John M Kane, Wolfgang W Fleischhacker, Lars Hansen, Roy Perlis, Andrei Pikalov, Sheila Assunção-Talbott
Akathisia: an updated review focusing on second-generation antipsychotics.
J Clin Psychiatry. 2009 Apr 21;70(5):627-43. doi: 10.4088/JCP.08r04210. Epub 2009 Apr 21.
Abstract/Text
OBJECTIVE: To provide a brief description of the pathophysiology of akathisia, the challenges of diagnosing and treating this condition, and potential associated clinical issues. Also, to provide a review of the literature on the incidence of drug-induced akathisia associated with the use of second-generation antipsychotics (SGAs) and first-generation antipsychotics (FGAs).
DATA SOURCES: English-language literature with no date restrictions cited in PubMed was searched for the keywords akathisia, placebo, neuroleptic, or haloperidol, and the generic names of SGAs (clozapine, risperidone, olanzapine, quetiapine, ziprasidone, or aripiprazole).
STUDY SELECTION: Limits were set to search clinical trials, meta-analyses, or randomized controlled trials reviewing data from adult schizophrenia or bipolar disorder clinical trials. Studies including SGA comparisons with placebo and with FGAs, and also between SGAs themselves, were selected. Studies that specifically assessed akathisia (either subjectively or objectively or both) were included. Studies reporting generalized results pertaining to extrapyramidal symptoms (EPS) were excluded.
DATA EXTRACTION: The incidence of akathisia, EPS rating scores, and required medications for the management of movement disorders were reviewed.
DATA SYNTHESIS: Seventy-seven trials were included in the comparative review. Akathisia was observed with the use of all the SGAs. The akathisia incidence reported in bipolar disorder trials was generally higher compared with schizophrenia trials. The incidence reported for FGAs was consistently higher than that reported for SGAs, regardless of the patient population studied.
CONCLUSION: Akathisia remains a concern with the use of SGAs. More accurate and standardized evaluations are required for a better understanding of the nature and incidence of akathisia.
Copyright 2009 Physicians Postgraduate Press, Inc.
Lindsey P Koliscak, Eugene H Makela
Selective serotonin reuptake inhibitor-induced akathisia.
J Am Pharm Assoc (2003). 2009 Mar-Apr;49(2):e28-36; quiz e37-8. doi: 10.1331/JAPhA.2009.08083.
Abstract/Text
OBJECTIVE: To review available information in the literature about akathisia (inner restlessness) caused by the selective serotonin reuptake inhibitors (SSRIs).
DATA SOURCES: Databases searched included Medline, PsychInfo, the International Pharmaceutical Abstracts, and Google Scholar. Search terms included drug-induced akathisia, psychomotor agitation, drug-induced side effect, movement disorders, and extrapyramidal symptoms. These search terms were cross-referenced with selective serotonin reuptake inhibitors and each of the currently marketed SSRIs: fluoxetine, fluvoxamine, sertraline, paroxetine, citalopram, and escitalopram.
STUDY SELECTION: Relevant articles were chosen if they specifically mentioned the word akathisia. Case reports were chosen based on a clear view that an SSRI was a contributing or causative agent of akathisia.
DATA SYNTHESIS: Recognizing akathisia is important because it can be very bothersome and may cause suicidal ideations. Akathisia can be recognized by examining symptoms, looking at predisposing factors, and using the Barnes Akathisia Rating Scale (BARS). Predisposing factors include use of multiple akathisia-inducing drugs, recent increases in SSRI dose, previous development of akathisia, baseline psychiatric disorders, and brain trauma. Treatment options include the addition of a centrally acting beta-blocker, a benzodiazepine, or an anticholinergic agent.
CONCLUSION: Pharmacists can play an active role in recognizing akathisia by being aware of its characteristics, conducting a thorough medication history to identify causative agents, and using BARS to evaluate patients. These efforts may preclude unnecessary discomfort for the patient and reduce the potential for nonadherence induced by akathisia.
Maximilian Huhn, Adriani Nikolakopoulou, Johannes Schneider-Thoma, Marc Krause, Myrto Samara, Natalie Peter, Thomas Arndt, Lio Bäckers, Philipp Rothe, Andrea Cipriani, John Davis, Georgia Salanti, Stefan Leucht
Comparative efficacy and tolerability of 32 oral antipsychotics for the acute treatment of adults with multi-episode schizophrenia: a systematic review and network meta-analysis.
Lancet. 2019 Sep 14;394(10202):939-951. doi: 10.1016/S0140-6736(19)31135-3. Epub 2019 Jul 11.
Abstract/Text
BACKGROUND: Schizophrenia is one of the most common, burdensome, and costly psychiatric disorders in adults worldwide. Antipsychotic drugs are its treatment of choice, but there is controversy about which agent should be used. We aimed to compare and rank antipsychotics by quantifying information from randomised controlled trials.
METHODS: We did a network meta-analysis of placebo-controlled and head-to-head randomised controlled trials and compared 32 antipsychotics. We searched Embase, MEDLINE, PsycINFO, PubMed, BIOSIS, Cochrane Central Register of Controlled Trials (CENTRAL), WHO International Clinical Trials Registry Platform, and ClinicalTrials.gov from database inception to Jan 8, 2019. Two authors independently selected studies and extracted data. We included randomised controlled trials in adults with acute symptoms of schizophrenia or related disorders. We excluded studies in patients with treatment resistance, first episode, predominant negative or depressive symptoms, concomitant medical illnesses, and relapse-prevention studies. Our primary outcome was change in overall symptoms measured with standardised rating scales. We also extracted data for eight efficacy and eight safety outcomes. Differences in the findings of the studies were explored in metaregressions and sensitivity analyses. Effect size measures were standardised mean differences, mean differences, or risk ratios with 95% credible intervals (CrIs). Confidence in the evidence was assessed using CINeMA (Confidence in Network Meta-Analysis). The study protocol is registered with PROSPERO, number CRD42014014919.
