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Home , Adrenergic receptor, Akathisia, Esmirtazapine, Mirtazapine, Ritanserin, Tic

Drugs https://doi.org/10.1007/s40265-020-01312-0

REVIEW ARTICLE

Treatment of ‑Induced : Role of 5‑HT2a Receptor Antagonists

Michael Poyurovsky1 · Abraham Weizman2

© Springer Nature Switzerland AG 2020

Abstract Akathisia is one of the most prevalent and distressing adverse efects associated with antipsychotic treatment. Pro- pranolol, a non-selective beta- , is currently considered a frst-line treatment for antipsychotic- induced akathisia (AIA). Surprisingly, the evidence for its anti-akathisia efect is modest. ’s side efects (e.g. orthostatic hypotension, bradycardia), contraindications (e.g. ) and increased complexity in titration schedules limit its use in some patients. agents and merely provide symptomatic relief in patients with AIA. Efective and well-tolerated treatment remains a major unmet need in akathisia and warrants a search for new anti-akathisia agents. Accumulating evidence during the last two decades indicates that agents with marked postsynaptic serotonin 5-HT2a receptor antagonism (, , , , ) may represent a new class of potential anti-akathisia remedies. Among these agents, low-dose mirtazapine (7.5 mg or 15 mg once daily) has demonstrated the most compelling evidence for therapeutic efcacy. In this narrative review we highlight the clinical signifcance of AIA, outline major approaches for its management and propose a practical algorithm for its treatment.

1 Introduction Key Points Akathisia is characterised by typical restless movements Akathisia remains one of the most prevalent and distress- associated with a subjective sense of inner restlessness and ing adverse efects associated with antipsychotic drug mental distress. Akathisia was identifed in patients with treatment, impacting adherence and response to treat- Parkinson’s disease and other neuro-psychiatric disorders ment. well before the development of psychopharmacological Propranolol, and benzodiazepines are agents. However, the introduction of antipsychotic medica- currently used for the treatment of akathisia. However, tions for the treatment of brought akathisia their side efects and limited efcacy warrant a search for to the forefront of clinical care. Subsequent detection of new anti-akathisia remedies. a meaningful incidence of akathisia among patients with mood and disorders treated with selective seroto- Agents with marked postsynaptic serotonin 5-HT2a nin inhibitors (SSRIs) further highlights its clini- receptor antagonism (ritanserin, cyproheptadine, tra- cal relevance. Akathisia also aficts some patients treated zodone, mianserin, mirtazapine), primarily low-dose with channel blockers, , anti-emetic mirtazapine, have emerged as a new class of efective and anti- agents, posing a diagnostic and treatment and well-tolerated anti-akathisia agents. challenge in non-psychiatric populations as well [1–4].

* Michael Poyurovsky 2 Geha Mental Health Center, Petah Tikva and Felsenstein [email protected] Medical Research Center, Sackler Faculty of , Tel-Aviv University, Tel‑Aviv, Israel 1 Maale HaCarmel Mental Health Center Afliated to the Rappaport Faculty of Medicine, Technion, Israel Institute of Technology, Tirat Carmel, POB 9, 30200 Haifa, Israel

