CNS Drugs

, Volume 33, Issue 1, pp 1–8 | Cite as

Revisiting the Concept of Subjective Tolerability to Antipsychotic Medications in Schizophrenia and its Clinical and Research Implications: 30 Years Later

  • A. George AwadEmail author
Current Opinion


Schizophrenia is a long-term psychiatric disorder that impacts important mental functions and requires indefinite treatment, as well as psychosocial and economic support. The introduction of chlorpromazine, the first antipsychotic, and the subsequent development of a long list of similar dopamine-blocking antipsychotic medications, has changed the treatment of schizophrenia as medications have become the cornerstone of clinical management. The enthusiasm that greeted the introduction of antipsychotics was soon tempered by the realisation that they induced significant side effects, such as extrapyramidal and autonomic symptoms. A less-recognized side effect at the time was the emergence of subtle subjective side effects that led patients to dislike medications and eventually discontinue them, with serious consequences of frequent relapses requiring hospitalization, poor outcomes and more health costs. The development of our dedicated programme for research into subjective tolerability to medications over the past 30 years has allowed us to establish the validity of the construct of ‘subjective tolerability’ to antipsychotics, applying research methodologies that are required for any scientific inquiry. We clarified definitions, developed reliable measuring tools, and constructed psychosocial and neurobiological conceptual models. We also documented the serious consequences of negative subjective tolerability to antipsychotics: poor medication adherence behaviour, impaired quality of life, and worse clinical and functional outcomes. More recently, using neuroimaging techniques, we and other international research groups were able to clearly elucidate the neurobiology of dysphoric negative subjective responses, linking it to low dopamine functioning in the striatal region of the brain. Such a discovery for the first time allowed us to also link the development of comorbid drug abuse in schizophrenia, which is a common occurrence, to the development of neuroleptic dysphoria, since both relate to the low dopamine function in the striatum. As an already validated scientific concept that has serious consequences, subjective tolerability to antipsychotics can serve as a model for patient-centered outcomes that really matter. Our long-serving research programme also illustrates the value of clinical observations to the development of important clinical research studies, i.e. from the bedside to the research bench, and back to the bedside.



The author acknowledges the contributions of Tom Hogan, Lakshmi Voruganti and Ron Heselgrave, who joined the programme at various stages of development.

Compliance with Ethical Standards


No sources of funding were used in the preparation of this article.