FINDINGS: We identified 54 417 citations and included 402 studies with data for 53 463 participants. Effect size estimates suggested all antipsychotics reduced overall symptoms more than placebo (although not statistically significant for six drugs), with standardised mean differences ranging from -0·89 (95% CrI -1·08 to -0·71) for clozapine to -0·03 (-0·59 to 0·52) for levomepromazine (40 815 participants). Standardised mean differences compared with placebo for reduction of positive symptoms (31 179 participants) varied from -0·69 (95% CrI -0·86 to -0·52) for amisulpride to -0·17 (-0·31 to -0·04) for brexpiprazole, for negative symptoms (32 015 participants) from -0·62 (-0·84 to -0·39; clozapine) to -0·10 (-0·45 to 0·25; flupentixol), for depressive symptoms (19 683 participants) from -0·90 (-1·36 to -0·44; sulpiride) to 0·04 (-0·39 to 0·47; flupentixol). Risk ratios compared with placebo for all-cause discontinuation (42 672 participants) ranged from 0·52 (0·12 to 0·95; clopenthixol) to 1·15 (0·36 to 1·47; pimozide), for sedation (30 770 participants) from 0·92 (0·17 to 2·03; pimozide) to 10·20 (4·72 to 29·41; zuclopenthixol), for use of antiparkinson medication (24 911 participants) from 0·46 (0·19 to 0·88; clozapine) to 6·14 (4·81 to 6·55; pimozide). Mean differences compared to placebo for weight gain (28 317 participants) ranged from -0·16 kg (-0·73 to 0·40; ziprasidone) to 3·21 kg (2·10 to 4·31; zotepine), for prolactin elevation (21 569 participants) from -77·05 ng/mL (-120·23 to -33·54; clozapine) to 48·51 ng/mL (43·52 to 53·51; paliperidone) and for QTc prolongation (15 467 participants) from -2·21 ms (-4·54 to 0·15; lurasidone) to 23·90 ms (20·56 to 27·33; sertindole). Conclusions for the primary outcome did not substantially change after adjusting for possible effect moderators or in sensitivity analyses (eg, when excluding placebo-controlled studies). The confidence in evidence was often low or very low.
INTERPRETATION: There are some efficacy differences between antipsychotics, but most of them are gradual rather than discrete. Differences in side-effects are more marked. These findings will aid clinicians in balancing risks versus benefits of those drugs available in their countries. They should consider the importance of each outcome, the patients' medical problems, and preferences.
FUNDING: German Ministry of Education and Research and National Institute for Health Research.
Copyright © 2019 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.
Del D Miller, Stanley N Caroff, Sonia M Davis, Robert A Rosenheck, Joseph P McEvoy, Bruce L Saltz, Silvana Riggio, Miranda H Chakos, Marvin S Swartz, Richard S E Keefe, T Scott Stroup, Jeffrey A Lieberman, Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) Investigators
Extrapyramidal side-effects of antipsychotics in a randomised trial.
Br J Psychiatry. 2008 Oct;193(4):279-88. doi: 10.1192/bjp.bp.108.050088.
Abstract/Text
BACKGROUND: There are claims that second-generation antipsychotics produce fewer extrapyramidal side-effects (EPS) compared with first-generation drugs.
AIMS: To compare the incidence of treatment-emergent EPS between second-generation antipsychotics and perphenazine in people with schizophrenia.
METHOD: Incidence analyses integrated data from standardised rating scales and documented use of concomitant medication or treatment discontinuation for EPS events. Mixed model analyses of change in rating scales from baseline were also conducted.
RESULTS: There were no significant differences in incidence or change in rating scales for parkinsonism, dystonia, akathisia or tardive dyskinesia when comparing second-generation antipsychotics with perphenazine or comparing between second-generation antipsychotics. Secondary analyses revealed greater rates of concomitant antiparkinsonism medication among individuals on risperidone and lower rates among individuals on quetiapine, and lower rates of discontinuation because of parkinsonism among people on quetiapine and ziprasidone. There was a trend for a greater likelihood of concomitant medication for akathisia among individuals on risperidone and perphenazine.
CONCLUSIONS: The incidence of treatment-emergent EPS and change in EPS ratings indicated that there are no significant differences between second-generation antipsychotics and perphenazine or between second-generation antipsychotics in people with schizophrenia.
P Sachdev
The epidemiology of drug-induced akathisia: Part II. Chronic, tardive, and withdrawal akathisias.
Schizophr Bull. 1995;21(3):451-61.
Abstract/Text
This article examines the epidemiological data on chronic akathisia, tardive akathisia, and withdrawal akathisia. The limitations of the data are discussed--in particular, the lack of consistent definitions of the syndromes. The studies suggest that a significant proportion of patients chronically treated with neuroleptics suffer from akathisia. The prevalence may be as high as 40 percent, although a conservative estimate would be closer to 30 percent. Risk factors for the development of chronic akathisia and tardive akathisia are poorly understood, but old age, female sex, iron deficiency, negative symptoms, cognitive dysfunction, and affective disorder diagnosis need to be studied further for their potential role. While there is convincing evidence that akathisia may develop after neuroleptic cessation or reduction in dose, the prevalence and risk factors for withdrawal akathisia are not known. Reports of akathisia in children and the elderly have been few, and more systematic research is necessary. Akathisia appears to be common in individuals with mental retardation treated chronically with neuroleptics.
H R Olivier
Benzodiazepine prescription abuse and the benzodiazepine withdrawal syndrome.
J La State Med Soc. 1989 Mar;141(3):18-22.
Abstract/Text
Benzodiazepines are among the most widely-prescribed medications in the world. Although tolerance is unlikely, abuse is widespread. Prescription abuse is especially common, with medication being taken for longer periods than intended, or at the wrong dosage, or for purposes not intended by the physician. Prolonged use, even at therapeutic levels, can produce a definite "benzodiazepine withdrawal syndrome" with disturbing symptoms such as insomnia, twitching, and restlessness, leading to prolongation of the already inappropriate usage. Suggestions for reducing this abuse are discussed.
Simon Zhornitsky, Emmanuel Stip, Tania Pampoulova, Elie Rizkallah, Olivier Lipp, Lahcen Aït Bentaleb, Jean-Pierre Chiasson, Stéphane Potvin
Extrapyramidal symptoms in substance abusers with and without schizophrenia and in nonabusing patients with schizophrenia.
Mov Disord. 2010 Oct 15;25(13):2188-94. doi: 10.1002/mds.23227.