Vol.:(0123456789) M. Poyurovsky, A. Weizman

Diagnosis of antipsychotic-induced akathisia (AIA) is and suicidal behaviour of patients with severe psychiatric challenging owing to the existence of various forms of illnesses. Mental distress that accompanies akathisia makes AIA [5]. Thus, acute akathisia usually emerges during it one of the most common reasons for non-adherence to the initiation of antipsychotic drug treatment. Chronic antipsychotic drug treatment [1, 2, 14, 15]. akathisia is defned as the persistence of symptoms for Akathisia appears to be one of the most frequent and more than 3 months. Akathisia may also arise following distressing drug-induced movement disorders, occurring reduction of dosage or cessation of antipsychotic medica- in around one in four patients treated with frst-generation tion, referred to as withdrawal akathisia. Similar to tardive (FGAs). Notably, high-potency FGAs, high , tardive akathisia develops late in the course doses and rapid dose escalation are among the predispos- of treatment, is exacerbated or provoked by antipsychotic ing factors for development of FGA-induced akathisia [1]. dose reduction or withdrawal, and improves at least tempo- Moreover, polypharmacy with two FGAs was found to be rarily when the antipsychotic dose is increased. Persistent associated with a substantially higher prevalence of akathisia akathisia is particularly disabling and often refractory to compared to those on monotherapy with FGAs (40% vs 21%, treatment. When a patient exhibits the objective signs of respectively), after controlling for confounding factors [16]. akathisia in the absence of awareness of the typical subjec- A similar pattern was found among patients treated with tive experience, it is sometimes called pseudo-akathisia second-generation antipsychotics (SGAs) (polypharmacy, [5]. 34.2% vs monotherapy, 10.9%) [16]. The accurate diagnosis of AIA is also complicated by Although low propensity to induce EPS is a defning diurnal variations in its expression and common associa- feature of SGAs, this seems not to hold entirely true for tion with other extrapyramidal syndromes (EPS), such as akathisia. The landmark Clinical Antipsychotic Trials of and [6]. The complex Intervention Efectiveness (CATIE) revealed no signifcant interplay of the observable restless movements and the diferences between the intermediate-potency FGA per- subjective sense of inner restlessness and distress account phenazine and four SGAs (, , risperi- for the difculties in diferentiating AIA from psychotic done, ) in the percentage of chronic schizophre- , anxiety, agitated , sub- nia patients who developed AIA [17]. Subsequent rigorous stance intoxication/withdrawal and tardive dyskinesia [3, analysis of the CATIE results using multiple criteria of AIA 4, 7]. (Barnes Akathisia Scale (BARS) [18] score ≥ 2, adminis- Risk factors for the development of akathisia remain tration of anti-akathisia , treatment discontinu- to be clarifed; however, several associations have been ation due to akathisia) estimated the 12-month akathisia detected. Patient’s age seems to play a role. An inverse rate at 26–35% for SGAs and 35% for , with a relationship between AIA and age has been reported; chil- trend towards the addition of anti-akathisia medications to dren and adolescents are more susceptible to the develop- more perphenazine- and -treated patients [19]. ment of EPS and akathisia than adults [8, 9]. Ethnicity is a A substantial rate of AIA induced by SGAs; putative risk factor with Caucasians being less vulnerable (200–800 mg, 16%), olanzapine (5–20 mg, 10%), quetiapine to AIA than other ethnic groups; however, this association (200–750 mg, 13%) and ziprasidone (40–160 mg, 28%) was was more robust among patients with tardive dyskinesia shown in the European First Episode Schizophrenia Trial [10, 11]. Individuals experiencing their frst episode of [20]. Lack of a substantial diference in moderate-to-severe psychosis previously untreated with antipsychotic agents akathisia (BARS score ≥ 3) between the FGA molindone are particularly vulnerable to the development of akathisia (10–140 mg) and the SGAs (olanzapine, 2.5–20 mg and ris- [1]. Notably, those with afective disorders, primarily peridone, 0.5–6 mg) was substantiated among adolescents bipolar depression, appeared to be more susceptible to in a Treatment of Early Onset Schizophrenia Spectrum AIA than schizophrenia patients. Non-psychiatric patients Disorders study (18%, 13%, 8% respectively) [21]. Overall, with delirium, substance abuse and those residing in pal- akathisia has been observed with all of the “older” SGAs; liative care settings, were also found to be sensitive to the however, there is a diference in incidence. Although direct development of AIA [1, 12, 13]. comparative studies that explicitly evaluated the incidence of Early detection and rapid amelioration of acute akathisia akathisia are lacking, it seems that risperidone, are essential because of its association with several serious and ziprasidone possess a higher risk than olanzapine, while clinical outcomes. There is compelling evidence indicating quetiapine and exhibit the lowest risk [1, 22, 23]. that AIA is associated with poor treatment response, exac- Newly approved SGAs also differ in their potential to erbation of psychosis. AIA can be a forerunner of tardive induce akathisia: and are associ- dyskinesia. AIA is a potential contributing factor to violent ated with dose-related and clinically meaningful rates of Antagonists for Antipsychotic-Induced Akathisia akathisia, whereas is not [23]. Thus, lurasi- 2 Current Management Approaches done-treated patients had a significantly higher incidence for Acute Antipsychotic‑Induced Akathisia of akathisia compared to placebo (15% vs 3%, respec- tively), especially with higher doses (80–120 mg/day). Management of acute akathisia is challenging. Adequate Similarly, significantly higher akathisia rates were noted adjustment of the antipsychotic drug regimen to avoid the in clinical trials of asenapine (6% vs 3% for placebo). development of akathisia is a primary clinical goal. The In contrast, patients treated with iloperidone (12–24 mg/ administration of a minimal efective dose of an antipsy- day) had comparable (to placebo) rates of akathisia as chotic, avoidance of rapid dose escalation and polyphar- assessed by the BARS, and their scores were substantially macy are essential to minimise the risk of akathisia [1, 26]. lower compared to patients treated with risperidone or Gradual dose reduction or switch to an antipsychotic with a ziprasidone [23]. Indeed, a recent systematic review and lower potential to induce akathisia are advised to deal with meta-analysis addressing the incidence of AIA induced by persisting akathisia. This strategy however carries a risk of newer SGAs in patients with severe mental illnesses sub- psychotic deterioration due to a loosening of the therapeu- stantiates these findings [24]. In general, the propensity tic efect. Overall, high incidence and clinical signifcance of newer SGAs to cause akathisia is more than twofold of akathisia, limitations of preventive approaches and risks higher than placebo [odds ratio (OR) 2.43, 95% confi- associated with switching antipsychotics to deal with exist- dence interval (CI) 1.91–3.10]. The estimated incidence ing akathisia, prompted a search for efective and safe anti- rate of akathisia for individual newly introduced SGAs akathisia remedies. is 3.9% (95% CI 2.4–6.3) for iloperidone, 6.8% (95% CI 5.1–9.0) for asenapine, 10.0% (95% CI 7.4–13.5) for 2.1 Adrenergic Agents , 12.7% (95% CI 10.1–16.1) for lurasidone, and 17.2% (95% CI 13.4–22.1) for . Overall, Propranolol, a non-selective centrally acting lipophilic iloperidone is characterised by the most benign akathisia beta (β)- antagonist, is currently con- profile comparable to that of quetiapine, followed by sidered a frst-line treatment for AIA. The anti-akathisia asenapine and brexpiprazole with a risk comparable to efect of β-blockers has been attributed to an interaction that of olanzapine. Lurasidone and cariprazine, as well between hyperactive adrenergic originating in the as , have the highest potential for akathisia locus coeruleus and the hypoactive dopaminergic neurons among the newly approved SGAs, both comparable to that in the midbrain [27]. However, this hypothesis is com- of risperidone [24, 25]. promised by the fact that interactions between adrener- Recently, a comprehensive systematic review of 40 stud- gic and dopaminergic neurons are primarily mediated by ies on akathisia was conducted and served as a foundation α- and not by β-adrenoceptors [27]. Clinical experience for evidence-based recommendations for the assessment and worldwide for several decades supports efcacy of pro- treatment of AIA [26]. In the present narrative review, we pranolol in the treatment of AIA. Surprisingly, the evi- briefy address currently available options for the manage- dence base for its anti-akathisia efect is modest at best ment of AIA, and then explicitly focus on the rationale for [28]. The majority of controlled studies that evaluated the use of and therapeutic efcacy of agents with marked anti-akathisia properties of propranolol were conducted serotonin 5-HT2a antagonistic properties (ritanserin, cypro- in the early 1990s, were of short duration (ranging from 2 heptadine, trazodone, mianserin, and mirtazapine) as puta- to 12 days) and included small samples of predominantly tive anti-akathisia remedies”. Although 5-HT2a antagonists schizophrenia patients [for review see 28]. Noteworthy, the are increasingly used by clinicians in the treatment of AIA, benefcial efect of propranolol on AIA has been extended we believe that there is still a need for an up-to-date review to other centrally acting non-selective beta-adrenergic summarising the current knowledge regarding therapeutic receptor antagonists (e.g. , ) [29]. How- efcacy and clinical utility of this unique pharmacological ever, these agents have not been widely used in clinical group for patients with akathisia. In this narrative review practice due to limited evidence of their clinical utility. we included open-label and controlled trials published in Finally, , a selective alpha-2 adrenergic presyn- PubMed until February 2020 that explicitly evaluated anti- aptic , can also improve AIA; however, clonidine akathisia properties of pharmacological agents with marked is not administered routinely owing to its frequent side 5-HT2a antagonism (ritanserin, cyproheptadine, trazodone, efects of sedation and hypotension. mianserin, mirtazapine). M. Poyurovsky, A. Weizman

