors present in locus coeru- should always be to identify the causative agent leus neurons31. The mechanism discussed above and if possible, discontinue treatment immediate- explains the efficacy of sympatholytic drugs such ly. This should not come as a surprise as individ- as beta blockers and clonidine in the treatment ualized treatment is the norm in psychiatry and of akathisia. The fact that the response to sym- akathisia is a syndrome diametrically opposed to patholytics is often partial suggests however that the stated goals of treatment for any psychiatric additional pathways are involved. The neurons condition2,32. A drug which causes akathisia in of the ventral tegmental area receive inhibitory a particular patient is ill suited to treat major serotonergic inputs from the dorsal raphe nucleus, depression, disorders, somatoform dis-

4749 N. Zareifopoulos, M. Katsaraki, P. Stratos, V. Villiotou, M. Skaltsa, et al. order, PTSD or OCD and it would be difficult to propranolol. It has been noted that the response is imagine how it could serve as a long-term mood often partial, in which case either further reduc- stabilizer. First, do no harm: one should bear in tion in dosage of the causative agent or addition mind that akathisia especially as an adverse effect of another drug for akathisia may be required42,43. of treatment is associated with We would not recommend clonidine as a first or suicidality and aggression37. The epidemiological even second line treatment for akathisia due to its association between antidepressants and suicide substantial side effects (hypotension, sedation) is stronger in the pediatric population and young and lack of clear evidence for efficacy30,31,43. adults, as reported in the black box warning of Anticholinergic drugs including , tri- all drugs in this class marketed in the US. Apart hexyphenidyl, benztropine and from SSRIs and SNRIs, akathisia may also occur are commonly used alongside antipsychotics to with tricyclic agents and mirtazapine in doses minimize their side effects and improve treat- higher than 30 mg per day38,39. Any antipsychotic ment adherence. They are the first line treatment prescribed off label to augment antidepressant for EPS and are routinely co-prescribed when treatment should be discontinued and short-term agents with a high probability of inducing EPS pharmacological treatment for akathisia should (haloperidol, fluphenazine) are used in high dos- be offered. es44. They are more useful for the treatment of In cases where neuroleptic treatment is abso- acute than parkinsonism. As they are lutely indicated (manic or mixed states in bipo- associated with delirium, cognitive impairment lar disorder, exacerbations of schizophrenia with and increased risk of falls in the elderly it is prominent positive symptoms) it is recommended recommended to avoid prolonged treatment espe- to prescribe antipsychotics at the lowest dose cially in geriatric patients45. They are extremely which adequately controls symptoms. High doses effective for acute dystonia but less so for neu- of neuroleptics may cause or exacerbate akathisia roleptic-induced Parkinsonism. It is not clear in virtually anyone but certain risk factors have whether they are of any benefit in akathisia and been identified. The most notable of these are use should only be prescribed for other manifesta- of high potency typical agents, rapid dose titra- tions of EPS. tion, young age and no previous exposure to an- Serotonergic antagonists, specifically mir- tipsychotic drugs40,41. Clozapine, quetiapine and tazapine in low doses (7.5-15 mg per day) and tra- iloperidone may be less likely to cause akathisia zodone (50-100 mg per day) have also been eval- than other drugs, but it still occurs in a substantial uated in clinical trials for akathisia. They may proportion of patients. be particularly effective for akathisia induced by The first line treatment for akathisia is propran- typical antipsychotics with negligible affinity for olol, the prototypical non-selective . 5-HT2A and 5-HT2C receptors38. Antagonism Though it does not appear particularly more effi- of these receptors may attenuate akathisia by cacious or well tolerated than other drugs, it is the promoting dopamine release in the mesocorti- one which has been more thoroughly evaluated colimbic pathway. Mirtazapine is a 5-HT2A and in clinical studies30,38. It is a lipophilic compound 5-HT2C antagonist but its affinity for H1 recep- which readily crosses the blood brain barrier and tors is approximately 20 times higher, suggesting is devoid of intrinsic sympathetic activity (mean- that it is significantly more potent as an antihista- ing that it is not a partial agonist). It is typically mine. At higher doses (more commonly employed prescribed at 40-120 mg per day in 3 divided dos- when it is used as an antidepressant) it induces es for the management of akathisia. The evidence norepinephrine release by blocking a2 autorecep- for other beta blockers is not as robust, though tors and may cause or worsen akathisia. Trazo- especially those with intrinsic sympathetic ac- done is a potent a1 adrenergic receptor antagonist tivity (such as pindolol which is also a 5-HT1A which may explain its notorious association with antagonist occasionally used off-label to augment priapism. Like mirtazapine it is a 5-HT2A and antidepressant treatment) should be avoided42,43. 5-HT2C antagonist, but its affinity for a1 recep- Beta blockers were the first recognized treat- tors is much higher. Doses in excess of 100 mg ment for akathisia and remain up to this day per day affect additional serotonergic receptors the most extensively evaluated in clinical trials. while also inhibiting serotonin reuptake. Trazo- Their action against akathisia does not appear to done has an active metabolite, meta-chloro-phe- be dose-dependent as a maximal response may nyl-piperazine (mCPP), a non-selective serotonin be obtained at the low end of the dosage range of agonist and releasing agent which induces dys-

