, Volume 236, Issue 2, pp 723–730 | Cite as

Incidence and predictors of acute akathisia in severely ill patients with first-episode schizophrenia treated with aripiprazole or risperidone: secondary analysis of an observational study

  • Bunta Yoshimura
  • Kojiro Sato
  • Shinji Sakamoto
  • Masaru Tsukahara
  • Yusaku Yoshimura
  • Ryuhei SoEmail author
Original Investigation



In the antipsychotic treatment of schizophrenia with little medication history, especially in drug-naïve cases, predictors of side effects are important. However, predictors of antipsychotic-induced akathisia remain unclear.


This study aimed to investigate the incidence and predictors of acute akathisia in severely ill patients with first-episode schizophrenia spectrum disorders (FES).


This is a secondary analysis of our retrospective observational study. Data were obtained from 129 consecutive patients with FES involuntarily hospitalized in a tertiary psychiatric public hospital and treated with aripiprazole or risperidone. The primary outcome was the presence of acute akathisia during the first 1 month. A Cox proportional hazard model was used to examine significant predictors of the onset of akathisia.


Acute akathisia was diagnosed in 54 patients (42%). Neither antipsychotics (aripiprazole or risperidone), duration of untreated psychosis, iron deficiency, sex, age nor baseline symptomatic severity was identified as an independent predictor of akathisia. Rapid risperidone initiation significantly increased the onset of akathisia (adjusted hazard ratio [HR], 6.47; 95%; 95% confidence interval [CI], 1.94–21.65; p = 0.002), but rapid aripiprazole initiation did not (adjusted HR, 1.08; 95% CI, 0.50–2.31; p = 0.84). A significant interaction was found between rapid antipsychotic initiation and the risk of akathisia with aripiprazole versus risperidone (p = 0.027).


Severely ill patients with FES initiating aripiprazole or risperidone could have a high risk for akathisia. Rapid risperidone initiation should be avoided because of the risk for akathisia, and careful monitoring of akathisia may be necessary for all patients initiating aripiprazole.


Akathisia Antipsychotic Schizophrenia Incidence Risk factor 



The authors appreciate that Mr. Kohei Kitagawa substantially helped in the data collection. The authors thank each attending physician at the Okayama Psychiatric Medical Center for data collection. We also thank Analisa Avila, ELS, of Edanz Group ( for editing a draft of this manuscript.


B.Y. and R.S. designed the study. R.S., M.T., and K.S. supervised the study. Y.Y. and S.S. analyzed the data. B.Y. drafted the report. All authors approved the final manuscript.

Compliance with ethical standards

The Institutional Review Board of our hospital approved this study.

Conflict of interest

Dr. Yoshimura has received honoraria for his participation as a speaker at educational events sponsored by Janssen. Dr. Sato has received honoraria for his participation as a speaker at educational events sponsored by Otsuka, Janssen, and Dainippon-Sumitomo. Dr. Sakamoto has received unrestricted research funding from Eli Lilly, which was deposited into research accounts at Okayama University Hospital. Dr. Sakamoto has received honoraria for his participation as a speaker at an educational event sponsored by Otsuka. Dr. Tsukahara, and Dr. So report no additional financial or other relationship relevant to this article.