2.2 Anticholinergic Agents suggested that the prevention of onset or mitigation of antipsychotic-induced EPS can be achieved with the pre- EPS have been attributed to the / ponderance of the serotonin (5-HT2a) receptor antagonism, imbalance produced by the antipsychotic blockage of the over the dopamine ­D2 blockade [37]. dopamine ­(D2) receptors in the nigrostriatal system. This Dopamine neurons in the ventral tegmental area and assumption is based on the inverse relationship between the substantia nigra ( regions apparently involved in afnity of conventional antipsychotic agents for muscarinic the of EPS and AIA) receive inhibi- receptors and their propensity for causing EPS. However, tory serotonergic input from midbrain raphe nuclei. It although anticholinergic agents have proven efcacious in was hypothesised that a reduction in brain serotonergic the treatment of antipsychotic-induced Parkinsonism and function (e.g. 5-HT2a antagonists, 5-HT1a , raphe acute , they produced equivocal results in AIA lesions) may increase the basal activity of dopaminergic [30–32]. Indeed, a recent review showed that the evidence neurons and thereby alleviate EPS induced by ­D2 recep- supporting the administration of the anticholinergic medica- tor antagonists [38]. An additional indication of a link tions benztropine and for the treatment of AIA is between EPS and the serotonergic system was provided limited and at high risk of bias, and the doses used exceeded by studies showing that SSRIs, which apparently increase those currently recommended [for review see 26]. Further- serotonin , have a propensity to induce more, treatment with anticholinergic agents is associated EPS and akathisia [39, 40]. Moreover, the SGAs, which with a substantial burden of side efects (e.g. cognitive display lower propensity to induce EPS and AIA, share at impairment, blurred vision, , ). least one pharmacological property that distinguishes them Co-administration of anticholinergics and antipsychotic from FGAs—the predominance of 5-HT2a receptor block- agents with marked anticholinergic properties highlights ade over D­ 2 receptor antagonism. Indeed, antipsychotics this problem even more. Some data suggest that anticho- with lower 5-HT2a/D2 receptor binding afnity ratio, indi- linergic medications may be more helpful in patients with cating higher afnity for 5-HT2a than ­D2 receptors (e.g. akathisia that co-exists with Parkinsonian symptoms leading clozapine, quetiapine), seem to have a lower potential to to the suggestion of a specifc Parkinsonian-related subtype induce akathisia (Table 1). In contrast, antipsychotics with of akathisia [33]. Overall, the available data pointing toward higher 5-HT2a/D2 ratio, indicating predominance of D­ 2 a questionable anti-akathisia efect of anticholinergics along over 5-HT2a receptor blockade (e.g. , aripipra- with the risk of adverse efects make them of limited thera- zole, cariprazine), are associated with a higher potential peutic value in AIA. to induce akathisia (Table 1). It is of note that risperidone, despite having a similar to quetiapine 5-HT2a/D2 receptor afnity ratio, possesses a relatively high risk to induce 2.3 Benzodiazepines akathisia, suggesting that additional pathophysiological mechanisms underlie AIA [41]. All these serve as a basis Benzodiazepines have some clinical utility in AIA, puta- for the use of agents with marked 5-HT2a antagonistic tively owing to their non-specifc anti-dysphoric and efect in the treatment of AIA. efects. Nevertheless, clinical practice indicates that these efects are not sufcient to ameliorate AIA. The evidence base is remarkably poor with only few small studies con- ducted in the early 1990s that addressed the anti-akathisia 4 Non‑selective 5‑HT2a Antagonists effects of the short-acting [34–36]. In addition, the side efects of benzodiazepines Although there are no selective 5-HT2a antagonists (e.g. cognitive impairment, addictive potential) limit their approved for clinical use in patients with AIA, several clinical utility in antipsychotic-treated patients. compounds from diferent pharmacological classes that share pronounced 5-HT2a antagonistic activity, ritanserin, cyproheptadine, trazodone, mianserin and mirtazapine, 3 Rationale for Using Serotonergic Agents have been suggested as putative anti-akathisia remedies for Acute Antipsychotic‑Induced Akathisia [2, 42, 43] (Table 2).

