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Antipsychotic Medications: Linking Receptor Antagonism to Neuropsychological Functioning in First Episode Psychosis

  • Heather A. Baitz (a1), Allen E. Thornton (a1), Ric M. Procyshyn (a2), Geoffrey N. Smith (a2), G. William MacEwan (a2), Lili C. Kopala (a2), Alasdair M. Barr (a3), Donna J. Lang (a4) and William G. Honer (a2)...


Antipsychotic medications can contribute to neurocognitive and motor impairments, but specific links to individualized pharmacological treatment regimens are unclear. In 68 participants with stabilized first-episode psychosis (FEP), we investigated the links between neuropsychological functions and an established anticholinergic potency index and a new D2 antagonist potency index developed in our lab. Each participant's psychiatric medication regimen was converted into estimated receptor antagonist loads based upon specific medication dosage(s) and reported in vitro brain muscarinic cholinergic and D2 receptor antagonism. In addition to the global neuropsychological impairments of FEP participants, the findings supported the hypothesized links between receptor antagonist loads and specific deficits. Higher anticholinergic load was associated with poorer delayed verbal memory but was not related to motor functioning. In contrast, higher D2 load was associated with poorer motor functioning but not verbal memory. These selective antagonist load associations explained 19% of the variance in motor functioning and 17% of the variance in delayed verbal memory. Evidently, some of the neuropsychological impairments found in persons with FEP are selectively related to the specific pharmacodynamics and the dosing of their medication regimens. Moreover, these effects can be readily estimated from practical and inexpensive indices. (JINS, 2012, 18, 1–11)


Corresponding author

Correspondence and reprint requests to: Allen E Thornton, Department of Psychology, Simon Fraser University, Burnaby, BC V5A 1S6, Canada. E-mail:


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Agid, O., Kapur, S., Arenovich, T., Zipursky, R.B. (2003). Delayed-onset hypothesis of antipsychotic action: A hypothesis tested and rejected. Archives of General Psychiatry, 60, 12281235.
American Psychiatric Association. (1994). Diagnostic and statistical manual of mental disorders: DSM-IV-TR (4th ed.). Washington, DC: American Psychiatric Association.
Arana, G.W., Goff, D.C., Baldessarini, R.J., Keepers, G.A. (1988). Efficacy of anticholinergic prophylaxis for neuroleptic-induced acute dystonia. American Journal of Psychiatry, 145(8), 993996.
Bäckman, L., Jones, S., Berger, A.K., Laukka, E.J., Small, B.J. (2005). Cognitive impairment in preclinical Alzheimer's disease: A meta-analysis. Neuropsychology, 19, 520531.
Barr, A.M., Honer, W.G., Johnson, J.L., Wu, T.K.Y., Procyshyn, R.M. (2010). A comparison of antipsychotic drug-defined daily doses versus chlorpromazine equivalent doses in patients with or without extrapyramidal motor symptoms. Journal of Clinical Psychopharmacology, 30(6), 741743.
Benton, A.L., Hamsher, K. (1978). Multilingual Aphasia Examination – Second Edition. Iowa City, IA: AJA Associates.
Blair, J.R., Spreen, O. (1989). Predicting premorbid IQ: A revision of the national adult reading test. The Clinical Neuropsychologist, 3(2), 129136.
Burstein, E.S., Ma, J., Wong, S., Gao, Y., Pham, E., Knapp, A.E., Brann, M.R. (2005). Intrinsic efficacy of antipsychotics at human D2, D3, and D4 dopamine receptors: Identification of the clozapine metabolite N-desmethylclozapine as a D2/D3 partial agonist. The Journal of Pharmacology and Experimental Therapeutics, 315(3), 12781287.
Campbell, D.T., Fiske, D.W. (1959). Convergent and discriminant validation by the multitrait-multimethod matrix. Psychological Bulletin, 56, 81105.
Chouinard, G., Ross-Chouinard, A., Annable, L., Jones, B.D. (1980). The extrapyramidal symptom rating scale. The Canadian Journal of Neurological Sciences, 7(3), 233.
Cohen, J. (1992). A power primer. Psychological Bulletin, 112(1), 155159.
Delis, D.C., Kramer, J.H., Kaplan, E., Ober, B.A. (2000). California Verbal Learning Test – second edition. San Antonio, TX: The Psychological Corporation.
Dunayevich, E., Ascher-Svanum, H., Zhao, F., Jacobson, J.G., Phillips, G.A., Dellva, M.A., Green, A.I. (2007). Longer time to antipsychotic treatment discontinuation for any cause is associated with better functional outcomes for patients with schizophrenia, schizophreniform disorder, or schizoaffective disorder. Journal of Clinical Psychiatry, 68(8), 11631171.
El Yazaji, M., Battas, O., Agoub, M., Moussaoui, D., Gutknecht, C., Dalery, J., Saoud, M. (2002). Validity of the depressive dimension extracted from principal component analysis of the PANSS in drug-free patients with schizophrenia. Schizophrenia Research, 56(1), 121127.
Élie, D., Poirier, M., Chianetta, J.M., Durand, M., Grégoire, C.A., Grignon, S. (2010). Cognitive effects of antipsychotic dosage and polypharmacy: A study with the BACS in patients with schizophrenia and schizoaffective disorder. Journal of Psychopharmacology, 24(7), 10371044.
Farde, L., Nordström, A.L., Wiesel, F.A., Pauli, S., Halldin, C., Sedvall, G. (1992). Positron emission tomographic analysis of central D1 and D2 dopamine receptor occupancy in patients treated with classical neuroleptics and clozapine. Archives of General Psychiatry, 49, 538544.
Ghoneim, M.M., Mewaldt, S.P. (1975). Effects of diazepam and scopolamine on storage, retrieval and organizational processes in memory. Psychopharmacologia, 44(3), 257262.
Goodman, S.H., Sewell, D.R., Cooley, E.L., Leavitt, N. (1993). Assessing levels of adaptive functioning: The role functioning scale. Community Mental Health Journal, 29(2), 119131.
Grant, C., Addington, J., Addington, D., Konnert, C. (2001). Social functioning in first- and multiepisode schizophrenia. Canadian Journal of Psychiatry, 46(8), 746749.
Kapur, S., Seeman, P. (2001). Does fast dissociation from the dopamine D2 receptor explain the action of atypical antipsychotics?: A new hypothesis. American Journal of Psychiatry, 158(3), 360369.
Kaufman, A.S., Kaufman, N.L. (1990). Kaufman Brief Intelligence Test manual. Circle Pines, MN: American Guidance Service.
Kay, S.R., Fiszbein, A., Opler, L.A. (1987). The Positive and Negative Syndrome Scale (PANSS) for schizophrenia. Schizophrenia Bulletin, 13(2), 261276.
Kinon, B.J., Chen, L., Ascher-Svanum, H., Stauffer, V.L., Kollack-Walker, S., Zhou, W., Naber, D. (2010). Challenging the assumption that improvement in functional outcomes is delayed relative to improvement in symptoms in the treatment of schizophrenia. Schizophrenia Research, 118, 176182.
Kopala, L.C., Good, K.P., Honer, W.G. (1997). Extrapyramidal signs and clinical symptoms in first-episode schizophrenia: Response to low-dose risperidone. Journal of Clinical Psychopharmacology, 17(4), 308313.
Kuenstler, U., Juhnhold, U., Knapp, W.H., Gertz, H.J. (1999). Positive correlation between reduction of handwriting area and D2 dopamine receptor occupancy during treatment with neuroleptic drugs. Psychiatry Research Neuroimaging, 90(1), 3139.
Lang, A.E., Lozano, A.M. (1998). Parkinson's disease: First of two parts. The New England Journal of Medicine, 339, 10441053.