  1. Barnes TR (1989) A rating scale for drug-induced akathisia. Br J Psychiatry 154:672–676CrossRefGoogle Scholar
  2. Barnes TR, Halstead SM, Little PW (1992) Relationship between iron status and chronic akathisia in an in-patient population with chronic schizophrenia. Br J Psychiatry 161:791–796CrossRefGoogle Scholar
  3. Berardi D, Giannelli A, Barnes TR (2000) Clinical correlates of akathisia in acute psychiatric inpatients. Int Clin Psychopharmacol 15(4):215–219CrossRefGoogle Scholar
  4. Buchanan RW, Kreyenbuhl J, Kelly DL, Noel JM, Boggs DL, Fischer BA, Himelhoch S, Fang B, Peterson E, Aquino PR, Keller W (2010) The 2009 schizophrenia PORT psychopharmacological treatment recommendations and summary statements. Schizophr Bull 36:71–93CrossRefGoogle Scholar
  5. Camaschella C (2015) Iron-deficiency anemia. N Engl J Med 372(19):1832–1843CrossRefGoogle Scholar
  6. Cotter PE, O'Keeffe ST (2007) Improvement in neuroleptic-induced akathisia with intravenous iron treatment in a patient with iron deficiency. J Neurol Neurosurg Psychiatry 78(5):548CrossRefGoogle Scholar
  7. Crespo-Facorro B, Pérez-Iglesias R, Ramirez-Bonilla M, Martínez-García O, Llorca J, Luis Vázquez-Barquero J (2006) A practical clinical trial comparing haloperidol, risperidone, and olanzapine for the acute treatment of first-episode nonaffective psychosis. J Clin Psychiatry 67(10):1511–1521CrossRefGoogle Scholar
  8. Crespo-Facorro B, de la Foz VO, Mata I, Ayesa-Arriola R, Suarez-Pinilla P, Valdizan EM, Martinez-Garcia O et al (2014) Treatment of first-episode non-affective psychosis: a randomized comparison of aripiprazole, quetiapine and ziprasidone over 1 year. Psychopharmacology 231(2):357–366CrossRefGoogle Scholar
  9. Galletly C, Castle D, Dark F, Humberstone V, Jablensky A, Killackey E, Kulkarni J, McGorry P, Nielssen O, Tran N (2016) Royal Australian and New Zealand College of Psychiatrists clinical practice guidelines for the management of schizophrenia and related disorders. Aust N Z J Psychiatry 50(5):410–472CrossRefGoogle Scholar
  10. Gardner DM, Murphy AL, O'Donnell H, Centorrino F, Baldessarini RJ (2010) International consensus study of antipsychotic dosing. Am J Psychiatry 167(6):686–693CrossRefGoogle Scholar
  11. Hansen L (2001) A critical review of akathisia, and its possible association with suicidal behaviour. Hum Psychopharmacol 16(7):495–505CrossRefGoogle Scholar
  12. Hansen LK, Nausheen B, Hart D, Kingdon D (2013) Movement disorders in patients with schizophrenia and a history of substance abuse. Hum Psychopharmacol 28(2):192–197CrossRefGoogle Scholar
  13. Hiemke C, Bergemann N, Clement HW, Conca A, Deckert J, Domschke K et al (2017) Consensus guidelines for therapeutic drug monitoring in neuropsychopharmacology: update 2017. Pharmacopsychiatry 51(1–02):9–62Google Scholar
  14. Hofmann M, Seifritz E, Botschev C, Kräuchi K, Müller-Spahn F (2000) Serum iron and ferritin in acute neuroleptic akathisia. Psychiatry Res 93(3):201–207CrossRefGoogle Scholar
  15. Horiguchi J (1991) Low serum iron in patients with neuroleptic-induced akathisia and dystonia under antipsychotic drug treatment. Acta Psychiatr Scand 84(3):301–303CrossRefGoogle Scholar
  16. Inada T (1996) Evaluation and diagnosis of drug-induced extrapyramidal symptoms: commentary on the DIEPSS and guide to its usage. Seiwa Shoten, TokyoGoogle Scholar
  17. Inada T, Yagi G, Gardos G (1996) Inter-rater reliability of the drug-induced extrapyramidal symptoms scale (DIEPSS). Eur Neuropsychopharmacol 6:64CrossRefGoogle Scholar
