Antipsychotic-induced parkinsonism is associated with working memory deficits in schizophrenia-spectrum disorders

Original Paper


In view of the significant cognitive deficits in schizophrenia and their impact on patients’ social and occupational functioning, and considering that the influence potential influence of antipsychotic-induced extrapyramidal symptoms on cognition in schizophrenia remains poorly understood, the current study sought to identify the clinical, socio-demographic and neurologic predictors of the cognitive performance of schizophrenia patients. Eighty-two schizophrenia-spectrum (DSM-IV criteria) outpatients were recruited. Psychiatric symptoms were evaluated with the Positive And Negative Syndrome Scale and the Calgary Depression Scale for Schizophrenia. Extrapyramidal symptoms were evaluated with the Extrapyramidal Symptoms Rating Scale, while spatial working, planning abilities and visual paired associates learning were evaluated with the CAmbridge Neuropsychological Tests Automated Battery. The Stroop test was also administered. Multivariate hierarchic linear regression analyses were performed. We found that negative symptoms were associated with cognitive flexibility, planning, visual learning and working memory performance in schizophrenia. Age, sex, number of hospitalizations and antipsychotic type also emerged as significant predictors. More importantly, we found a significant association between antipsychotic-induced parkinsonism and working memory performance. The fact that negative symptoms and socio-demographic variables predicted cognitive performance in schizophrenia is consistent with the previous literature on the topic. The finding of an association between parkinsonism and working memory may have clinical implications, since working memory deficits are considered putative endophenotypes of schizophrenia and are known to impair patients’ social and occupational functioning. Our results will need to be replicated in longitudinal studies involving larger samples of patients.


Schizophrenia Parkinsonism Working memory Cognitive flexibility Negative symptoms 