4750 Pathophysiology and management of Akathisia phoria and hallucinations. Its contribution to the ment as they are safer than propranolol and ben- action of throughout its dosage range zodiazepines. Unlike propranolol, they have no remains unclear, though at low doses it is not organic contraindications whereas propranolol is likely to be significant46. Both trazodone and mir- not recommended in patients with bronchial asth- tazapine cause significant sedation. 5-HT2 antag- ma, COPD and diabetes. Physical dependence to onism is not however a particularly convincing and withdrawal reactions are mild in comparison explanation for their efficacy against akathisia. to benzodiazepines, they are not associated with Many antipsychotics also function as 5-HT2A paradoxical disinhibition and their abuse poten- and 5-HT2C antagonists and although it has been tial is limited as tolerance develops rapidly to the hypothesized that an inverse correlation exists effects recreational users find desirable. As they between a drug’s affinity for these receptors and are safer for long term use, they are particularly its propensity to cause akathisia, this has not attractive for the treatment of tardive akathisia, been definitively proven and it is not supported though prolonged treatment with high doses may by routine clinical experience. Akathisia is com- be required55. monly observed with antipsychotics which sat- Amantadine, an NMDA antagonist indicated urate 5-HT2 receptors throughout their clinical for the early stages of Parkinson’s disease is a dosage range, including risperidone, second line treatment which clinicians should be and olanzapine27,47. aware of as a possible adjunctive treatment6. It Benzodiazepines are the final first line treat- has been successfully used in such cases, though ment for akathisia, as they provide significant concerns regarding physical toxicity and psychot- symptomatic relief. This is attributed to their omimetic effects necessitate caution. The use of general sedative and anxiolytic action rather than dopamine agonists is generally not indicated as an effect which specifically addresses the patho- they may exacerbate psychosis, with the risk being genesis of akathisia. They may be especially significantly greater for patients who have been useful for patients with severe symptoms which maintained on antipsychotics for many years. D2 adversely affect sleep by causing frequent awak- receptors tend to upregulate after long-term ex- enings48. In practice they are commonly initiated posure to antipsychotics and other D2 antagonists alongside antipsychotics for acute psychosis, thus and this compensatory mechanism accounts both they confer some protection from akathisia and for the emergence of tardive dyskinesia and for the neuroleptic-induced dysphoria. It should be noted increased sensitivity of this population to the psy- that there is a risk of paradoxical disinhibition chotomimetic effects of dopamine agonists. This as a consequence of treatment option may be considered if the offending neuro- especially in young adults and geriatric patients, leptic has been discontinued and akathisia persists though it is reduced significantly by use of an despite treatment with first-line drugs, despite the antipsychotic. In rare occasions they have been substantial risk of supersensitivity psychosis56. known to induce akathisia, with case reports of Mu opioid receptor agonists may be regarded patients experiencing akathisia on one benzodiaz- as the last resort in the pharmacological manage- epine while tolerating equivalent doses of another ment of akathisia. Only two articles57,58 regarding well49. Concerns regarding physical dependence, this use of opioids have been identified, noting a cognitive impairment and delirium necessitate substantial response in acute akathisia but more using the lowest dose which adequately treats modest therapeutic effects in the tardive syn- symptoms for the shortest possible time span. drome. This is an option to be considered in in- Recent case reports50-53 and a pilot study sug- patients either in acute care wards or in long term gest gabapentin and its analog gabapentin enacar- care facilities who failed to adequately respond to bil may be effective for the management of other treatments. They typically have a long his- akathisia. This should not come as a surprise, as tory of neuroleptic exposure and may have con- gabapentinoids are a first line treatment for RLS, current tardive dyskinesia. Since the prognosis of which apart from a similar clinical presentation such patients in terms of functional rehabilitation may overlap in terms of pathogenesis as well. is poor, the use of opioids if informed consent is Theoretically pregabalin could be effective as provided may offer substantial relief from dys- well, though at least one case of pregabalin caus- phoria and despair, even if only a partial response ing akathisia has been reported54. If there was a is attained. This should not be a controversial stronger evidence base to support their efficacy position, as the care of such patients is essentially they would be recommended as a first line treat- palliative59. Table I provides an overview of the