Lack of efcacy in a meaningful proportion of patients and 4.1 Ritanserin poor of the existing anti-akathisia agents led to the search for new efective and better-tolerated treat- Miller et al. evaluated the putative anti-akathisia properties ment options. With the introduction of SGAs, the seroton- of ritanserin, an agent with a pronounced 5-HT2a and 5-HT2c ergic system attracted researchers’ attention. It has been antagonistic activity, in an open-label study of patients with Serotonergic Antagonists for Antipsychotic-Induced Akathisia

Table 1 Serotonin (5-HT2a), dopamine ­(D2) and 5-HT2a/D2 receptor binding afnity ratio and the potential of antipsychotic agents to induce akathisia Antipsychotic Clinically efective dose Ki values (nM)a Potential (mg/day) to induce 5-HT2a D2 5HT2a/D2 ­akathisiab

Haloperidol 5–10 61.0 2.6 37.4 ++++ Aripiprazole 10–15 8.7 0.66 18.42 +++/++ Cariprazine 1.5–6 18.6 0.49 37.9 +++/++ Risperidone 1–4 0.15 3.8 0.04 +++/++ Paliperidone 3–6 1.2 2.8 0.42 ++ Ziprasidone 120–160 0.1 2.6 0.04 ++ Lurasidone 40–80 2.03 1.68 1.2 ++ Asenapine 10–20 10.15 8.9 1.14 ++ Brexpiprazole 2–4 0.47 0.3 1.5 ++ 300–900 0.41 11 0.04 ++ Olanzapine 10–15 1.5 20 0.08 + Iloperidone 12–24 1.94 3.5 0.55 + Quetiapine 150–750 31 770 0.04 −/+ Clozapine 300–800 2.6 210 0.01 −/+

Ki, constant of dissociation (lower Ki values correspond to higher receptor afnity), ++++ high potential to induce akathisia, +++ high-to- moderate, ++ moderate, + low, −/+ questionable a Ki values for 5HT­ 2a and ­D2 receptors are taken from Li et al. [65] b References [22–26]

akathisia induced by FGAs [42]. Ten patients received a showed a more than 50% reduction in the BARS global mean dose of 13.5 mg/day (5–20 mg/day) of ritanserin score. In six patients, the AIA disappeared completely. for 2 to 4 days. Treatment response was assessed by the These results were replicated in a double-blind comparison Hillside Akathisia Scale (HAS). After 3 days of treatment, study of cyproheptadine (n = 18, 16 mg/day) and proprano- HAS baseline ratings dropped from 16.4 ± 6 to 7.4 ± 5.2 lol (n = 12, 80 mg/day) in patients with acute FGA-induced (p = 0.0069 matched pairs signed rank test). Two patients did AIA [46]. Both demonstrated signifcant anti-AIA not respond. The efect of ritanserin was rapid and clinically activity (46% vs 42% decrease in the BARS score, respec- signifcant, and no signifcant side efects were noted. Ritan- tively) within four days of treatment. Cyproheptadine was serin was also shown to be efective in patients with AIA well tolerated, and side efects of mild sedation, dry mouth who failed to respond to conventional anti-akathisia agents and blurred vision occurred only in those patients receiving (e.g. anticholinergics, benzodiazepines and a β-blocker), concurrent anticholinergic . highlighting the diversity of mechanisms underlying AIA [44]. Notably, ritanserin was never marketed for clinical use. 4.3 Trazodone