  1. 1.
    Kalkstein S, Hurford I, Gur RC (2010) Neurocognition in schizophrenia. Curr Top Behav Neurosci 4:373–390CrossRefPubMedGoogle Scholar
  2. 2.
    Nuechterlein KH, Barch DM, Gold JM, Goldberg TE, Green MF, Heaton RK (2004) Identification of separable cognitive factors in schizophrenia. Schizophr Res 72:29–39CrossRefPubMedGoogle Scholar
  3. 3.
    Stip E (2006) Cognition, schizophrenia and the effects of antipsychotics. Encephale 31:341–350CrossRefGoogle Scholar
  4. 4.
    Green MF (1996) What are the functional consequences of neurocognitive deficits in schizophrenia? Am J Psychiatry 153:321–330CrossRefPubMedGoogle Scholar
  5. 5.
    Ventura J, Helleman GS, Thames AD, Koellner V, Nuechterlein KH (2009) Symptoms as mediators of the relationship between neurocognition and functional outcomes in schizophrenia: a meta-analysis. Schizophr Res 113:189–199CrossRefPubMedCentralPubMedGoogle Scholar
  6. 6.
    Mendrek A, Stip E (2011) Sexual dimorphism in schizophrenia: is there a need for gender-based protocols? Exp Rev Neurother 11:951–959CrossRefGoogle Scholar
  7. 7.
    Shah JN, Qureshi SU, Jawaid A, Schulz PE (2012) Is there evidence for late cognitive decline in chronic schizophrenia? Psychiatr Q 83:127–144CrossRefPubMedGoogle Scholar
  8. 8.
    Leucht S, Cipriani A, Spineli L, Mavridis D, Orey D, Richter F, Samara M, Barbui C, Engel RR, Geddes JR, Kissling W, Stapf MP, Lassig B, Salanti G, Davis JM (2013) Comparative efficacy and tolerability of 15 antipsychotic drugs in schizophrenia: a multiple-treatment meta-analysis. Lancet 382:951–962CrossRefPubMedGoogle Scholar
  9. 9.
    Tandon R, Jibson MD (2002) Extrapyramidal side effects of antipsychotic treatment: scope of problem and impact on outcome. Ann Clin Psychiatry 14:123–129CrossRefPubMedGoogle Scholar
  10. 10.
    Garcia-Cabeza I, Gomez JC, Sacristan JA, Edgell E, Gonzalez de Chavez M (2001) Subjective response to antipsychotic treatment and compliance in schizophrenia: a naturalistic study comparing olanzapine, risperidone and haloperidol (EFESO Study). BMC Psychiatry 1:7CrossRefPubMedCentralPubMedGoogle Scholar
  11. 11.
    Aarsland D, Andersen K, Larsen JP, Lolk A, Kragh-Sorensen P (2003) Prevalence and characteristics of dementia in Parkinson disease: an 8-year prospective study. Arch Neurol 60:387–392CrossRefPubMedGoogle Scholar
  12. 12.
    Hely MA, Reid WG, Adena MA, Halliday GM, Morris JG (2008) The Sydney multicenter study of Parkinson’s disease: the inevitability of dementia at 20 years. Mov Disord 23:837–844CrossRefPubMedGoogle Scholar
  13. 13.
    Pagonabarraga J, Kulisevsky J (2012) Cognitive impairment and dementia in Parkinson’s disease. Neurobiol Dis 46:590–596CrossRefPubMedGoogle Scholar
  14. 14.
    Kudlicka A, Clare L, Hindle JV (2011) Executive functions in Parkinson’s disease: systematic review and meta-analysis. Mov Disord 26:2305–2315CrossRefPubMedGoogle Scholar
  15. 15.
    Kim JH, Byun HJ (2009) Non-motor cognitive-perceptual dysfunction associated with drug-induced parkinsonism. Hum Psychopharmacol Clin Exp 24:129–133CrossRefGoogle Scholar
  16. 16.
    Süllwold L (1977) Symptome schizophrener Erkrankungen: Uncharakteristische Basisstörungen. Springer, BerlinCrossRefGoogle Scholar
  17. 17.
    Krausz M, Moritz SH, Naber D, Lambert M, Andresen B (1999) Neuroleptic-induced extrapyramidal symptoms accompanied by cognitive dysfunction in schizophrenia. Eur Psychiatry 14:84–88CrossRefPubMedGoogle Scholar
  18. 18.
    Tanaka T, Tomotake M, Ueoka Y, Kaneda Y, Taniguchi K, Nakataki M, Numata S, Tayoshi S, Yamauchi K, Sumitani S, Ohmori T, Ueno SI, Ohmori T (2012) Clinical correlates associated with cognitive dysfunction in people with schizophrenia. Psychiatry Clin Neurosci 66:491–498CrossRefPubMedGoogle Scholar