4751 N. Zareifopoulos, M. Katsaraki, P. Stratos, V. Villiotou, M. Skaltsa, et al. pharmacological treatment of akathisia. Clinical likely to be implicated in treatment discontinua- algorithms for the management of both acute and tion and adverse clinical outcomes including ag- chronic akathisia are provided in Table II. gressive behavior and suicidality. Though it may be managed with the use of other drugs, the best course of action is usually to discontinue the of- Conclusions fending agent as the emergence of akathisia is not compatible with the stated purpose of treatment. Akathisia is among the most common adverse Further research is warranted particularly for the effects of antipsychotic drugs and the one most evaluation of gabapentinoids and opioids in the

Table I. Overview of drug classes used in the pharmacological management of Akathisia. Common Drug class Dosage adverse effects Contraindications Comments

Propranolol 40-120 mg per Bradycardia, malaise Asthma, chronic Consider first line in day in 2 doses Considered marginally obstructive pulmonary patients with a psychoactive but may disease, diabetes concomitant medical precipitate depression mellitus under indication for beta or psychotic insulin treatment, blocker therapy. May symptomatology acute decompensated cause hypertensive heart failure crisis with concomitant stimulant use or pheochromocytoma due to unopposed a adrenergic receptor mediated vasoconstriction

Anticholinergics Benztropine: Tachycardia, xerostomia, Glaucoma, urinary Not particularly 1-4 mg per day sedation, hallucinations, tract obstruction effective for akathisia : mydriasis, constipation, but commonly routinely 5-15 mg per day urinary retention used for parkinsonism Biperiden: May precipitate delirium and dystonia. Consider 4-12 mg per day in the elderly prophylactic treatment in patients receiving high potency first generation agents (haloperidol, luphenazine)

5-HT2A Mirtazapine: Sedation, weight gain, Previous adverse Consider first line in antagonists 7.5-15 mg vivid dreams reaction to the drug patients on high potency per day May worsen akathisia first generation drugs Trazodone: in higher doses and benzamides. 50-100 mg Most other antipsychotics per day block 5-HT2A-2C receptors to a significant degree at clinically relevant doses

Benzodiazepines 15-30 mg Sedation, respiratory Myasthenia Consider first line in diazepam repression when gravis, obstructive inpatients with a history equivalent combined with other sleep apnea of alcohol abuse. per day in sedatives, paradoxical Treatment duration divided doses disinhibition, euphoria should be limited due to May precipitate delirium the development of in the elderly tolerance and dependence

Continued

4752 Pathophysiology and management of Akathisia

Table I (Continued). Overview of drug classes used in the pharmacological management of akathisia. Common Drug class Dosage adverse effects Contraindications Comments

Α2δ voltage Gabapentin: Sedation, euphoria, Dose must be As they are well tolerated gated calcium 1200-3600 mg ataxia, weight gain adjusted in may be considered first channel blockers per day renal failure line drugs for akathisia. Pregabalin: In patients on long-term 300-600 mg treatment rotation with per day agents of a different class Gabapentin may help prevent the enacarbil: development of tolerance 300-600 mg per day