Abstract/Text
Extrapyramidal symptoms (EPS) such as parkinsonism, dystonia, dyskinesia, and akathisia are conditions of impaired motor function, which are associated with chronic antipsychotic treatment in schizophrenia. In addition, EPS is often exacerbated by psychoactive substance (PAS) abuse, which is frequently observed in this population. Few studies, however, have investigated the contribution of PAS abuse on EPS in PAS-abusers without comorbid psychosis. This study compared the occurrence of EPS in outpatient schizophrenia patients with (DD group; n= 36) and without PAS abuse (SCZ group; n = 41) as well as in nonschizophrenia PAS abusers undergoing detoxification [substance use disorder (SUD) group; n = 38]. Psychiatric symptoms were measured using the Positive and Negative Syndrome Scale and the Calgary Depression Scale for schizophrenia. Extrapyramidal symptoms were evaluated with the Extrapyramidal Symptoms Rating Scale and the Barnes Akathisia Scale. SUD diagnoses were complemented with urine drug screenings. We found that DD patients exhibited significantly more parkinsonism than SCZ patients. Our subanalyses revealed that cocaine and alcohol abuse/dependence was responsible for the increase in parkinsonism in DD patients. Additionally, we found that SUD individuals exhibited significantly more akathisia than SCZ patients. In these latter individuals, subanalyses revealed that alcohol and cannabis abuse/dependence was responsible for the increase in akathisia. Our results suggest that PAS abuse is a contributor to EPS in individuals with and without schizophrenia.
Naveed Iqbal, Tim Lambert, Prakash Masand
Akathisia: problem of history or concern of today.
CNS Spectr. 2007 Sep;12(9 Suppl 14):1-13.
Abstract/Text
Akathisia is a neurological side effect of antipsychotic medications, which are used to treat various psychiatric disorders, and is characterized by physical restlessness and a subjective urge to move. Although side effects, such as akathisia, dystonia, and dyskinesia, are common for conventional medications, these effects occur in reduced frequency with the use of new-generation antipsychotics. Despite a lowered incidence profile, akathisia and similar conditions continue to affect patients. Neuroleptic-induced akathisia can present as fidgety movements while seated, rocking in place while standing, pacing, or the inability to sit or stand still for an extended period of time as well as the overwhelming urge to move, which can cause severe distress and an increased risk of suicide for affected patients. First-line treatment of akathisia includes benzodiazepines or beta-blockers for patients who do not have symptoms of Parkinson's disease and anticholinergics for patients with Parkinson's symptoms. Clinicians should ensure that an accurate diagnosis of akathisia is made and target symptoms are decreasing due to treatment, which does not negatively affect the mental health of the patient. This expert roundtable supplement will address the diagnosis, pathophysiology, phenomenology, classification, and history of akathisia as well as provide screening tools and treatment options for the condition.
Ruchita Shah, Sandeep Grover, Uma Maheshwari, Natasha Kate, Nidhi Malhotra
Acute akathisia with quetiapine: A case report and review of literature.
Indian J Pharmacol. 2010 Dec;42(6):416-7. doi: 10.4103/0253-7613.71896.
Abstract/Text
Quetiapine is an atypical antipsychotic which has been shown to have greater relative affinity for 5-HT(2A) receptors than for D(2) receptors, due to which it is thought to lead to lower incidence of extrapyramidal symptoms (EPS). However, over the years literature in the form of case reports have accumulated which shows that quetiapine can lead to akathisia, especially in subjects prone to develop EPS. In this study, we report the case of a 22-year-old female who developed akathisia with quetiapine 150 mg/day, which subsided with reduction in dose. We have also reviewed the existing literature with respect to akathisia with quetiapine.
DSM-5 精神疾患の診断・統計マニュアル. 医学書院,2014.
R Sandyk, S R Kay, G I Awerbuch, R P Iacono
Risk factors for neuroleptic-induced movement disorders.
Int J Neurosci. 1991 Dec;61(3-4):149-88.
Abstract/Text
Chronic neuroleptic therapy may be associated with the development of diverse movement disorders including Tardive dyskinesia (TD), Parkinsonism, dystonia, and akathisia in a subset of schizophrenic patients. It is presently unknown why only a proportion of neuroleptic-treated patients develop these movement disorders. In the following communication, we present a series of studies which demonstrate that the development of these movement disorders may be facilitated by certain risk factors including disturbances in pineal melatonin functions, diabetes mellitus, cognitive deficits, suicidal behavior, and disturbances in the functions of the choroid plexus. Recognition of these biological factors may prove useful in: (a) further understanding of the pathophysiology of these disorders, and (b) identifying patients at risk for these movement disorders.
Emmanuelle Lévy, Howard C Margolese, Lawrence Annable, Guy Chouinard
Diabetes, tardive dyskinesia, parkinsonism, and akathisia in schizophrenia: a retrospective study applying 1998 diabetes health care guidelines to antipsychotic use.
Can J Psychiatry. 2004 Jun;49(6):398-402.
Abstract/Text
BACKGROUND: This study examines the links among diabetes, tardive dyskinesia (TD), and other extrapyramidal symptoms (EPS) in schizophrenia outpatients treated with typical and atypical antipsychotics.
OBJECTIVES: Using a retrospective chart review, we compared 30 schizophrenia patients with diabetes mellitus (DM) with 30 schizophrenia patients, matched for age and sex, with no DM. We compared prevalence and severity of parkinsonism, akathisia, TD, dystonia, and antipsychotic type (that is, typical vs atypical).
RESULTS: We found no statistically significant differences between the DM group and the non-DM group prevalence and severity of EPS, including TD.
CONCLUSION: We did not find DM and TD association to be significant in the era of atypical antipsychotics, possibly because of their antidyskinetic effect.
Georgios Schoretsanitis, Adriani Nikolakopoulou, Daniel Guinart, Christoph U Correll, John M Kane
Iron homeostasis alterations and risk for akathisia in patients treated with antipsychotics: A systematic review and meta-analysis of cross-sectional studies.
Eur Neuropsychopharmacol. 2020 Jun;35:1-11. doi: 10.1016/j.euroneuro.2020.04.001. Epub 2020 May 19.