4.2 Cyproheptadine Trazodone is an acting as a potent seroto- nin 5-HT2a receptor and α1-adrenergic receptor antagonist, Cyproheptadine, a frst-generation , possesses a weak serotonin and a weak potent 5-HT2a and 5HT­ antagonistic properties, in addi- ­H1 receptor antagonist. Initially its anti-akathisia efect tion to anti- and anti- properties. was demonstrated in an open-label study [47]. Nine female Its anti-akathisia efect was explored in an open trial of 17 patients with a global BARS score of at least 2 and receiv- patients with acute AIA induced by FGAs [45]. The drug ing a stable dose of FGAs were titrated up to 100 mg/day was administered in a fxed oral dose of 16 mg/day, in four of trazodone over a period of 5 days. The addition of trazo- divided doses for the duration of 4 days. The therapeutic done was associated with rapid improvement in symptoms efect of cyproheptadine was rapid and pronounced and of akathisia to at least some degree in all participants. These could already be discerned by Day 2 of treatment. By Day results were substantiated in a controlled cross-over design 4, all 17 participants had improved to some degree, and 15 study of 13 schizophrenia inpatients with FGA-induced M. Poyurovsky, A. Weizman lol were efcacious (46% and 42% lol were respectively) BARS, improvement in 5/11 in placebo group in BARS subscales in Trazodone vs vs subscales in Trazodone in BARS patients placebo treated BARS subscales. 7/13 (53.8%) of BARS mirtazapine 1/13 (7.7%)in group vs placebo group responded subscales in the mirtazapine group group (29%) vs (34%), propranolol placebo group (11%) jective distress and global sub-scales. and global distress jective 5/8 (62.5%) rate Response jective distress and global subscales. and global distress jective 5/12 (41.6%) rate Response Results 15/17 improved; 6/17 complete 15/17 improved; 8/10 improved - Both cyproheptadine and proprano Improvement in all 4 BARS subscales in all 4 BARS Improvement 14/15 of mianserin group improved vs vs 14/15 of mianserin group improved Improvement in all 4 BARS subscales in all 4 BARS Improvement Statistically signifcant improvement signifcant improvement Statistically Improvement in global and objective and objective in global Improvement Signifcant decrease in global BARS BARS in global Signifcant decrease Signifcant decrease in the BARS sub - in theSignifcant decrease BARS Signifcant decrease in the BARS sub - in theSignifcant decrease BARS HRSD CGI, HRSD SAS Outcome measures HAS, BPRS, HRSD,AIMS HAS, CGI BARS, BPRS, SAS BARS, BARS, SAS BARS, BARS, SAS, BPRS, mLAS, BPRS, mLAS, SAS, BARS, BARS, SAS, PANSS, mLAS, mLAS, PANSS, SAS, BARS, BARS BARS, PANSS, HRSD, SAS PANSS, BARS, BARS, BARS, PANSS, HRSD, PANSS, BARS, BARS, BARS BARS Dose (mg/day) 16 5–20 Cyproheptadine 16 80 Propranalol 15 15 100 100 15 Mirtazapine 15 80 Propranolol 15 7.5 Treatment Treatment duration (days) 4 3 4 14 5 5 6 5 7 8.5 10.3 N 17 10 18 cyproheptadine 12 propranalol 16 15 mianserin 11 placebo 9 8 trazadone/placebo 5 placebo/trazadone 13 mirtazapine 13 placebo 30 mirtazapine 30 propranolol 30 placebo 8 12 propranalol placebo trial placebo vs placebo placebo and propranalol placebo review review Study design Study Open trial Open trial Double-blind trial vs Open trial Double-blind trial vs Open trial Double-blind crossover Double-blind crossover Double-blind trial vs Double-blind trial vs Retrospective chart Retrospective Retrospective chart Retrospective Reports on the efcacy of serotonergic agents in patients with antipsychotic-induced akathisia in patients with antipsychotic-induced agents Reports on the efcacy of serotonergic antagonists 2a [ 61 ] Weiss et al. [ 45 ] et al. Weiss Miller et al. [ 67 ] Miller et al. Fischel et al. [ 46 ] et al. Fischel Poyurovsky et al. [ 50 ] et al. Poyurovsky Poyurovsky et al. [ 51 ] et al. Poyurovsky Stryjer [ 47 ] et al. Stryjer [ 48 ] et al. Poyurovsky et al. [ 53 ] et al. Poyurovsky Poyurovsky et al. [ 54 ] et al. Poyurovsky Poyurovsky et al. [ 60 ] et al. Poyurovsky Poyurovsky and Weizman and Weizman Poyurovsky 2 Table agent Serotonergic Reference 5-HT Cyproheptadine Ritanserin Mianserin Trazodone Mirtazapine Serotonergic Antagonists for Antipsychotic-Induced Akathisia

akathisia [48]. Patients were randomly assigned to receive trazodone (100 mg/day before bedtime) for 3 days followed by placebo for 3 consecutive days (8 patients) or the reversed order placebo-trazodone (5 patients). Statistically signifcant and clinically meaningful improvement in most symptoms of AIA was detected with trazodone compared to placebo. Although expected, no patients complained of drowsiness or dizziness attributed to sedation and orthostatic hypotension, both relatively common side efects of trazodone. Notewor- thy, there is a single indicating that trazodone cacious (26.1% and 39.5% decrease cacious (26.1% and 39.5% decrease respectively) in BARS, improved worse Both ef - and propranolol Results 3/10 dropouts, 5/10 unchanged, 2/10 5/10 unchanged, 3/10 dropouts, 2/10 improved, 6/10 unchanged, 2/10 6/10 unchanged, 2/10 improved, (100 mg/day) may exert an anti-akathisia efect when other medications (e.g. propranolol, clonazepam, biperiden, tetra- benazine) fail [49].

4.4 Low‑Dose Mianserin

Mianserin is a antidepressant that possesses Simpson and Angus Scale for extrapyramidal side efects extrapyramidal and Angus Scale for Simpson marked 5-HT2a and 5-HT2c antagonism, as well as anti- histaminergic and α2 antagonistic activity, without marked HRSD BARS, HRSD, SAS, PANSS HRSD, SAS, BARS, Outcome measures BARS, SAS, mLAS, BPRS, mLAS, SAS, BARS, BARS, SAS BARS, anticholinergic properties. Mianserin in higher doses (30–90 mg/day) is used for treatment of major depressive disorder. It was suggested that the 5-HT2a antagonism pre- ponderates in a low dose of mianserin (15 mg) and con- tributes to its anti-akathisia properties [50]. In a prelimi- nary open trial, 16 patients who developed FGA-induced 7.5 120 Dose (mg/day) 2 10–30 akathisia were treated with low-dose mianserin (15 mg/day) [50]. A benefcial efect was detected in 14 patients on the third day of treatment, consisting primarily of the disap- pearance of the subjective sense of inner restlessness, fol- 3 Treatment Treatment duration (days) 4 4 lowed by a substantial decrease in characteristic akathisia movements. The drug was well tolerated, and the only side efect, mild sedation in fve patients, was transient. These promising preliminary results were confrmed in a double- blind placebo-controlled study in which patients who met the criteria for acute AIA were randomly allocated to receive either low-dose mianserin (15 mg/day; n = 15) or placebo 14 zolmitriptan 19 propranolol N 10 10 (n = 15) once a day (at 08.00 h) for 5 days [51]. Treatment response was defned as a reduction of at least one point on the BARS global sub-scale. Results indicated that 14 of the 15 patients treated with mianserin (93.3%) responded, compared with only fve of the 11 patients (45.6%) given placebo who completed the trial. When a more rigorous response criterion was applied, namely, reduction of at least propranolol Double-blind trial vs Study design Study Open trial Open trial two points on the BARS, the positive response rate was 40% in the mianserin group and only 9.1% in the placebo group. Complete disappearance of the AIA occurred in four patients in the mianserin group (26.6%) but in none of the placebo group. Moreover, the benefcial efect of mianserin was accompanied by a corresponding reduction in neuroleptic- induced . By contrast, mianserin had no efect on (continued) agonist