Opioids Highly Sedation, euphoria, , Monoamine oxidase Particularly effective for individualized. miosis respiratory inhibitor therapy acute akathisia (in the Less than 30 mg depression, nausea for tramadol, emergency setting and per day of oral and vomiting, pethidine, , in restrained patients) morphine tapentadol due to immediate onset equivalent may constipat pruritus, ion, Paralytic ileus of therapeutic benefit be sufficient in allergic reactions If long term treatment opiate-naive for chronic or tardive patients akathisia is required rotation with agents of a different class may help prevent the development of tolerance and dependence

Dopamine Amantadine: Sedation, unexpected sleep Hypersensitivity to Not recommended agonists and 100-200 mg attacks, hallucinations, the drugs, renal failure amantadine per day impulse control disorders, for amantadine Ropinirole: dopamine agonist 4-12 mg per day withdrawal syndrome with prolonged treatment

Table II. Management algorithms for Akathisia. Acute akathisia

Discontinue the causative agent if it is not an antipsychotic; prior to discontinuation of antipsychotic treatment a dose adjustment may be considered. Switching from a high potency first generation drug to a low potency first generation or a second generation drug may resolve symptoms. A final option is switching to clozapine or quetiapine which do not cause akathisia as often as other drugs. Symptomatic treatment of akathisia with a benzodiazepine, or opioid drug is recommended due to the intense dysphoria associated with the condition. Long term prophylactic treatment with an anti-akathisia drug is not recommended; the mainstay of management is reducing or removing the causative agent. Treatment may have to be continued for a few weeks to months if the akathisia is due to a drug with a particularly long half-life (fluspirilene, pimozide) or if it occurred due to use of a long-acting injectable formulation). In this case see principles mentioned below in the management of chronic akathisia.

Chronic or Tardive Akathisia

Reducing neuroleptic burden should be a priority but must be done gradually to minimize the risk of rebound psychosis or relapse. The same principles outlined above apply here as well: Switching from a high potency first generation drug to a low potency first generation or a second generation drug may resolve symptoms. A final option is switching to clozapine or quetiapine which do not cause akathisia as often as other drugs. Treatment with a single agent (propranolol, gabapentinoid, benzodiazepine or opioid) should be attempted first. In patients treated with for opioid use disorder switching to methadone or increasing methadone dose should be considered. If there is no response to a single agent at an adequate dose a combination may be tried. In patients who relapse despite discontinuation of neuroleptic therapy but respond adequately to pharmacological treatment a rotation between opioids, gabapentinoids and benzodiazepines may be attempted to reduce tolerance and prevent dependence.