Abstract/Text
Iron homeostasis may be implicated in the pathophysiology of antipsychotic-related akathisia. We performed a systematic review in six databases from database inception until 03/2020, conducting a meta-analysis of studies investigating iron metabolism in antipsychotic-treated patients with versus without akathisia. Using a fixed- and a random-effects model, standardized mean difference (SMD) was estimated for levels of iron, ferritin, transferrin and total iron-binding capacity. Meta-regression analyses included sex, age, illness duration and antipsychotic treatment and dose. Subgroup analyses included chronic vs. acute akathisia and different diagnoses. Study quality was assessed using the Newcastle-Ottawa scale. In 10 studies (n = 395), compared to non-akathisia patients (n = 213), iron levels were lower in patients with akathisia (n = 182; fixed-effect model: SMD=-0.49, 95%CI=-0.28,-0.70, p<0.001; random-effects model: SMD=-0.55, 95%CI=-0.14,-0.96, p = 0.008). For secondary outcomes, differences were significant regarding lower ferritin levels in patients with akathisia in the fixed-effect model (SMD=-0.32, 95%CI=-0.08,-0.55, p = 0.007), but not in the random-effects model (SMD=-0.29, 95%CI=0.20,-0.79, p = 0.24). None of the moderators/mediators had a significant effect on the group difference of iron levels. Subgroup analyses reported lower iron levels in both patients with chronic and acute akathisia vs. patients without. Iron levels for schizophrenia patients were lower in the fixed-effect model (SMD=-0.55, 95%CI=-0.23, -0.86, p<0.001), while a trend was observed in the random-effects model (SMD=-0.52, 95%CI=-0.07, -1.12, p = 0.08). The studies' quality was overall poor, with one exception. This meta-analysis suggests lower iron levels in akathisia patients, while ferritin differences were significant only in the fixed-effect model. Further data are required to promote the understanding of related pathways.
Copyright © 2020 Elsevier B.V. and ECNP. All rights reserved.
R Gold, R H Lenox
Is there a rationale for iron supplementation in the treatment of akathisia? A review of the evidence.
J Clin Psychiatry. 1995 Oct;56(10):476-83.
Abstract/Text
BACKGROUND: An association found between akathisia and iron deficiency led to the suggestion that iron supplementation might be a useful therapeutic intervention for patients with akathisia. There is, however, a body of literature on the abnormal deposition of iron in the brain in several degenerative diseases like Hallervorden-Spatz syndrome, Parkinson's disease, and Alzheimer's disease. Given the ability of neuroleptics to chelate iron and promote its deposition in the brain, we questioned whether peripheral measures of iron are an accurate reflection of central iron levels and thus whether there was a rationale for iron supplementation in akathisia.
METHOD: A MEDLINE search for literature relating to iron and akathisia, tardive dyskinesia, and Parkinson's disease was carried out and critically reviewed.
RESULTS: Evidence is presented for the ability of neuroleptics to chelate iron, mobilize it from peripheral stores, and deposit it in the basal ganglia. The effect of iron on dopaminergic receptor activity in brain and the potential role of iron in degenerative and neuroleptic-induced movement disorders are reviewed. The preponderance of the evidence shows a relationship between iron excess in the basal ganglia and the movement disorders. We found no studies that have examined the regulation of central levels of iron in patients with akathisia.
CONCLUSION: The rationale for iron supplementation in the treatment of akathisia is relatively weak, and there are potentially adverse long-term consequences as outlined in our review. More research is required to directly measure the level of iron in the brain of patients with akathisia, e.g., using magnetic resonance imaging, before such therapeutic intervention can be recommended.
D A Wirshing, G Bartzokis, J M Pierre, W C Wirshing, A Sun, T A Tishler, S R Marder
Tardive dyskinesia and serum iron indices.
Biol Psychiatry. 1998 Sep 15;44(6):493-8. doi: 10.1016/s0006-3223(97)00453-8.
Abstract/Text
BACKGROUND: This study was undertaken to evaluate whether peripheral (serum) markers of iron status are associated with severity of the choreoathetoid movements seen in tardive dyskinesia (TD).
METHODS: Serum iron indices (ferritin, iron, and total iron binding capacity) and fluphenazine levels were measured in a group of 30 male DSM-III diagnosed schizophrenic patients chronically treated with fluphenazine decanoate. The severity of choreoathetoid movements was assessed with the Abnormal Involuntary Movement Scale (AIMS), and akathisia was assessed with the Barnes scale.
RESULTS: A significant positive correlation was observed between AIMS scores and serum ferritin. This relationship remained significant after controlling for age and plasma fluphenazine levels. No significant correlations were observed between serum iron or total iron binding capacity and choreoathetoid movement ratings. There were no significant associations between serum iron indices and akathisia ratings.
CONCLUSIONS: The data suggest that choreoathetoid movements are associated with serum ferritin levels in chronically medicated male schizophrenic patients. This relationship does not seem to be caused by an association of these variable with age or plasma fluphenazine levels. In addition, the relationship seems to be specific, since other iron indices and another extrapyramidal side effect (akathisia) do not demonstrate a similar relationship. In view of reports that antipsychotic medications change normal iron metabolism and increase iron uptake into the brain, the current results could be interpreted to suggest that serum ferritin levels may be a risk factor for TD in patients treated with "classic" antipsychotic medications.
Lynn M Trotti, Srinivas Bhadriraju, Lorne A Becker
Iron for restless legs syndrome.
Cochrane Database Syst Rev. 2012 May 16;5:CD007834. doi: 10.1002/14651858.CD007834.pub2. Epub 2012 May 16.
Abstract/Text
BACKGROUND: Restless legs syndrome (RLS) is a common neurologic syndrome and is associated with iron deficiency in many patients. It is unclear whether iron therapy is effective treatment for RLS.
OBJECTIVES: The objective of this review was to assess the effects of iron supplementation (oral or intravenous) for patients with RLS.
SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE (Jan 1995 to April 2011); EMBASE (Jan 1995 to April 2011); PsycINFO (Jan 1995 to April 2011); and CINAHL (Jan 1995 to April 2011). Corresponding authors of included trials and additional members of the International Restless Legs Syndrome Study Group were contacted to locate additional published or unpublished trials.
SELECTION CRITERIA: Controlled trials comparing any formulation of iron with placebo, other medications, or no treatment in adults diagnosed with RLS according to expert clinical interview or explicit diagnostic criteria.
DATA COLLECTION AND ANALYSIS: Two review authors extracted data and at least two authors assessed trial quality. We contacted trial authors for missing data.