concurrent symptoms of neuroleptic-induced Parkinsonism antagonist 1A 3 1D [ 65 ] [ 39 ] in AIA patients. These studies confrmed the tolerability Poyurovsky and Weizman and Weizman Poyurovsky Poyurovsky and Weizman and Weizman Poyurovsky Zolmitriptan [ 66 ] et al. Avital Barnes Scale, BARS Akathisia scale, HAS Hillside Akathisia Scale, BPRS Brief Scale, CGI Clinical Global Impression Rating HRSD Scale, Psychiatric Movement AIMS Abnormal Involuntary Scale, SAS Syndrome and Negative Positive mLAS Depression, Scale, PANSS Scale for Rating Hamilton Modifed Leeds Anxiety 2 Table Serotonergic agent Serotonergic Reference 5HT 5HT 5HT and safety of low-dose mianserin; mild, transient sedation M. Poyurovsky, A. Weizman and clinically irrelevant orthostatic hypotension were the FGA-induced akathisia [55]. Using the fxed-efects model, only side efects. Notably, a benefcial anti-akathisia efect, it was found that risk ratio (RR) for response and remission as well as safety and tolerability of low-dose mianserin was 6.67 (95% CI 2.14–20.78; p = 0.001) and 6.20 (95% were substantiated in a patient who exhibited symptoms of CI 1.74–22.08; p = 0.005), respectively, indicating that mir- chronic akathisia [52]. tazapine is about six times more efective than placebo in ameliorating symptoms of acute AIA. The relative clinical 4.5 Low‑Dose Mirtazapine efectiveness was high, with one in four patients showing partial response (NNT = 4; 95% CI 2.6–8.6) and one in fve Mirtazapine is structurally and pharmacologically similar patients (NNT = 5; 95% CI 2.9–11.6) showing complete to mianserin. Mirtazapine is characterised by potent presyn- remission. aptic alpha-2 adrenergic antagonism, which accounts for its This meaningful therapeutic efcacy of mirtazapine in antidepressant activity, and marked 5-HT2a blockade that AIA was associated with a low side-efect burden, with mild seems to predominate in a low dose and contribute to its sedation as the most common adverse efect. Notably, this anti-akathisia properties. In addition, mirtazapine is a potent meta-analysis is limited by the number of studies included, anti-histaminergic compound. In a randomised double-blind short duration of treatment varying from 5 to 7 days and the design study, 26 FGA-treated schizophrenic patients with fxed dose of mirtazapine (15 mg). AIA received add-on mirtazapine (15 mg/day) or placebo In addition, to address the overall class efect of agents for 5 days [53]. Low-dose mirtazapine was associated with with marked 5HT­ 2a antagonism (ritanserin, cyproheptadine, rapid and clinically signifcant improvement in akathisia mianserin, mirtazapine and trazodone) in the treatment of ratings and signifcantly more mirtazapine-than placebo- FGA-induced akathisia, a systematic review and meta-anal- treated patients (53.8% vs 7.7%, respectively; p = 0.004), met ysis of six controlled studies (4 placebo-controlled, 1 pro- operational response criterion, a reduction of at least two pranolol-controlled; 1 propranolol- and placebo-controlled; points on the BARS global subscale. Mirtazapine treatment N = 249 patients) was conducted [56]. was also associated with modest improvement of psychotic Using the BARS to quantify symptoms of AIA and defn- symptoms. Mild sedation was the only side efect. These ing response as a reduction of the BARS score by at least encouraging results were substantiated by the subsequent two points, the meta-analysis revealed that 5-HT2a antag- largest-to-date randomised placebo-controlled trial compar- onists are about seven times more efective than placebo ing low-dose mirtazapine and propranolol in 90 patients with in the treatment of AIA [RR = 7.10 (95% CI 3.08–16.40, FGA-induced akathisia [54]. Mirtazapine, given once daily p < 0.0001)]. Remission rates were also signifcantly higher (15 mg) was as efective as propranolol (40 mg twice daily) in the drug groups than in the placebo groups (RR = 4.95, in producing a greater improvement in AIA compared to 95% CI 2.01–12.22, p = 0.0005). There were no signifcant placebo [reduction in BARS global scale: 1.10 ± 1.37 points diferences between the drug and placebo groups in adverse (34%) and 0.80 ± 1.11 (29%) vs 0.37 ± 0.72 (11%), respec- efects and dropouts, suggesting that short-term administra- tively, p = 0.036]. Responder analysis (BARS global scale tion of these agents is safe and well-tolerated in antipsy- reduction ≥ 2) yielded a similar robust anti-akathisia efect in chotic-treated patients. Notably, 5-HT2a antagonists did not mirtazapine and propranolol versus placebo (43.3%, 30% vs interfere with the antipsychotic efect of the ofending drug. 6.7%, respectively, p = 0.005). Low number-needed-to-treat (NNT) supports high clinical efectiveness of both mirtazap- 4.5.1 Low‑Dose Mirtazapine for Aripiprazole‑Induced ine and propranolol (3 and 4, respectively). Mirtazapine did Akathisia not interfere with the antipsychotic efect of FGAs. Nota- bly, mirtazapine and propranolol had no efect on Parkin- A robust anti-akathisia efect of low-dose mirtazapine sonian symptoms coincident with akathisia, reinforcing the comparable to propranolol has consistently been shown hypothesis that antipsychotic-induced Parkinsonism might in patients treated with FGAs, underscoring the role of be related to dopamine/acetylcholine dysfunction and may 5-HT2a antagonism in the pathophysiology and treatment preferentially respond to anticholinergic agents [33]. An of acute akathisia. The clinically reasonable question is imbalance between dopaminergic and noradrenergic/sero- whether low-dose mirtazapine would exert a similar ben- tonergic systems seems to predominate in AIA that responds efcial efect in patients who developed akathisia while to β-adrenergic and 5-HT2a antagonists [2, 38]. being treated with SGAs. Among SGAs, aripiprazole is These two randomised placebo-controlled trials were associated with a substantial rate of emerging akathisia; at meta-analysed to address therapeutic efcacy and toler- clinically efective doses (10–30 mg/day) it exerts marked ability of low-dose mirtazapine in patients (N = 86) with striatal ­D2 receptor occupancy, and is distinguished from Serotonergic Antagonists for Antipsychotic-Induced Akathisia