4753 N. Zareifopoulos, M. Katsaraki, P. Stratos, V. Villiotou, M. Skaltsa, et al. treatment of chronic and tardive akathisia associ- 11) Rasmussen SA, Rosebush PI, Mazurek MF. ated with long-term antipsychotic treatment. The The Relationship Between Early Haloperi- management of this clinical entity is particularly dol Response and Associated Extrapyramidal Side Effects. J Clin Psychopharmacol 2017; challenging as it may persist after antipsychotics 37: 8-12. are discontinued, requiring prolonged treatment 12) Belmaker RH, Wald D. Haloperidol in normals. Br to attain symptomatic relief. Furthermore, in long J Psychiatry 1977; 131: 222-223. term patients abrupt or even gradual antipsy- 13) Sachdev P, Longragan C. The present status of chotic discontinuation presents significant risks akathisia. J Nerv Ment Dis 1991; 179: 381-391. because of D2 receptor upregulation and the risk 14) Leschziner G, Gringras P. Restless legs syn- of rebound psychosis. drome. BMJ 2012; 344: e3056. 15) Ferré S, García-Borreguero D, Allen RP, Earley CJ. New insights into the neurobiology of rest- Conflict of Interest less legs syndrome. Neuroscientist 2019; 25: The Authors declare that they have no conflict of interests. 113-125. 16) Lipinski JF, Hudson JI, Cunningham SL, Aizley HG, Keck PE, Mallya G, Aranow RB, Lukas SE. Polysomnographic characteristics of neurolep- Funding Statement tic-induced akathisia. Clin Neuropharmacol 1991; No funding was received for this review. 14: 413-419. 17) Inami Y, Horiguchi J, Nishimatsu O, Sasaki A, Sukegawa T, Katagiri H, Yamawaki S. A poly- References somnographic study on periodic limb movements in patients with and neu- 1) Poyurovsky M, Weizman A. Treatment of an- roleptic-induced akathisia. Hiroshima J Med Sci tipsychotic-induced akathisia: role of serotonin 1997; 46: 133-141. 5-HT(2a) receptor antagonists. Drugs 2020; 80: 18) Silver B V, Yablon SA. Akathisia resulting from 871-882. traumatic brain injury. Brain Inj 1996; 10: 609-614. 2) Lohr JB, Eidt CA, Abdulrazzaq Alfaraj A, Soliman 19) Han SH, Park KY, Youn YC, Shin HW. Restless MA. The clinical challenges of akathisia. CNS legs syndrome and akathisia as manifestations of Spectr 2015; 20: 1-6. acute pontine infarction. J Clin Neurosci 2014; 21: 3) Drake RE, Ehrlich J. Suicide attempts associated 354-355. with akathisia. Am J Psychiatry 1985; 142: 499- 20) Tuisku K, Lauerma H, Holi MM, Honkonen T, Ri- 501. mon R. Akathisia masked by . Phar- 4) Friedman JH. Movement disorders induced by macopsychiatry 2000; 33: 147-149. psychiatric drugs that do not block dopamine re- 21) Crisafulli C, Drago A, Sidoti A, Serretti A. A genet- ceptors. Parkinsonism Relat Disord 2020; 79: 60- ic dissection of antipsychotic induced movement 64. disorders. Curr Med Chem 2013; 20: 312-330. 5) Correll CU, Kane JM, Citrome LL. Epidemiology, 22) Wong AH, Ray JM, Rosenberg A, Crispino L, prevention, and assessment of tardive dyskine- Parker J, McVaney C, Iennaco JD, Bernstein SL, sia and advances in treatment. J Clin Psychiatry Pavlo AJ. Experiences of individuals who were 2017; 78: 1136-1147. physically restrained in the emergency depart- 6) Blaisdell GD. Akathisia: a comprehensive re- ment. JAMA Netw Open 2020; 3: e1919381. view and treatment summary. Pharmacopsychia- 23) Klein LR, Driver BE, Horton G, Scharber S, Mar- try 1994; 27: 139-146. tel ML, Cole JB. Rescue sedation when treating 7) Sabaawi M, Holmes TF, Fragala MR. Drug-in- acute agitation in the emergency department with duced akathisia: subjective experience and ob- intramuscular antipsychotics. J Emerg Med 2019; jective findings. Mil Med 1994; 159: 286-291. 56: 484-490. 8) Metin B, Metin SZ, Gunduz A, Poyraz BC, Ozmen 24) Zareifopoulos N, Panayiotakopoulos G. Treat- M, Kiziltan G, Kiziltan ME. Brainstem reflexes are ment options for acute agitation in psychiatric pa- hyperactive in patients with drug-induced akathi- tients: theoretical and empirical evidence. Cureus sia. Neurol Sci Off J Ital Neurol Soc Ital Soc Clin 2019; 11: e6152. Neurophysiol 2017; 38: 1683-1689. 25) Suzuki H, Gen K, Takahashi Y. A naturalistic com- 9) Temmingh H, Stein DJ. Anxiety in patients with parison study of the efficacy and safety of intra- schizophrenia: epidemiology and management. muscular olanzapine, intramuscular haloperidol, CNS Drugs 2015; 29: 819-832. and intramuscular levomepromazine in acute ag- 10) Keks N, Hope J, Schwartz D, McLennan H, Copo- itated patients with schizophrenia. Hum Psycho- lov D, Meadows G. Comparative tolerability of do- pharmacol 2014; 29: 83-88. pamine D2/3 receptor partial agonists for schizo- 26) Sachdev PS, Saharov T. Effects of specific do- phrenia. CNS Drugs 2020; 34: 473-507. pamine D1 and D2 receptor antagonists and ag-