Conflicts of interest

A. George Awad has no conflicts of interests relevant to the content of this article.


  1. 1.
    Seeman MV. Schizophrenia and its sequelae. In: Awad AG, Voruganti LNP, editors. Beyond assessment of quality of life in schizophrenia. Switzerland: Springer International Publishing; 2016. p. 3–13.Google Scholar
  2. 2.
    Awad AG, Voruganti LNP, Heselgrave RJ. The aim of antipsychotic medications: what are they and are they being achieved? CNS Drugs. 1995;4:8–16.CrossRefGoogle Scholar
  3. 3.
    Singh MM, Smith JM. Dysphoric response to neuroleptic treatment in schizophrenia and its prognostic significance. Dis Nerv Syst. 1976;37:191–7.Google Scholar
  4. 4.
    Van Putten T, May PRA, Marader S, Wittman LA. Subjective response to antipsychotic drugs. Arch Gen Psychiatry. 1981;38:187–90.CrossRefGoogle Scholar
  5. 5.
    Van Putten T, May PRA. “Akinetic depression” in schizophrenia. Arch Gen Psychiatry. 1978;15:1101–7.CrossRefGoogle Scholar
  6. 6.
    Van Putten T, Marder SR. Behavioural toxicity of antipsychotic drugs. J Clin Psychiatry. 1987;48:13–9.Google Scholar
  7. 7.
    Caine ED, Polensky RJ. Haloperidol induced dysphoria in patients with Tourette’s syndrome. Am J Psychiatry. 1979;136:1216–7.CrossRefGoogle Scholar
  8. 8.
    Van Putten, T. Mutalipassi LR, Malkin MD. Phenothiazine induced decompensation. Arch Gen Psychiatry. 1974;30:102–105.Google Scholar
  9. 9.
    Awad AG. The psychology of medication-taking: the development of a research program in psychopharmacology. In: Ban TA, Healy D, Shorter E, editors. From psychopharmacology to neuropsychopharmacology in the 1980s and the story of CINP as told in autobiography. Budapest: Animula Publishing House; 2002. p. 130–4.Google Scholar
  10. 10.
    Hogan TP, Awad AG. Pharmacotherapy and suicide risk in schizophrenia. Can J Psychiatry. 1983;28:277–81.CrossRefGoogle Scholar
  11. 11.
    Hogan TP, Awad AG, Eastwood MR. A self-report scale, predictive of drug compliance in schizophrenia: reliability and discriminative ability. Psychol Med. 1983;13:177–83.CrossRefGoogle Scholar
  12. 12.
    Hogan TP, Awad AG, Eastwood MR. Early subjective response and prediction of outcome to neuroleptic therapy in schizophrenia. Can J Psychiatry. 1985;30:246–8.CrossRefGoogle Scholar
  13. 13.
    Awad AG, Hogan TP. Early treatment and prediction of response to neuroleptics in schizophrenia. Prog Neuropsychopharmacol Biol Psychiatry. 1985;9:585–8.CrossRefGoogle Scholar
  14. 14.
    Awad AG. Subjective response to neuroleptics in schizophrenia. Schizophr Bulletin. 1993;19:609–17.CrossRefGoogle Scholar
  15. 15.
    Naber D. Subjective effects of antipsychotic treatment (editorial). Acta Psychiatr Scand. 2005;111:81–3.CrossRefGoogle Scholar
  16. 16.
    Voruganti LNP, Awad AG. Subjective and behavioural consequences of striatal dopmaine depletion in schizophrenia: findings from in vivo SPECT study. Schiz Res. 2006;88:179–88.CrossRefGoogle Scholar
  17. 17.
    Mueser KT, Yarnold PR, Levinson DF. Prevalence of substance abuse in schizophrenia: demographics and clinical correlates. Schizophr Bull. 1990;16:31–54.CrossRefGoogle Scholar
  18. 18.
    Reigier DA, Famer ME, Rae DS. Comorbidity of mental disorders with alcohol and other drugs of abuse. JAMA. 1990;264:3511–8.Google Scholar
  19. 19.
    Cleary TA, Linn RL. Variability of Kuder-Richardson variability estimates. Princeton: Educational Testing Services, Formula 20; 1968.Google Scholar
  20. 20.
    Kaiser HF, Caffrey J. Alpha factor analysis. Psychometrics. 1965;30:1–14.CrossRefGoogle Scholar
  21. 21.
    Nielsen RE, Lindstrom E, Nielsen J, Levander S. DAI-10 is as good as DAI-30 in schizophrenia. Eur Neuropsychopharmacol. 2012;10:747–50.CrossRefGoogle Scholar
  22. 22.
    Wieden PJ, Rapkin B, Mott T, Zygmunt A, Goldman D, Horvitz-Lennon M, Frances A. Rating of medication influences (ROMI) scale in schizophrenia. Schizophr Bull. 1994;20:297–310.CrossRefGoogle Scholar
  23. 23.
    Naber D, Walther A, Kircher T, Hayek D, Holzbach R. Subjective effects of neuroleptics predict compliance. In: Gaebel W, Awad AG, editors. Prediction of Neuroleptic treatment outcome in schizophrenia—concepts and methods. Wien: Springer; 1994. p. 85–98.CrossRefGoogle Scholar
  24. 24.
    Voruganti LNP, Awad AG. Personal evaluation of transitions in treatment (PETiT): a scal to measure subjective tolerability of antipsychotic medications. Schizophr Res. 2002;56:37–46.CrossRefGoogle Scholar
  25. 25.
    Baumstrack K, Boyer L, Boucekine M, Aghababian V, Parola N, Lancon C, Auquier P. Self-reported quality of life measure is reliable and valid in adult patients suffering from schizophrenia with executive impairment. Schizophr Res. 2013;147:58–67.CrossRefGoogle Scholar