  19. 19.
    Palmer BW, Heaton RK, Jeste DV (1999) Extrapyramidal symptoms and neuropsychological deficits in schizophrenia. Biol Psychiatry 45:791–794CrossRefPubMedGoogle Scholar
  20. 20.
    Pantelis C, Stuart GW, Nelson HE, Robbins TW, Barnes TRE (2001) Spatial working memory deficits in schizophrenia: relationship with tardive dyskinesia and negative symptoms. Am J Psychiatry 158:1276–1285CrossRefPubMedGoogle Scholar
  21. 21.
    Wu JQ, Chen DC, Xiu MH, Tan YL, Yang FD, Kosten TR, Zhang XY (2013) Tardive dyskinesia is associated with greater cognitive impairment in schizophrenia. Prog Neuropsychopharmacol Biol Psychiatry 46:71–77CrossRefPubMedGoogle Scholar
  22. 22.
    Miller DD, McEvoy JP, Davis SM, Caroff SN, Saltz BL, Chakos MH, Swartz MS, Keefe RSE, Rosenheck RA, Stroup TS, Lieberman JA (2005) Clinical correlates of tardive dyskinesia in schizophrenia: baseline data from the CATIE schizophrenia trial. Schizophr Res 80:33–43CrossRefPubMedGoogle Scholar
  23. 23.
    Kay SR, Fiszbein A, Opler LA (1987) The positive and negative syndrome scale (PANSS) for schizophrenia. Schizophr Bull 13:261–276CrossRefPubMedGoogle Scholar
  24. 24.
    Addington D, Addington J, Maticka-Tyndale E, Joyce J (1992) Reliability and validity of a depression rating scale for schizophrenics. Schizophr Res 6:201–208CrossRefPubMedGoogle Scholar
  25. 25.
    Chouinard G, Margolese HC (2005) Manual for the extrapyramidal symptom rating scale (ESRS). Schizophr Res 76:247–265CrossRefPubMedGoogle Scholar
  26. 26.
    Knol W, Keijsers CJ, Jansen PA, van Marum RJ (2010) Systematic evaluation of rating scales for drug-induced parkinsonism and recommendations for future research. J Clin Psychopharmacol 30:57–63CrossRefPubMedGoogle Scholar
  27. 27.
    Elliott R, McKenna PJ, Robbins TW, Sahakian BJ (1998) Specific neuropsychological deficits in schizophrenic patients with preserved intellectual function. Cogn Neuropsychiatry 3:45–70CrossRefGoogle Scholar
  28. 28.
    Levaux MN, Potvin S, Sepehry AA, Sablier J, Mendrek A, Stip E (2007) Computerized assessment of cognition in schizophrenia: promises and pitfalls of CANTAB. Eur Psychiatry 22:104–115CrossRefPubMedGoogle Scholar
  29. 29.
    Golden CJ (1978) Stroop color and word test: a manual for clinical and experimental uses. Stoelting, Wood Dale, ILGoogle Scholar
  30. 30.
    Rajji TK, Mulsant BH (2008) Nature and course of cognitive function in late-life schizophrenia. Schizophr Res 102:122–140CrossRefPubMedGoogle Scholar
  31. 31.
    Jimenez JA, Mancini-Marie A, Lakis N, Rinaldi M, Mendrek A (2010) Disturbed sexual dimorphism of brain activation during mental rotation in schizophrenia. Schizophr Res 122:53–62CrossRefPubMedGoogle Scholar
  32. 32.
    Torniainen M, Suvisaari J, Partonen T, Castaneda AE, Kuha A, Perala J, Saarni S, Lonnqvist J, Tuulio-Henriksson A (2011) Sex differences in cognition among persons with schizophrenia and healthy first-degree relatives. Psychiatry Res 188:7–12CrossRefPubMedGoogle Scholar
  33. 33.
    Cuesta MJ, Sanchez-Torres Am, de Jalon EG, Campos MS, Ibanez B, Moreno-Izco L, Peralta V (2013) Spontaneous parkinsonism with cognitive impairment in antipsychotic-native patients with first-episode psychosis: a 6-month follow-up study. Schizophr Bull [Epub ahead of print]Google Scholar
  34. 34.
    Tauscher J, Kufferle B, Asenbaum S, Tauscher-Wisniewski S, Kasper S (2002) Striatal dopamine-2 receptor occupancy as measured with [123I]iodobenzamide and SPECT predicted the occurrence of EPS in patients treated with atypical antipsychotics and haloperidol. Psychopharmacology 162:42–49CrossRefPubMedGoogle Scholar
  35. 35.