4754 Pathophysiology and management of Akathisia

onists and neuroleptic drugs on emotional defe- and propranolol-controlled trial. Biol Psychiatry cation in a rat model of akathisia. Psychiatry Res 2006; 59: 1071-1077. 1998; 81: 323-332. 39) Koliscak LP, Makela EH. Selective serotonin re- 27) Orsolini L, Tomasetti C, Valchera A, Vecchiotti uptake inhibitor-induced akathisia. J Am Pharm R, Matarazzo I, Vellante F, Iasevoli F, Buonaguro Assoc (2003) 2009; 49: e28-36 EF, Fornaro M, Fiengo ALC, Martinotti G, Mazza 40) Sachdev P, Kruk J. Clinical characteristics and M, Perna G, Carano A, De Bartolomeis A, Di Gi- predisposing factors in acute drug-induced annantonio M, De Beradis D. An update of safety akathisia. Arch Gen Psychiatry 1994; 51: 963- of clinically used atypical antipsychotics. Expert 974. Opin Drug Saf 2016; 15: 1329-1347. 41) Juncal-Ruiz M, Ramirez-Bonilla M, Gomez-Ar- 28) Sachdev PS, Brüne M. Animal models of acute nau J, Ortiz-Garcia de la Foz V, Suarez-Pinil- drug-induced akathisia - a review. Neurosci la P, Martinez-Garcia O, Neergaard KD, Taba- Biobehav Rev 2000; 24: 269-277. res-Seisdedos R, Crespo-Facorro B. Incidence 29) Sachdev PS, Saharov T. The effects of beta-ad- and risk factors of acute akathisia in 493 indi- renoceptor antagonists on a rat model of neuro- viduals with first episode non-affective psycho- leptic-induced akathisia. Psychiatry Res 1997; 72: sis: a 6-week randomised study of antipsychot- 133-140. ic treatment. Psychopharmacology (Berl) 2017; 30) Wilbur R, Kulik FA, Kulik AV. Noradrenergic ef- 234: 2563-2570. fects in tardive dyskinesia, akathisia and pseu- 42) Tundo A, de Filippis R, Proietti L. Pharmacolog- doparkinsonism via the limbic system and basal ic approaches to treatment resistant depression: ganglia. Prog Neuropsychopharmacol Biol Psy- Evidences and personal experience. World J Psy- chiatry 1988; 12: 849-864. chiatry 2015; 5: 330-341. 31) Naguy A. Clonidine use in psychiatry: panacea or 43) Ohashi K, Hamamura T, Lee Y, Fujiwara Y, Kuro- panache. Pharmacology 2016; 98: 87-92. da S. Propranolol attenuates haloperidol-induced Fos expression in discrete regions of rat brain: 32) Poyurovsky M. Acute antipsychotic-induced possible brain regions responsible for akathisia. akathisia revisited. Br J Psychiatry 2010; 196: 89- Brain Res 1998; 802: 134-140. 91. 44) Duncan EJ, Adler LA, Stephanides M, Sanfilipo 33) Teicher MH, Klein DA, Andersen SL, Wallace P. M, Angrist B. Akathisia and exacerbation of psy- Development of an animal model of fluoxetine chopathology: a preliminary report. Clin Neuro- akathisia. Prog Neuropsychopharmacol Biol Psy- pharmacol 2000; 23: 169-173. chiatry 1995; 19: 1305-1319. 45) Bergman H, Soares-Weiser K. Anticholinergic 34) Veselinović T, Vernaleken I, Cumming P, Hen- medication for antipsychotic-induced tardive dys- ning U, Winkler L, Kaleta P, Paulzen M, Luck- kinesia. Cochrane database Syst Rev 2018; 1: haus C, Gründer G. Antidopaminergic medication CD000204. in healthy subjects provokes subjective and ob- jective mental impairments tightly correlated with 46) Laoutidis ZG, Luckhaus C. 5-HT2A receptor an- perturbation of biogenic monoamine metabolism tagonists for the treatment of neuroleptic-in- and prolactin secretion. Neuropsychiatr Dis Treat duced akathisia: a systematic review and me- 2018; 14: 1125-1138. ta-analysis. Int J Neuropsychopharmacol 2014; 17: 823-832. 35) Yoshimura B, Sato K, Sakamoto S, Tsukaha- ra M, Yoshimura Y, So R. Incidence and predic- 47) Corena-McLeod M. Comparative pharmacology tors of acute akathisia in severely ill patients with of risperidone and . Drugs R D 2015; first-episode schizophrenia treated with aripip- 15: 163-174. razole or risperidone: secondary analysis of an 48) Lima AR, Soares-Weiser K, Bacaltchuk J, Barnes observational study. Psychopharmacology (Berl) TR. Benzodiazepines for neuroleptic-induced 2019; 236: 723-730. acute akathisia. Cochrane Database Syst Rev 36) Schoretsanitis G, Nikolakopoulou A, Guinart D, 2002; 1999: CD001950. Correll CU, Kane JM. Iron homeostasis alter- 49) Joseph AB, Wroblewski BA. Paradoxical akathi- ations and risk for akathisia in patients treated sia caused by , clorazepate and lora- with antipsychotics: a systematic review and me- zepam in patients with traumatic ta-analysis of cross-sectional studies. Eur Neuro- and disorders: a subtype of benzodiaze- psychopharmacol 2020; 35: 1-11. pine-induced disinhibition? Behav Neurol 1993; 6: 37) Sharma T, Guski LS, Freund N, Gøtzsche PC. 221-223. Suicidality and during antidepressant 50) Takeshima M, Ishikawa H, Kikuchi Y, Kanbayashi treatment: systematic review and meta-analyses T, Shimizu T. Successful management of clozap- based on clinical study reports. BMJ 2016; 352: ine-induced akathisia with gabapentin enacarbil: i65. a case report. Clin Psychopharmacol Neurosci 38) Poyurovsky M, Pashinian A, Weizman R, Fuchs 2018; 16: 346-348. C, Weizman A. Low-dose mirtazapine: a new 51) Takeshima M, Ishikawa H, Kanbayashi T, Shi- option in the treatment of antipsychotic-induced mizu T. Gabapentin enacarbil for antipsychotic akathisia. A randomized, double-blind, placebo- induced akathisia in schizophrenia patients: a pi-