Lindenmayer, J.P., Bernstein-Hyman, R., Grochowski, S. (1994). Five-factor model of schizophrenia: Initial validation. The Journal of Nervous and Mental Disease, 182(11), 631638.
Lines, C.R., Ambrose, J.H., Heald, A., Traub, M. (1993). A double-blind, placebo-controlled study of the effects of eptastigmine on scopolamine-induced cognitive deficits in healthy male subjects. Human Psychopharmacology: Clinical and Experimental, 8(4), 271278.
Matthews, C.G., Klove, K. (1964). Instruction manual for the Adult Neuropsychology Test Battery. Madison, WI: University of Wisconsin Medical School.
Mehta, M.A., Hinton, E.C., Montgomery, A.J., Bantick, R.A., Grasby, P.M. (2005). Sulpiride and mnemonic function: Effects of a dopamine D2 receptor antagonist on working memory, emotional memory and long-term memory in healthy volunteers. Journal of Psychopharmacology, 19(1), 2938.
Mesholam-Gately, R.I., Giuliano, A.J., Goff, K.P., Faraone, S.V., Seidman, L.J. (2009). Neurocognition in first-episode schizophrenia: A meta-analytic review. Neuropsychology, 23(3), 315336.
Milev, P., Ho, B.C., Arndt, S., Andreasen, N.C. (2005). Predictive values of neurocognition and negative symptoms on functional outcome in schizophrenia: A longitudinal first-episode study with 7-year follow-up. American Journal of Psychiatry, 162(3), 495506.
Minzenberg, M.J., Poole, J.H., Benton, C., Vinogradov, S. (2004). Association of anticholinergic load with impairment of complex attention and memory in schizophrenia. American Journal of Psychiatry, 161(1), 116124.
Minzenberg, M.J., Yoon, J.H. (2011). An index of relative central alpha-adrenergic receptor antagonism by antipsychotic medications. Experimental and Clinical Psychopharmacology, 19(1), 3139.
Power, A.E., Vazdarjanova, A., McGaugh, J.L. (2003). Muscarinic cholinergic influences in memory consolidation. Neurobiology of Learning and Memory, 80, 178193.
Preacher, K.J., Hayes, A.F. (2004). SPSS and SAS procedures for estimating indirect effects in simple mediation models. Behavior Research Methods, Instruments, & Computers, 36, 717731.
Reilly, J.L., Harris, M.S.H., Keshavan, M.S., Sweeney, J.A. (2006). Adverse effects of risperidone on spatial working memory in first-episode schizophrenia. Archives of General Psychiatry, 63(11), 11891197.
Richelson, E., Souder, T. (2000). Binding of antipsychotic drugs to human brain receptors: Focus on newer generation compounds. Life Sciences, 68(1), 2939.
Robbins, T.W., James, M., Owen, A.M., Sahakian, B.J., McInnes, L., Rabbitt, P. (1994). Cambridge Neuropsychological Test Automated Battery: A factor analytic study of a large sample of normal elderly volunteers. Dementia and Geriatric Cognitive Disorders, 5, 266281.
Robinson, D.G., Woerner, M.G., Delman, H.M., Kane, J.M. (2005). Pharmacological treatments for first-episode schizophrenia. Schizophrenia Bulletin, 31(3), 705722.
Seeman, P. (2001). Antipsychotic drugs, dopamine receptors, and schizophrenia. Clinical Neuroscience Research, 1, 5360.
Spreen, O., Strauss, E. (1991). A compendium of neuropsychological tests: Administration, norms and commentary. New York: Oxford University Press.
Strauss, M.E., Reynolds, K.S., Jayaram, G., Tune, L.E. (1990). Effects of anticholinergic medication on memory in schizophrenia. Schizophrenia Research, 3(2), 127129.
Strauss, E., Sherman, E.M.S., Spreen, O. (2006). A compendium of neuropsychological tests: Administration, norms, and commentary (3rd ed.). New York, NY: Oxford University Press.
Sweeney, J.A., Keilp, J.G., Haas, G.L., Hill, J., Weiden, P.J. (1991). Relationships between medication treatments and neuropsychological test performance in schizophrenia. Psychiatry Research, 37(3), 297308.
Tabachnick, B.G. (2001). Using multivariate statistics (4th ed.). Boston, MA: Allyn and Bacon.
Thornton, A.E., Van Snellenberg, J.X., Sepehry, A.A., Honer, W.G. (2006). The impact of atypical antipsychotic medications on long-term memory dysfunction in schizophrenia spectrum disorder: A quantitative review. Journal of Psychopharmacology, 20(3), 335346.
Vinogradov, S., Fisher, M., Warm, H., Holland, C., Kirshner, M.A., Pollock, B.G. (2009). The cognitive cost of anticholinergic burden: Decreased response to cognitive training in schizophrenia. American Journal of Psychiatry, 166(9), 10551062.
Wechsler, D. (1997a). WAIS-III administration and scoring manual. San Antonio, TX: The Psychological Corporation.
Wechsler, D. (1997b). WMS-III administration and scoring manual. San Antonio, TX: The Psychological Corporation.
Yang, Y.K., Yeh, T.L., Chiu, N.T., Lee, I.H., Chen, P.S., Lee, L.C., Jeffries, K.J. (2004). Association between cognitive performance and striatal dopamine binding is higher in timing and motor tasks in patients with schizophrenia. Psychiatry Research Neuroimaging, 131(3), 209216.


Antipsychotic Medications: Linking Receptor Antagonism to Neuropsychological Functioning in First Episode Psychosis

  • Heather A. Baitz (a1), Allen E. Thornton (a1), Ric M. Procyshyn (a2), Geoffrey N. Smith (a2), G. William MacEwan (a2), Lili C. Kopala (a2), Alasdair M. Barr (a3), Donna J. Lang (a4) and William G. Honer (a2)...


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