MAIN RESULTS: Six studies (192 total subjects) were identified and included in this analysis. The quality of trials was variable. Our primary outcome was restlessness or uncomfortable leg sensations, which was quantified using the IRLS severity scale in four trials and another RLS symptom scale in a fifth trial. Combining data from the four trials using the IRLS severity scale, there was no clear benefit from iron therapy (mean difference in IRLS severity scores of -3.79, 95% CI: -7.68 to 0.10, p = 0.06). However, the fifth trial did find iron therapy to be beneficial (median decrease of 3 points in the iron group and no change in the placebo group on a 10 point scale of RLS symptoms, p = 0.01). Quality of life was improved in the iron group relative to placebo in some studies but not others. Changes in periodic limb movements were not different between groups (measured in two studies). Objective sleep quality, subjective sleep quality and daytime functioning were not different between treatment groups in the studies that assessed them. The single study of subjects with end stage renal disease did show a benefit of therapy. Most trials did not require subjects to have co-morbid iron deficiency and several excluded patients with severe anemia. The single study that was limited to iron deficient subjects did not show clear benefit of iron supplementation on RLS symptoms. There was no clear superiority of oral or intravenous delivery of iron. Iron therapy did not result in significantly more side effects than placebo (RR 1.39, 95% CI 0.85 to 2.27).
AUTHORS' CONCLUSIONS: There is insufficient evidence to determine whether iron therapy is beneficial for the treatment of RLS. Further research to determine whether some or all types of RLS patients may benefit from iron therapy, as well as the best route of iron administration, is needed.
F Berna, D Misdrahi, L Boyer, B Aouizerate, L Brunel, D Capdevielle, I Chereau, J M Danion, J M Dorey, C Dubertret, J Dubreucq, C Faget, F Gabayet, C Lancon, J Mallet, R Rey, C Passerieux, A Schandrin, F Schurhoff, A M Tronche, M Urbach, P Vidailhet, P M Llorca, G Fond, FACE-SZ (FondaMental Academic Centers of Expertise for Schizophrenia) group, FACE-SZ FondaMental Academic Centers of Expertise for Schizophrenia group
Akathisia: prevalence and risk factors in a community-dwelling sample of patients with schizophrenia. Results from the FACE-SZ dataset.
Schizophr Res. 2015 Dec;169(1-3):255-61. doi: 10.1016/j.schres.2015.10.040. Epub 2015 Nov 15.
Abstract/Text
The main objective of this study was to determine the prevalence of akathisia in a community-dwelling sample of patients with schizophrenia, and to determine the effects of treatments and the clinical variables associated with akathisia. 372 patients with schizophrenia or schizoaffective disorder were systematically included in the network of FondaMental Expert Center for Schizophrenia and assessed with validated scales. Akathisia was measured with the Barnes Akathisia Scale (BAS). Ongoing psychotropic treatment was recorded. The global prevalence of akathisia (as defined by a score of 2 or more on the global akathisia subscale of the BAS) in our sample was 18.5%. Patients who received antipsychotic polytherapy were at higher risk of akathisia and this result remained significant (adjusted odd ratio=2.04, p=.025) after controlling the influence of age, gender, level of education, level of psychotic symptoms, substance use comorbidities, current administration of antidepressant, anticholinergic drugs, benzodiazepines, and daily-administered antipsychotic dose. The combination of second-generation antipsychotics was associated with a 3-fold risk of akathisia compared to second-generation antipsychotics used in monotherapy. Our results indicate that antipsychotic polytherapy should be at best avoided and suggest that monotherapy should be recommended in cases of akathisia. Long-term administration of benzodiazepines or anticholinergic drugs does not seem to be advisable in cases of akathisia, given the potential side effects of these medications.
Copyright © 2015 Elsevier B.V. All rights reserved.
重篤副作用疾患別対応マニュアル アカシジア（令和3年4月改定）. 厚生労働省, 2021.
A R Lima, J Bacalcthuk, T R E Barnes, K Soares-Weiser
Central action beta-blockers versus placebo for neuroleptic-induced acute akathisia.
Cochrane Database Syst Rev. 2004 Oct 18;(4):CD001946. doi: 10.1002/14651858.CD001946.pub2. Epub 2004 Oct 18.
Abstract/Text
BACKGROUND: Neuroleptic-induced akathisia is a common, distressing early-onset adverse effect of neuroleptic drugs. It has been associated with poor treatment compliance and an increased risk of relapse.
OBJECTIVES: To determine the effects of central action beta-blockers compared with placebo for people with neuroleptic-induced acute akathisia.
SEARCH STRATEGY: We updated previous searches of the Cochrane Schizophrenia Group Register (May 1999), Biological Abstracts (January 1982-March 1999), The Cochrane Library (issue 3 1999), EMBASE (January 1980-March 1999), LILACS (January 1982-March 1999), MEDLINE (January 1964-March 1999), PsycLIT (January 1974-March 1999), and SCISEARCH by searching the Cochrane Schizophrenia Group Register (November 2003). We sought further references from published trials and their authors.
SELECTION CRITERIA: We included all randomised controlled clinical trials of central action beta-blockers versus placebo for people with neuroleptic-induced acute akathisia.
DATA COLLECTION AND ANALYSIS: Working independently, we selected and critically appraised studies, extracted data and analysed on an intention-to-treat basis. Where possible and appropriate we calculated risk ratios (RR) and their 95% confidence intervals (CI) with the number needed to treat (NNT). For continuous data we calculated Weighted Mean Differences (WMD).
MAIN RESULTS: We identified three randomised controlled trials (total n=51, maximum duration 72 hours). We were not able to draw any firm conclusions from such a small data set. In the two 48 hour studies no-one experienced full remission of akathisia, and only one person in each group experienced a 50% remission (n=11, 1 RCT, RR 1.04 CI 0.59 -1.83). One trial stated that no adverse effects occurred in the two groups (n=20, 1 RCT, RR not estimable). The 72 hour study did not show any statistical difference between the central acting beta-blocker (ICI 118,551) and placebo for the outcome 'no change/worse' (n=10, RR 0.22 CI 0.0 to 1.5).
REVIEWERS' CONCLUSIONS: There are insufficient data to recommend beta-blocking drugs for akathisia. These drugs are experimental for this problem, and this review highlights the need for more evaluative studies.
Michael Poyurovsky, Artashes Pashinian, Ronit Weizman, Camil Fuchs, Abraham Weizman
Low-dose mirtazapine: a new option in the treatment of antipsychotic-induced akathisia. A randomized, double-blind, placebo- and propranolol-controlled trial.
Biol Psychiatry. 2006 Jun 1;59(11):1071-7. doi: 10.1016/j.biopsych.2005.12.007. Epub 2006 Feb 21.