4755 N. Zareifopoulos, M. Katsaraki, P. Stratos, V. Villiotou, M. Skaltsa, et al.

lot open-labeled study. Neuropsychiatr Dis Treat 56) Nakata Y, Kanahara N, Iyo M. Dopamine super- 2018; 14: 3179-3184. sensitivity psychosis in schizophrenia: Concepts 52) Pfeffer G, Chouinard G, Margolese HC. Gab- and implications in clinical practice. J Psycho- apentin in the treatment of antipsychotic-induced pharmacol 2017; 31: 1511-1518. akathisia in schizophrenia. Int Clin Psychophar- 57) Walters A, Hening W, Chokroverty S, Fahn S. macol 2005; 20: 179-181. Opioid responsiveness in patients with neurolep- 53) Sullivan MA, Wilbur R. Gabapentin pharmaco- tic-induced akathisia. Mov Disord 1986; 1: 119- therapy for antipsychotic-induced akathisia: sin- 127. gle-patient experiment and case report. Ther Adv 58) Walters AS, Hening A. Opioids a better treat- Psychopharmacol 2014; 4: 100-102. ment for acute than tardive akathisia: possible 54) Rissardo JP, Caprara ALF. Pregabalin-associat- role for the endogenous opiate system in neuro- ed movement disorders: A literature review. Brain leptic-induced akathisia. Med Hypotheses 1989; Circ 2020; 6: 96-106. 28: 1-2. 55) De Berardis D, Serroni N, Moschetta FS, Mar- 59) Trachsel M, Irwin SA, Biller-Andorno N, Hoff P, tinotti G, Di Giannantonio M. Reversal of aripipra- Riese F. Palliative psychiatry for severe persistent zole-induced tardive akathisia by addition of pre- mental illness as a new approach to psychiatry? gabalin. J Clin Neurosci 2013; Definition, scope, benefits, and risks. BMC Psy- 25: E9-10. chiatry 2016; 16: 26.

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