  18. Jones SH, Thornicroft G, Coffey M, Dunn G (1995) A brief mental health outcome scale-reliability and validity of the Global Assessment of Functioning (GAF). Br J Psychiatry 166:654–659CrossRefGoogle Scholar
  19. Josiassen RC, Shaughnessy RA, Filymer DM, Donohue AM, Kacso M, Finkel N, Skuban N et al (2010) Early intervention with second-generation antipsychotics in first-episode psychosis: results of an 8-week naturalistic study. Early Interv Psychiatry 4(1):57–63CrossRefGoogle Scholar
  20. Juncal-Ruiz M, Ramirez-Bonilla M, Gomez-Arnau J, Ortiz-Garcia de la Foz V, Suarez-Pinilla P, Martinez-Garcia O, Neergaard KD et al (2017) Incidence and risk factors of acute akathisia in 493 individuals with first episode non-affective psychosis: a 6-week randomised study of antipsychotic treatment. Psychopharmacology 234(17):2563–2570CrossRefGoogle Scholar
  21. Kahn RS, Fleischhacker WW, Boter H, Davidson M, Vergouwe Y, Keet IP, Gheorghe MD et al (2008) Effectiveness of antipsychotic drugs in first-episode schizophrenia and schizophreniform disorder: an open randomised clinical trial. Lancet 371(9618):1085–1097CrossRefGoogle Scholar
  22. Kane JM, Fleischhacker WW, Hansen L, Perlis R, Pikalov A 3rd, Assunção-Talbott S (2009) Akathisia: an updated review focusing on second-generation antipsychotics. J Clin Psychiatry 70(5):627–643CrossRefGoogle Scholar
  23. Kim JH, Byun HJ (2007) Association of subjective cognitive dysfunction with akathisia in patients receiving stable doses of risperidone or haloperidol. J Clin Pharm Ther 32(5):461–467CrossRefGoogle Scholar
  24. Kuloglu M, Atmaca M, Ustündag B, Canatan H, Gecici O, Tezcan E (2003) Serum iron levels in schizophrenic patients with or without akathisia. Eur Neuropsychopharmacol 13(2):67–71CrossRefGoogle Scholar
  25. Maat A, Fouwels A, de Haan L (2008) Cocaine is a major risk factor for antipsychotic induced akathisia, parkinsonism and dyskinesia. Psychopharmacol Bull 41(3):5–10Google Scholar
  26. McEvoy JP, Lieberman JA, Perkins DO, Hamer RM, Gu H, Lazarus A, Sweitzer D et al (2007) Efficacy and tolerability of olanzapine, quetiapine, and risperidone in the treatment of early psychosis: a randomized, double-blind 52-week comparison. Am J Psychiatry 164(7):1050–1060CrossRefGoogle Scholar
  27. McGavin JK, Goa KL (2002) Aripiprazole. CNS Drugs 16(11):779–786CrossRefGoogle Scholar
  28. Miller CH, Hummer M, Oberbauer H, Kurzthaler I, DeCol C, Fleischhacker WW (1997) Risk factors for the development of neuroleptic induced akathisia. Eur Neuropsychopharmacol 7(1):51–55CrossRefGoogle Scholar
  29. Osser DN, Roudsari MJ, Manschreck T (2013) The psychopharmacology algorithm project at the Harvard South Shore Program: an update on schizophrenia. Harv Rev Psychiatry 21:18–40CrossRefGoogle Scholar
  30. Potvin S, Blanchet P, Stip E (2009) Substance abuse is associated with increased extrapyramidal symptoms in schizophrenia: a meta-analysis. Schizophr Res 113(2–3):181–188CrossRefGoogle Scholar
  31. Poyurovsky M (2010) Acute antipsychotic-induced akathisia revisited. Br J Psychiatry 196(2):89–91CrossRefGoogle Scholar
  32. Robinson DG, Schooler NR, John M, Correll CU, Marcy P, Addington J, Brunette MF, Estroff SE, Mueser KT, Penn D, Robinson J, Rosenheck RA, Severe J, Goldstein A, Azrin S, Heinssen R, Kane JM (2015) Prescription practices in the treatment of first-episode schizophrenia spectrum disorders: data from the national RAISE-ETP study. Am J Psychiatry 172:237–248CrossRefGoogle Scholar