Abstract/Text
BACKGROUND: Preliminary evidence indicates a beneficial effect of serotonin 2A (5-HT(2A)) receptor antagonists in antipsychotic-induced akathisia (AIA). We investigated the antiakathisia effect, safety, and tolerability of low-dose mirtazapine, an agent with marked 5-HT(2A) antagonism.
METHODS: In a 7-day double-blind trial, 90 antipsychotic-treated patients meeting DSM-IV criteria for AIA were randomly assigned to mirtazapine (n = 30; 15 mg), propranolol (n = 30; 80 mg), or placebo (n = 30). Primary outcome measures were between-group differences in Barnes Akathisia Scale (BAS) global scores and in the proportion of responders (reduction of > or = 2 points on BAS). Analysis was by intention to treat.
RESULTS: Twenty-four patients (26.6%) who were assigned treatment did not complete the study (7 mirtazapine, 8 propranolol, 9 placebo), due to lack of response (n = 19) and adverse events (n = 5). Both mirtazapine and propranolol significantly reduced AIA severity (BAS: -34% mirtazapine and -29% propranolol vs. placebo -11%; p = .012 and p = .023, respectively). Thirteen (43.3%) mirtazapine and 9 (30.0%) propranolol-treated patients versus 2 (6.7%) placebo-treated patients responded (the corresponding odds ratios 10.7 [95% confidence interval (CI), 2.1-53.3] and 6.0 [95% CI, 1.1-30.7]). Five (16.7%) of 30 propranolol-treated patients and none in the mirtazapine and placebo groups (p = .0195 for both) prematurely discontinued the study due to clinically significant hypotension or bradycardia.
CONCLUSIONS: The comparable efficacy and better tolerability of low-dose mirtazapine versus propranolol, the current first-line treatment for AIA, position mirtazapine as a favorable candidate for the treatment of acute AIA and may improve current therapeutic practices.
Samir Kumar Praharaj, Sreejayan Kongasseri, Rishikesh V Behere, Podila Satya Venkata Narasimha Sharma
Mirtazapine for antipsychotic-induced acute akathisia: a systematic review and meta-analysis of randomized placebo-controlled trials.
Ther Adv Psychopharmacol. 2015 Oct;5(5):307-13. doi: 10.1177/2045125315601343.
Abstract/Text
OBJECTIVE: To conduct a systematic review and meta-analysis of randomized placebo-controlled trials of mirtazapine for the treatment of antipsychotic-induced acute akathisia (AIAA).
METHODS: Studies were identified using online searches of PUBMED/MEDLINE and Cochrane database (CENTRAL), along with websites recording trial information such as www.clinicaltrials.gov, www.controlled-trials.com, and www.clinicalstudyresults.org. The study eligibility criteria were randomized, double-blind clinical trials comparing mirtazapine with placebo for AIAA with standardized rating for akathisia as outcome measure. The methodological quality of included trials was assessed using the Jadad Scale. Separate meta-analyses were undertaken for each outcome (response rate and complete remission) and treatment effects were expressed as Mantel-Haenszel risk ratio (RR). Fixed-effect meta-analysis was performed as heterogeneity was not significant. Number need to treat (NNT) as a measure of relative treatment effectiveness was calculated.
RESULTS: A systematic review of the literature revealed six studies that had assessed mirtazapine for the treatment of AIAA. Of these, two studies (n = 86) met the review inclusion criteria and were included in the final analysis. A meta-analysis was performed to see the effect size of response rate and complete remission. For response rate, RR was 6.67 [95% confidence interval (CI) 2.14-20.78], favoring mirtazapine compared with placebo, and the overall effect was significant (p = 0.001, NNT 4, 95% CI 2.6-8.6). For complete remission, RR was 6.20 (95% CI 1.74-22.08), favoring mirtazapine compared with placebo, and the overall effect was significant (p = 0.005, NNT 5, 95% CI 2.9-11.6).
CONCLUSIONS: Although limited to only two studies and small sample, existing data support the efficacy of mirtazapine for the treatment of AIAA, with one in four patients showing partial response and one in five patients showing complete remission.
A R Lima, K Soares-Weiser, J Bacaltchuk, T R Barnes
Benzodiazepines for neuroleptic-induced acute akathisia.
Cochrane Database Syst Rev. 2002;(1):CD001950. doi: 10.1002/14651858.CD001950.
Abstract/Text
BACKGROUND: Neuroleptic-induced akathisia is one of the most common and distressing early-onset adverse effects of antipsychotic drugs, being associated with poor compliance with treatment, and thus, ultimately, to an increase risk of relapse. This review assesses the role of benzodiazepines in the pharmacological treatment of this problem.
OBJECTIVES: To determine the effects of benzodiazepines versus placebo for people with neuroleptic-induced acute akathisia.
SEARCH STRATEGY: Biological Abstracts (January 1982-March 1999), The Cochrane Library (Issue 3 1999), The Cochrane Schizophrenia Group's Register (May 2001), EMBASE (January 1980-March 1999), LILACS (January 1982-March 1999), MEDLINE (January 1964-March 1999), PsycLIT (January 1974-March 1999), and SCISEARCH were searched. Further references were sought from published trials and their authors.
SELECTION CRITERIA: All randomised clinical trials comparing benzodiazepines with placebo for people with antipsychotic-induced acute akathisia.
DATA COLLECTION AND ANALYSIS: Two reviewers, working independently, selected, quality assessed and extracted data. These data were then analysed on an intention-to-treat basis. For homogeneous dichotomous data the fixed effects relative risk (RR), the 95% confidence intervals (CI) and, where appropriate, the number needed to treat (NNT) were calculated on an intention-to-treat basis. For continuous data, reviewers calculated weighted mean differences.
MAIN RESULTS: Two small (total N=27) randomised controlled trials were included. By seven to 14 days, there was a reduction in symptoms for those patients receiving clonazepam compared with placebo (2 RCTs, N=26, RR 0.09 CI 0.01 to 0.6, NNT 1.2 CI 0.9 to 1.5). No significant difference was found for adverse events (2 RCTs, N=26, RR 3.00 CI 0.2 to 62) or the need for anticholinergic medication (2 RCTs, N=26, RR 1.56 CI 0.9 to 2.7). No one left the two studies early. Data on mental, social and family outcomes could not be pooled and there was little or no data on user satisfaction, deaths, violence, criminal behaviour and costs.
REVIEWER'S CONCLUSIONS: Over a short follow-up period, the use of benzodiazepines may reduce the symptoms of antipsychotic-induced acute akathisia. This review highlights the need for well designed, conducted and reported clinical trials to address the claims of open studies.