the majority of SGAs by relatively low 5-HT2a antagonism in the 2 studies yielded a remarkably similar response rate in schizophrenia patients [57]. We previously suggested (62.5%). that aripiprazole’s low 5-HT2a/D2 receptor afnity ratio (Table 1), may account at least in part for its high propen- sity to induce akathisia, and proposed low-dose mirtazap- 5 Proposed Treatment Algorithm for Acute ine as a potential remedy [58]. Notably, brexpiprazole, a Antipsychotic‑Induced Akathisia: partial dopamine agonist similar to aripiprazole, has an Incorporating Serotonin 5‑HT2a approximately tenfold higher afnity for the 5-HT2a recep- Antagonists tor and is associated with a substantially lower incidence of akathisia (number-needed-to-harm for akathisia: aripipra- There are two major treatment strategies for dealing with zole, 25; brexpiprazole, 112) [59]. A benefcial efect of acute AIA: modifcation of the antipsychotic drug regimen mirtazapine (15 mg/day for the duration of 8.5 ± 2.3 days) and/or the addition of an anti-akathisia agent (Fig. 1). A was indeed revealed in a retrospective analysis of com- dose reduction of the antipsychotic or switch to an antip- puterised medical charts of 8 patients with schizophrenia sychotic with a lower potential to induce akathisia is a or afective disorders who were treated with aripiprazole (mean 12.5 ± 3.5 mg) and who developed acute akathisia Acute antipsychotic-induced akathisia [60]. The response rate was clinically meaningful (5 of 8 patients; 62.5%). Similar to the mirtazapine trials among patients who experienced FGA-induced akathisia, the benefcial anti-akathisia efect of mirtazapine in aripipra- Step 1 Change antipsychotic drug regimen Reduce dose of antipsychotic agent zole-treated patients was detected early in the course of OR treatment, was exerted at a fxed daily dose (15 mg) and Switch to antipsychotic agent with low potential to was safe and well-tolerated with mild sedation as its only induce akathisia (e.g., quetiapine) detected side efect. Retrospective study design, small sample size and short duration of administration preclude Step 2 defnite conclusions regarding the clinical utility of mir- Add anti-akathisia agent tazapine in aripiprazole-induced akathisia. Beta-blocker:Propranolol (20-120mg/day) OR 5-HT2a antagonist:Mirtazapine 4.5.2 Very Low‑Dose Mirtazapine (7.5 mg) for SGA‑Induced (7.5mg -15 mg/day) Akathisia