  26. 26.
    Awad AG, Voruganti LNP. Measuring quality of life in patients with schizophrenia—an update. Pharmacoeconomics. 2012;30:183–95.CrossRefGoogle Scholar
  27. 27.
    Niv N, Cohen AN, Mintz J, Ventura J, Young AS. The validity of using patient self-report to assess psychotic symptoms in schizophrenia. Schizophr Res. 2007;90:245–50.CrossRefGoogle Scholar
  28. 28.
    Wehmeier PM, Kluge M, Schact A. Correlation of physician and patient-related quality of life during antipsychotic treatment in outpatients with schizophrenia. Schizophr Res. 2007;91:178–86.CrossRefGoogle Scholar
  29. 29.
    Becchi A, Rucci P, Placentino A, Neri G, de Girolamo G. Quality of life in patients with schizophrenia—comparison of self-reports and proxy assessments. Soc Psychiat and Psychiatr Epidemiol. 2004;39:397–401.CrossRefGoogle Scholar
  30. 30.
    Lirand F, Droulout T, Parrot N, Verdoux H. Agreement between self-rated and clinically assessed symptoms in subjects with psychosis. J Nerv Ment Dis. 2004;192:352–6.CrossRefGoogle Scholar
  31. 31.
    Awad AG, Voruganti LNP. The subjective/objective dichotomy: relevance to nosology, research and management. In: Gaebel W, editor. Zukunfts Perspectives in psychiatries and psychotherapie. Darmstadt: Steinkopff; 2002. p. 21–7.CrossRefGoogle Scholar
  32. 32.
    Voruganti LNP, Heselgrave RS, Awad AG, Seeman M. Quality of life measurement in schizophrenia; reconciling the question of subjectivity with the quest of reliability. Psychol Med. 1998;28:165–72.CrossRefGoogle Scholar
  33. 33.
    Voruganti LNP, Awad AG. Neuroleptic dysphoria: towards a new synthesis. Psychopharmacology. 2004;171:121–32.CrossRefGoogle Scholar
  34. 34.
    Delespaul PH. Consensus regarding the definition of persons with severe mental illness and the number of such persons in the Netherlands. Tijdschr Psychiatr. 2013;55:427–38.Google Scholar
  35. 35.
    Awad AG, Hogan TP, Voruganti LNP, Heselgrave RJ. Patient subjective experiences on antipsychotic medication; implications for outcome and quality of life. Int Clin Psychopharmacol. 1995;10(Suppl 3):123–32.Google Scholar
  36. 36.
    Awad AG. Drug therapy in schizophrenia—variability of the outcome and prediction of response. Can J Psychiatry. 1989;34:711–20.CrossRefGoogle Scholar
  37. 37.
    Laruelle M, D’Souza CD, Baldwin RM, Abi-Dergham A, Kanes SJ, Fingado CL, et al. Imaging D2 receptor occupancy by endogenous dopamine in humans. Neuropsychopharmacology. 1997;17:162–74.CrossRefGoogle Scholar
  38. 38.
    Laruelle M. Abi-Dargham A, von Dyck CH, Rosenblatt W, Zia-Ponce Y, Zoghbi SS et al. SPECT imaging of striatal dopamine release after amphetamine challenge. J Nucl Med. 1995;36:1182–1190.Google Scholar
  39. 39.
    Voruganti LNP, Awad AG. Role of dopmaine in pleasure, reward and subjective responses as important aspects of quality of life. In: Ritsner M, Awad AG, editors. Quality of life impairment in schizophrenia, mood and anxiety disorders. Dordrecht: Springer; 2007. p. 21–31.CrossRefGoogle Scholar
  40. 40.
    Voruganti LNP, Slomka P, Zabel P, Costa G, So A, Mattar A, et al. The correlation between D2 binding ratio and dysphoric responses. Neuropsychopharmacol. 2001;25:642–50.CrossRefGoogle Scholar
  41. 41.
    McNair DM, Lorr M, Droppleman L. Manual for the profile of mood states. San Diego: Educational and Industrial Testing Services; 1992.Google Scholar
  42. 42.
    Haertzen CA. Addiction Research Centre Inventory (ARCI): development of a general drug estimation scale. J Ner Ment Dis. 1965;141:300–7.CrossRefGoogle Scholar
  43. 43.
    Kay S, Fiszbein A, Opler L. The positive and negative syndrome scale for schizophrenia. Schizophr Bull. 1987;13:261–7.CrossRefGoogle Scholar
  44. 44.
    Barnes TRE. A rating scale for drug-induced akathesia. Br J Psychiatry. 1989;154:672–6.CrossRefGoogle Scholar
  45. 45.
    Simpson G, Angus J. A rating scale for extrapyramidal side effects. Acta Psychiatr Scand Suppl. 1970;212:11–9.CrossRefGoogle Scholar
  46. 46.
    de Haan L, Lavalaye J, Linszen D, Dingemans PMJ, Booij J. Subjective experiences and striatal dopamine D2 receptor occupancy in patients with schizophrenia stabilized by olanzapine or risperidone. Am J Psychiatry. 2000;157:1019–20.CrossRefGoogle Scholar
  47. 47.
    de Haan L, Van Pruggen M, Lavalaye J, Booij J, et al. Subjective experiences and D2 receptor occupany in patients with recent-onset schizophrenia treated with low dose olanzapine or haloperidal: a randomized double blind study. J Psychiatry. 2003;160:303–9.Google Scholar
  48. 48.
    Mizrahi R, Mamo D, Rusjan P, Graff A, et al. The relationship between subjective well-being and dopamine D2 in patients treated with dopamine partial agonist and antagonist antipsychotics. Int J neuropsychopharmacology. 2009;5:715–21.CrossRefGoogle Scholar