  33. Sachdev P (1995a) The epidemiology of drug-induced akathisia: part I. Acute akathisia. Schizophr Bull 21(3):431–449CrossRefGoogle Scholar
  34. Sachdev P (1995b) The epidemiology of drug-induced akathisia: part II. Chronic, tardive, and withdrawal akathisias. Schizophr Bull 21(3):451–461CrossRefGoogle Scholar
  35. Schooler N, Rabinowitz J, Davidson M, Emsley R, Harvey PD, Kopala L, De Smedt G et al (2005) Risperidone and haloperidol in first-episode psychosis: a long-term randomized trial. Am J Psychiatr 162(5):947–953CrossRefGoogle Scholar
  36. Seemüller F, Schennach R, Mayr A, Musil R, Jäger M, Maier W, Klingenberg S, Heuser I, Klosterkötter J, Gastpar M, Schmitt A, Schlösser R, Schneider F, Ohmann C, Lewitzka U, Gaebel W, Möller HJ, Riedel M (2012) Akathisia and suicidal ideation in first-episode schizophrenia. J Clin Psychopharmacol 32(5):694–698CrossRefGoogle Scholar
  37. Soni SD, Tench D, Routledge RC (1993) Serum iron abnormalities in neuroleptic-induced akathisia in schizophrenic patients. Br J Psychiatry 163:669–672CrossRefGoogle Scholar
  38. Sundram S, Lambert T, Piskulic D (2008) Acculturation is associated with the prevalence of tardive dyskinesia and akathisia in community-treated patients with schizophrenia. Acta Psychiatr Scand 117(6):474–478CrossRefGoogle Scholar
  39. Takaki M, Yoshimura B (2012) High doses or rapid dose escalation of aripiprazole may be more effective for treating schizophrenia. Clin Neuropsychopharmacol Ther 3:3–4CrossRefGoogle Scholar
  40. Takeuchi H, Thiyanavadivel S, Agid O, Remington G (2018) Rapid vs. slow antipsychotic initiation in schizophrenia: a systematic review and meta-analysis. Schizophr Res 193:29–36CrossRefGoogle Scholar
  41. US Dept Health, Education, and Welfare (1976) Clinical global impression (CGI) scale. In: Guy W (ed) ECDEU assessment manual for psychopharmacology, revised. 36. US Dept Health, Education, and Welfare, Washington, DC, pp 218–222Google Scholar
  42. Woerner MG, Mannuzza S, Kane JM (1988) Anchoring the BPRS: an aid to improved reliability. Psychopharmacol Bull 24:112–117Google Scholar
  43. Yoshimura B, Sato K, Takaki M, Yamada N (2017) Algorithm-based pharmacotherapy for first-episode schizophrenia involuntarily hospitalized: a retrospective analysis of real-world practice. Early Interv Psychiatry.
  44. Zhang JP, Gallego JA, Robinson DG, Malhotra AK, Kane JM, Correll CU (2013) Efficacy and safety of individual second-generation vs. first-generation antipsychotics in first-episode psychosis: a systematic review and meta-analysis. Int J Neuropsychopharmacol 16(6):1205–1218CrossRefGoogle Scholar
  45. Zhu Y, Krause M, Huhn M, Rothe P, Schneider-Thoma J, Chaimani A, Li C, Davis JM, Leucht S (2017) Antipsychotic drugs for the acute treatment of patients with a first episode of schizophrenia: a systematic review with pairwise and network meta-analyses. Lancet Psychiatry 4(9):694–705CrossRefGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  • Bunta Yoshimura
    • 1
  • Kojiro Sato
    • 1
  • Shinji Sakamoto
    • 2
  • Masaru Tsukahara
    • 1
  • Yusaku Yoshimura
    • 3
  • Ryuhei So
    • 1
    Email author
  1. 1.Department of PsychiatryOkayama Psychiatric Medical CenterOkayama CityJapan
  2. 2.Department of NeuropsychiatryOkayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesOkayamaJapan
  3. 3.Department of PsychiatryZikei HospitalOkayamaJapan

Personalised recommendations