T Fischel, H Hermesh, D Aizenberg, Z Zemishlany, H Munitz, Y Benjamini, A Weizman
Cyproheptadine versus propranolol for the treatment of acute neuroleptic-induced akathisia: a comparative double-blind study.
J Clin Psychopharmacol. 2001 Dec;21(6):612-5.
Abstract/Text
The purpose of this study was to investigate the efficacy of cyproheptadine, an antiserotonergic agent, in the treatment of neuroleptic-induced akathisia (NIA), as compared with propranolol, the current gold standard. In a double-blind trial, 30 patients with schizophrenia and NIA received either cyproheptadine 16 mg/day (N = 18) or propranolol 80 mg/day (N = 12) for 4 days, followed by 3 days without any anti-NIA treatment. The Barnes Akahisia Scale, Simpson-Angus Extrapyramidal Effects Rating Scale, and Brief Psychiatric Rating Scale were used to assess the severity of NIA, parkinsonism, and psychosis, respectively. In both groups, the severity of NIA decreased significantly over time (cyproheptadine, -46%; propranolol, -42%), with no significant intergroup difference. The NIA symptoms worsened significantly when cyproheptadine and propranolol were discontinued. We conclude that cyproheptadine 16 mg/day is as effective as propranolol for the treatment of acute NIA. The antiakathisic effect of cyproheptadine may be mostly attributable to its serotonin antagonistic activity.
Chanoch Miodownik, Vladimir Lerner, Nikolay Statsenko, Tzvi Dwolatzky, Boris Nemets, Elina Berzak, Joseph Bergman
Vitamin B6 versus mianserin and placebo in acute neuroleptic-induced akathisia: a randomized, double-blind, controlled study.
Clin Neuropharmacol. 2006 Mar-Apr;29(2):68-72. doi: 10.1097/00002826-200603000-00002.
Abstract/Text
Treatment strategies against acute neuroleptic-induced akathisia (NIA) include anticholinergic (antimuscarinic) agents, dopamine agonists, GABAergic agents, beta-blockers, benzodiazepines, and serotonin antagonists. However, many patients who have acute akathisia fail to respond. In previous studies, mianserin and vitamin B6 were found to be effective in the treatment of acute akathisia. The purpose of this study was to compare the efficacy of B(6), mianserin and placebo in the treatment of acute NIA. Sixty schizophrenia and schizoaffective inpatients who have NIA were randomly divided to receive vitamin B(6) 1,200 mg/d, mianserin 15 mg/d, or placebo for 5 days, in a double-blind design. The Barnes Akathisia Rating Scale, Brief Psychiatric Rating Scale, and Clinical Global Impression were used to assess the severity of NIA and psychotic symptoms. The assessment was made at baseline and daily for the duration of the study. Compared with the placebo group, the vitamin B(6)-treated and mianserin-treated patients showed a significant improvement in the subjective (P < 0.0001), subjective distress (P < 0.0001), and global (P < 0.0001) subscales. The objective subscale did not show significant positive results (P = 0.056), but there was a trend toward symptom amelioration in both groups. A reduction of at least 2 points on the Barnes Akathisia Rating Scale global subscale was noted in the vitamin B(6) group (13/23, 56%) as well as in the mianserin groups (13/20, 65%), and in only one patient in the placebo group (1/17, 6%; P < 0.0005). Our results indicate that high doses of B(6) and a low dose of mianserin may be a useful addition to current treatments of NIA. The efficacy of vitamin B(6) and mianserin suggests that the pathophysiology of acute NIA is heterogeneous with the various subtypes of acute NIA responding differently to the various pharmacological approaches.
J Rathbone, K Soares-Weiser
Anticholinergics for neuroleptic-induced acute akathisia.
Cochrane Database Syst Rev. 2006 Oct 18;(4):CD003727. doi: 10.1002/14651858.CD003727.pub3. Epub 2006 Oct 18.
Abstract/Text
BACKGROUND: Neuroleptic-induced akathisia is one of the most common and distressing early-onset adverse effects of first generation 'typical' antipsychotic drugs. It is associated with poor compliance with treatment, and thus, ultimately, with an increased risk of relapse. We assessed the role of anticholinergic drugs as an adjunct therapy to standard antipsychotic medication in the pharmacological treatment of this adverse effect.
OBJECTIVES: To review anticholinergic drugs for neuroleptic-induced acute akathisia.
SEARCH STRATEGY: We searched the Cochrane Schizophrenia Group's Register (October 1999), Biological Abstracts (1982-1999), CINAHL (1982-1999), Cochrane Library (Issue 4 1999), EMBASE (1980-1999), LILACS (1982-1999), MEDLINE (1966-1999) and PsycLIT (1974-1999). References of all identified studies were inspected for more trials and we contacted first authors. Each included study was sought as a citation on the Science Citation Index database. For this 2005-6 update, we searched the Cochrane Schizophrenia Group's Register (July 2005).
SELECTION CRITERIA: We included all randomised clinical trials of adjunctive anticholinergic drugs in addition to antipsychotic medication compared with placebo, for people with neuroleptic-induced acute akathisia.
DATA COLLECTION AND ANALYSIS: We quality assessed and extracted data independently. We calculated the fixed effects relative risk (RR), the 95% confidence intervals (CI) and, where appropriate, the number needed to treat (NNT) for homogeneous dichotomous data on an intention-to-treat basis. For continuous data, we calculated weighted mean differences (WMD).
MAIN RESULTS: We identified no relevant randomised controlled trials.
AUTHORS' CONCLUSIONS: At present, there is no reliable evidence to support or refute the use of anticholinergics for people suffering from neuroleptic-induced acute akathisia. Akathisia is a distressing movement disorder that remains highly prevalent in people with schizophrenia, both in the developed and developing world. This review highlights the need for well designed, conducted and reported clinical trials to address the claims of open studies as regards the effects of the anticholinergic group of drugs for akathisia.
Bora Baskak, E Cem Atbasoglu, Halise Devrimci Ozguven, Meram Can Saka, Ali Kemal Gogus
The effectiveness of intramuscular biperiden in acute akathisia: a double-blind, randomized, placebo-controlled study.
J Clin Psychopharmacol. 2007 Jun;27(3):289-94. doi: 10.1097/jcp.0b013e3180582439.