  49. 49.
    Lafaster J, Van Os J, de Haan L, Thewissen V, et al. Emotional experience and estimates of D2 receptor occupancy in psychotic patients treated with haloperidol, risperidone or olanzapine: an experience sampling study. J Clin Psychiatry. 2011;10:1397–404.CrossRefGoogle Scholar
  50. 50.
    Awad AG, Vorguanti LNP. Revisiting the self-medication hypothesis in light of the new data linking low striatal dopamine to comorbid addictive behaviour. Ther Adv Psychopharmacol. 2015;5:172–8.CrossRefGoogle Scholar
  51. 51.
    Van Putten T. Subjective response as a predictor of outcome in pharmacotherapy. Arch Gen Psychaitry. 1978;35:477–80.CrossRefGoogle Scholar
  52. 52.
    Blyerler CR, Fenton WS. Satisfaction with treatment outcome and non-compliance in schizophrenia. Schizophr Res. 1997;24:205.CrossRefGoogle Scholar
  53. 53.
    Awad AG. Antipsychotic medications; compliance and attitudes towards treatment. Curr Opin Psychiatry. 2004;17:75080.CrossRefGoogle Scholar
  54. 54.
    Awad AG, Voruganti LNP. New antipsychotics, compliance, quality of life and subjective tolerability—are patients better off? Can J Psychiatry. 2004;49:297–302.CrossRefGoogle Scholar
  55. 55.
    Garcia-Cabeza I, Gomez JC. Subjective response to antipsychotic treatment and compliance in schizophrenia? A naturalistic study comparing olanzapine, risperidone and haloperidal (EFESO study). BMC Psychiatry. 2001;1:7.CrossRefGoogle Scholar
  56. 56.
    de Haan L, von Nimwegin Van, Amelsvoort T, Linszen DH, et al. Improvement of subjective well-being and enduring symptomatic remission, a 5 year follow-up of first episode schizophrenia. Pharmacopyshciatry. 2008;41:125–8.CrossRefGoogle Scholar
  57. 57.
    Lambert M, Schimmelmann BG, Naber D, Karow A, et al. Early and delayed antipsychotic response and prediction of outcome in 528 severely imparied patients with schizophrenia treated with amisulpride. Pharmacopsychiatry. 2009;42:277–83.CrossRefGoogle Scholar
  58. 58.
    Naber D, Karow A. Good tolerability equal good results: the patient’s perspective. Eur Neuropsychopharmacol. 2001;11:S391–5.CrossRefGoogle Scholar
  59. 59.
    Gaebel W, Riesbeck M, von Wilmsdorf M, Burns T, et al. Drug attitude as predictor for effectiveness in first-episode schizophrenia: results of an open randomized trial (EUFEST). Eur Neuropsychopharmacol. 2010;20:310–6.CrossRefGoogle Scholar
  60. 60.
    Khantzian EJ. The self-medication hypothesis of addictive disorders: focus on heroin and cocaine dependence. Am J Psychiatry. 1985;142:1259–64.CrossRefGoogle Scholar
  61. 61.
    Voruganti LNP, Heselgrave RJ, Awad AG. Neuroleptic dysphoria may be the missing link between schizophrenia and substance abuse. J Ner Ment Dis. 1997;185:463–5.CrossRefGoogle Scholar
  62. 62.
    Thompson J, Urban N, Slifstein M, Xu X, et al. Striatal dopmaine release in schizophrenia comorbid with substance dependence. Mol Psychiatry. 2013;18:909–15.CrossRefGoogle Scholar
  63. 63.
    Trifilieff P, Martinez D. Blunted dopamine release as a biomarker for vulnerability for substance use disorders. Biol Psychiatry. 2014;76:4–5.CrossRefGoogle Scholar
  64. 64.
    Awad AG. The neurobiology of comorbid drug abuse in schizophrenia and psychotic disorders. In: Preedy V (ed). Neuropathology of drug addictions and substance misuse. Volume I. Elsevier Inc.; 2016. pp. 82–88.Google Scholar
  65. 65.
    Samaha A-N. Can antipsychotic treatment contribute to drug addiction in schizophrenia. Prog Neuropsychopharmacal Biol Psychiatry. 2014;52:6–16.Google Scholar
  66. 66.
    Awad AG. Is it time to consider comorbid substance abuse as a new indication for antipsychotic drug development. J Psychopharmacology. 2012;26:953–7.CrossRefGoogle Scholar
  67. 67.
    Awad AG, Voruganti LNP. The impact of newer atypical antipsychotics on patient-reported outcomes in schizophrenia. CNS Drugs. 2013;27:725–36.CrossRefGoogle Scholar
  68. 68.
    Awad AG, Voruganti LNP. Neuroleptic dysphoria, comorbid drug abuse in schizophrenia and the emerging science of subjective tolerability—towards a new synthesis. J Dual Diagnosis. 2005;1:83–93.CrossRefGoogle Scholar
  69. 69.
    Awad AG. Subjective tolerability of antipsychotic medications and the emerging science of subjective tolerability disorders. Expert Rev Pharmacoecon Outcomes Res. 2010;10:1–4.CrossRefGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2018

Authors and Affiliations

  1. 1.Professor Emeritus, Department of Psychiatry and the Institute of Medical Science, Humber River HospitalUniversity of TorontoTorontoCanada

Personalised recommendations