    Surmeier DJ, Guzman JN, Sanchez-Padilla J, Schumacker PT (2011) The role of calcium and mitochondrial oxidant stress in the loss of substantia nigra pars compacta dopaminergic neurons in Parkinson’s disease. Neuroscience 198:221–231CrossRefPubMedCentralPubMedGoogle Scholar
  36. 36.
    Poletti M, De Rosa A, Bonucelli U (2012) Affective symptoms and cognitive functions in Parkinson’s disease. J Neurol Sci 317:97–102CrossRefPubMedGoogle Scholar
  37. 37.
    Howes OD, Kambeitz J, Kim E, Stahl D, Slifstein M, Abi-Dargham A, Kapur S (2012) The nature of dopamine dysfunction in schizophrenia and what this means for treatment. Arch Gen Psychiatry 69:776–786CrossRefPubMedCentralPubMedGoogle Scholar
  38. 38.
    Van Snellenberg JX, Torres IJ, Thornton AE (2006) Functional neuroimaging of working memory in schizophrenia: task performance as a moderating variable. Neuropsychology 20:497–510CrossRefPubMedGoogle Scholar
  39. 39.
    Kim E, Howes OD, Turkheimer FE, Kim BH, Jeong JM, Kim JW, Lee JS, Jang IJ, Shin SG, Kapur S, Kwon JS (2013) The relationship between antipsychotic D2 occupancy and change in frontal metabolism and working memory: a dual [11C]raclopride and [18F]FDG imaging study with aripiprazole. Psychopharmacology 227:221–229CrossRefPubMedGoogle Scholar
  40. 40.
    Bubser M, Byun N, Wood MR, Jones CK (2012) Muscarinic receptor pharmacology and circuitry for the modulation of cognition. Handb Exp Pharmacol 208:121–166CrossRefPubMedGoogle Scholar
  41. 41.
    Honer WG, Thornton AE, Chen EY, Chan RC, Wong JO, Bergmann A, Falkai P, Pomarol-Clotet E, McKenna PJ, Stip E, Williams R, MacEwan GW, Wasan K, Procyshyn R (2006) Clozapine and risperidone enhancement (CARE) study group. N Engl J Med 354:472–482CrossRefPubMedGoogle Scholar
  42. 42.
    Ojeda N, Pena J, Schretlen DJ, Sanchez P, Aretouli E, Elizagarate E, Ezcurra J, Gutierrez M (2012) Hierarchical structure of the cognitive processes in schizophrenia; the fundamental role of processing speed. Schizophr Res 135:72–78CrossRefPubMedGoogle Scholar
  43. 43.
    Barch DM, Moore H, Nee DE, Manoach DS, Luck SJ (2012) CNTRICS imaging biomarkers selection: working memory. Schizophr Bull 38:43–52CrossRefPubMedCentralPubMedGoogle Scholar
  44. 44.
    Fusar-Poli P, Deste G, Smieskova R, Barlatti S, Yung AR, Howes O, Stieglitz RD, Vita A, McGuire P, Borgwardt S (2012) Cognitive functioning in prodromal psychosis: a meta-analysis. Arch Gen Psychiatry 69:562–571PubMedGoogle Scholar
  45. 45.
    Bowie CR, Harvey PD (2005) Cognition in schizophrenia: impairments, determinants and functional importance. Psychiatr Clin N Am 28:613–633CrossRefGoogle Scholar
  46. 46.
    Patel MX, Arista IA, Taylor M, Barnes TR (2013) How to compare doses of different antipsychotics: a systematic review of methods. Schizophr Res 149(1–3):141–148Google Scholar
  47. 47.
    Zhornistky S, Stip E, Pampoulova T, Rizkallah E, Lipp O, Bentaleb LA, Chiasson JP, Potvin S (2010) Extrapyramidal symptoms in substance abusers with and without schizophrenia and in nonabusing patients with schizophrenia. Mov Disord 25:2188–2194CrossRefGoogle Scholar
  48. 48.
    Toupoulouand T, Murray RM (2004) Verbal memory deficits in patients with schizophrenia: an important future target for treatment. Expert Rev Neurother 4:43–52CrossRefGoogle Scholar
  49. 49.
    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 32:461–467CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2014

Authors and Affiliations

  • Stéphane Potvin
    • 1
    • 2
  • Ginette Aubin
    • 2
    • 3
  • Emmanuel Stip
    • 2
    • 3
  1. 1.Centre de recherche de lInstitut Universitaire en Santé Mentale de MontréalMontréalCanada
  2. 2.Department of Psychiatry, Faculty of MedicineUniversity of MontrealMontrealCanada
  3. 3.Centre de recherche du Centre Hospitalier de lUniversité de MontréalMontrealCanada

Personalised recommendations