Clinical experience has indicated that although in general, mirtazapine 15 mg/day is well tolerated by patients with Add Benzodiazepine (for symptomatic sedative and anti-dysphoric effect) AIA, increased , subsequent weight gain and day- (1-2 mg/day) time drowsiness observed in some patients prompted drug Step 3 Clonazepam (0.5-1 mg/day) (5-15 mg/day) discontinuation. A retrospective chart review was under- OR taken to determine whether mirtazapine, in a lower dose Add Anticholinergics of 7.5 mg, maintains its anti-akathisia properties while (mainly in patients with concurrent parkinsonism) Biperiden (2-6 mg/day) exhibiting better tolerability in patients with schizophrenia Benztropine (1.5-8 mg/day) and mood disorders who developed acute SGA-induced (2-10 mg/day) akathisia [61]. Indeed, the results of this small study revealed that mirtazapine at a very low dose (7.5 mg) given for mean 10.3 days (Table 2) maintained its benefcial anti- akathisia efect and exhibited an excellent tolerability pro- fle in 12 patients with acute risperidone- and aripiprazole- induced akathisia. Mirtazapine (7.5 mg) demonstrated a Step 4 Switch to Clozapine (in case of intractable akathisia) rapid and clinically signifcant anti-akathisia efect with a response rate comparable to that found in a higher mirtazap- ine dose (15 mg) (41.6% and 62.5%, respectively) [60, 61]. Noteworthy, comparison of the 2 mirtazapine doses (7.5 Fig. 1 Practical guidelines for treatment of acute antipsychotic- and 15 mg) for patients with aripiprazole-induced akathisia induced akathisia. 5-HT2a serotonin M. Poyurovsky, A. Weizman reasonable frst step in the management of acute AIA 6 Future Directions (Fig. 1). Close follow-up is required to ensure that an antipsychotic efect is maintained. In cases of persistent Akathisia remains one of the most frequent and distress- intractable akathisia, initiation of clozapine may be neces- ing adverse efects associated with antipsychotic drug sary [1, 2, 26]. treatment. Efective, well-tolerated and easy-to-use anti- When the decision is to add an anti-akathisia agent, akathisia agents continue to be a major unmet need in propranolol (20–120 mg) or low-dose mirtazapine patients with AIA that justifes a search for new treatment (7.5–15 mg) have the most supportive evidence. Propran- options. Extensive research during the last two decades olol has a long record of clinical utility in patients with indicates that non-selective 5-HT2a antagonists (ritanserin, AIA. However, it has not been formally approved for the cyproheptadine, trazodone, mianserin and mirtazapine) treatment of AIA. Limitations of propranolol’s use are exert a benefcial efect in patients with AIA (Table 2). its side efects (e.g. orthostatic hypotension, bradycardia), Low-dose mirtazapine has the most compelling evidence contraindications (e.g. asthma), drug–drug interactions of efficacy and tolerability in patients who developed and increased complexity in administration and titration akathisia treated by FGAs. Elucidation of an anti-akathisia schedules. In contrast, low-dose mirtazapine achieves an effect of mirtazapine in patients with SGA-induced anti-akathisia efect with more convenient dosing than akathisia is a reasonable next step. The demonstration of propranolol and better tolerability, with mild transient a positive efect of mirtazapine on aripiprazole-induced sedation as the only observed side efect. The favourable akathisia in a small open-label study is the initial step mirtazapine safety profle is also supported by the absence in this direction [60]. Large-scale explicit evaluation of of signifcant changes in vital signs. Long-term use of mir- anti-akathisia properties of low-dose mirtazapine in SGA- tazapine, however, can be associated with weight gain, and induced akathisia, especially in antipsychotics with partial very rarely with . Mirtazapine is used of- dopamine agonistic activity, such as aripiprazole, caripra- label and has not yet been approved for the treatment of zine, and to a lesser degree, brexpiprazole, is warranted. AIA. It is of note, that the recently published evidenced- Identifcation of predictors of response to mirtazapine ver- based recommendations consider a trial of propranolol as sus propranolol, that remains a “gold standard” of anti- a frst-choice option, after reviewing contraindications and akathisia treatment, is of particular clinical importance. associated precautions on a per-patient basis [26]. When An additional limitation of the current evidence is that it propranolol is contraindicated, inefective or not tolerated does not provide data on durability of response beyond and long-term pharmacological management of AIA is 7–14 days of treatment. Longer prospective investigations anticipated, a trial of low-dose mirtazapine may be con- are needed to clarify an adequate duration of treatment sidered [26]. with mirtazapine and propranolol as anti-akathisia agents. Mianserin (15 mg once daily), cyproheptadine (8–16 mg/ Moreover, the efective dose range of mirtazapine should day) and trazodone (100 mg) are potential alternative be addressed in future studies. It seems that mirtazapine in options. However, large-scale trials are not yet available, a dose as low as 7.5 mg is efective in ameliorating symp- and their clinical utility has yet to be determined. Mianserin toms of AIA in some individuals. Explicit comparison of is not approved for clinical use in the USA. Mianserin and the anti-akathisia efect of mirtazapine in 2 dose regimens especially trazodone, have marked α1-adrenolytic properties, (7.5 mg and 15 mg) in patients treated with FGAs and which can cause , impairment of cognitive func- SGAs is warranted. An additional clinically relevant ques- tioning and orthostatic hypotension. Trazodone can cause tion is whether patients with AIA who do not respond to priapism, an infrequent but clinically signifcant side efect. 7.5 mg would respond to a higher dose of mirtazapine Cyproheptadine and trazodone can slow cardiac repolarisa- (15 mg) or would need a switch to another anti-akathisia tion causing QT prolongation, a clinically relevant adverse agent, such as propranolol. Notably, even lower doses such efect with antipsychotic co-administration. as 1.5–4.5 mg of signifcantly improved Anticholinergic agents can help in achieving sympto- quantity and quality of and were well tolerated in matic improvement in some cases of AIA associated with individuals with ; thus, it is possible that even antipsychotic-induced Parkinsonism [33]. Similarly, symp- doses lower than 7.5 mg might exert anti-akathisia prop- tomatic anti-dysphoric and sedative efects can be achieved erties [62]. with benzodiazepines [34, 36]. Co-administration of ben- There is a preliminary indication that mirtazapine zodiazepines with propranolol may be benefcial in some might cause akathisia in susceptible individuals [63]. The patients, while co-administration of benzodiazepines with mechanism of this bi-directional efect of mirtazapine, mirtazapine should be avoided owing to their shared seda- akathisia ameliorating versus akathisia provoking, is yet tive properties. 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