Abstract/Text
Neuroleptic-induced acute akathisia (NIA) is a distressing condition and an important clinical problem because it is associated with treatment noncompliance and suicidal or impulsive behavior. Anticholinergics are among the treatment options; however, a review of the literature fails to identify a double-blind, randomized, placebo-controlled study of these medications in NIA. In a randomized, double-blind, placebo-controlled design, we studied the effectiveness of intramuscular biperiden (n = 15) or isotonic saline (n = 15) in the treatment of NIA diagnosed with the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition criteria. Injections were repeated up to 3 times unless akathisia was completely treated (scored 0 for global akathisia with the Barnes Akathisia Rating Scale). Patients were assessed for akathisia, other movement disorders, and psychiatric symptoms at baseline and 3 times after the first injection at 2-hour intervals. Response was defined as at least a 2-point decline in the global akathisia score. The numbers of responders in the 2 groups were not significantly different (7 and 5 in the biperiden and placebo groups, respectively). The courses of individual items on the Barnes Akathisia Rating Scale were also similar. Our results suggest that intramuscular biperiden should not be considered as a first-line treatment of NIA.
Sharon See, Erin Hendriks, Leslie Hsiung
Akathisia induced by gabapentin withdrawal.
Ann Pharmacother. 2011 Jun;45(6):e31. doi: 10.1345/aph.1Q057. Epub 2011 Jun 7.
Abstract/Text
OBJECTIVE: To report a case of akathisia in a patient with type 2 diabetes after abrupt discontinuation of gabapentin.
CASE SUMMARY: A 76-year-old female with type 2 diabetes was admitted for change in mental status, agitation, and restless limb movements. She had been taking gabapentin 3600 mg daily for approximately 1 month for diabetic neuropathy. Her other home medications were glyburide 10 mg twice daily, oxycodone/acetaminophen 5 mg/325 mg every 6 hours as needed for leg pain, and zolpidem 5 mg at bedtime. She had taken none of these drugs for 4 days prior to admission because she was unable to have the prescriptions refilled. Subsequently, the patient exhibited repeated arm and leg motions in response to an inner restlessness. Upon admission to the emergency department, she was agitated and restless; all vital signs and results of laboratory studies were within normal limits. Gabapentin was restarted at the original dosage and the symptoms resolved within 8 hours. Because the patient developed lethargy, the gabapentin dosage was reduced and titrated to the original level over 2 days. After 3 days, the patient was well oriented and experienced no further symptoms. She was discharged on the original dosage of gabapentin.
DISCUSSION: To our knowledge, this is the first reported cases of akathisia induced by gabapentin withdrawal. Available case reports suggest that gabapentin withdrawal can occur at doses ranging from 400-8000 mg/day. Patients experienced symptoms similar to those that develop with benzodiazepine withdrawal and were taking gabapentin for as little as 3 weeks to as long as 5 years. This is the first case report to describe akathisia induced by gabapentin withdrawal. The Naranjo probability scale revealed a probable relationship between akathisia and gabapentin withdrawal.
CONCLUSIONS: If gabapentin discontinuation is desired, it is prudent to gradually taper the dose to avoid withdrawal symptoms, which may occur after as little as 1 month of treatment. Should the patient experience withdrawal symptoms, the optimal treatment is to restart gabapentin.
Tamara Pringsheim, David Gardner, Donald Addington, Davide Martino, Francesca Morgante, Lucia Ricciardi, Norman Poole, Gary Remington, Mark Edwards, Alan Carson, Thomas R E Barnes
The Assessment and Treatment of Antipsychotic-Induced Akathisia.
Can J Psychiatry. 2018 Nov;63(11):719-729. doi: 10.1177/0706743718760288. Epub 2018 Apr 23.
Abstract/Text
BACKGROUND: Akathisia is a common and distressing neuropsychiatric syndrome associated with antipsychotic medication, characterised by subjective and objective psychomotor restlessness. The goal of this guideline is to provide clinicians with recommendations on the assessment and treatment of akathisia.
METHODS: We performed a systematic review of therapeutic studies assessing the treatment of antipsychotic-induced extrapyramidal symptoms. Forty studies on akathisia and 4 systematic reviews evaluating the adverse effects of antipsychotics were used in the formulation of recommendations. Studies were rated for methodological quality using the American Academy of Neurology Risk of Bias Classification system. The overall level of evidence classifications and grades of recommendation were made using the Scottish Intercollegiate Guidelines Network framework.
RESULTS: As a good practice point, clinicians should systematically assess akathisia with a validated scale before starting antipsychotics and during antipsychotic dosage titration. For the management of akathisia, there was adequate evidence to allow recommendations regarding antipsychotic dose reduction, antipsychotic polypharmacy, switching antipsychotic medication, and the use of adjuvant medications including beta-blockers, anticholinergics, 5HT2A antagonists, benzodiazepines, and vitamin B6.
CONCLUSION: The treatment of antipsychotic-induced akathisia should be personalised, with consideration of antipsychotic dose reduction, cessation of antipsychotic polypharmacy, and switching to an antipsychotic with a perceived lower liability for akathisia, before the use of adjuvant medications. The choice of adjuvant medications should favour the more established treatments, with careful consideration of contraindications and side effects. Limitations in the evidence should be acknowledged and prompt cautious prescribing, particularly with respect to the duration of use of adjuvant medications, is warranted.
Michael Poyurovsky, Abraham Weizman
Treatment of Antipsychotic-Induced Akathisia: Role of Serotonin 5-HT2a Receptor Antagonists.
Drugs. 2020 Jun;80(9):871-882. doi: 10.1007/s40265-020-01312-0.
Abstract/Text
Akathisia is one of the most prevalent and distressing adverse effects associated with antipsychotic drug treatment. Propranolol, a non-selective beta-adrenergic receptor antagonist, is currently considered a first-line treatment for antipsychotic-induced akathisia (AIA). Surprisingly, the evidence for its anti-akathisia effect is modest. Propranolol's side effects (e.g. orthostatic hypotension, bradycardia), contraindications (e.g. asthma) and increased complexity in titration schedules limit its use in some patients. Anticholinergic agents and benzodiazepines merely provide symptomatic relief in patients with AIA. Effective 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 (ritanserin, cyproheptadine, trazodone, mianserin, mirtazapine) 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 efficacy. In this narrative review we highlight the clinical significance of AIA, outline major approaches for its management and propose a practical algorithm for its treatment.
