Guest Editorial
Second-Generation Antipsychotics: Looking Beyond Efficacy
A George Awad, MB, BCh, FRCPC, PhD1
A few years ago, I was asked to write about “The Aim of Antipsychotic Medications: What Are They and Are They Being Achieved?”(1). I always believed that the aims of therapy with antipsychotic medications in schizophrenia are basically similar to the aims of therapy with medications used to treat long-term medical conditions that may require life-long treatment. Such aims include efficacy without adverse effects, improved subjective tolerability and quality of life, positive long-term outcomes, and cost-effectiveness. When I review data from the drug-development programs of the recently introduced second-generation antipsychotics, it is clear that the major thrust of research has been directed toward demonstrating efficacy in both the short and long terms. Obviously, efficacy and safety are the major prerequisites for approval of new medications. However, in a long-term illness like schizophrenia, which has significant impact on several aspects of behaviour and mental and emotional functioning, it is equally important to demonstrate the impact of new medications on such issues as subjective tolerability, compliance, and quality of life. The best medications have no value unless they are taken (2). Enhanced tolerability can improve medication compliance, which contributes to less-frequent relapse and less use of health resources, as well as improved quality of life.
A few decades ago, research on such outcomes as subjective tolerability or quality of life was looked at as soft science—a view reflected in a certain publication bias and low priority in research funding. In addition, new medical technology such as neuroimaging and neurogenetics attracted much of the research interest, particularly among young researchers. As the late Dr Theodore Van Putten, an early pioneer of research in neuroleptic dysphoria, once lamented: “Research in neuroleptic dysphoria and subjective responses to medications, compared with neuroimaging, is not sexy anymore” (personal communication). I am sure he would be pleased to learn that the few of us who have persisted in researching these areas have already moved them to the forefront. Subjective tolerability, quality of life, and medication compliance behaviour are now all recognized as important outcomes in the long-term management of schizophrenia (3,4).
This issue’s review of psychopharmacology includes 3 contributions that deal with recent studies in the areas of neuroleptic dysphoria, subjective tolerability, quality of life, and medication compliance behaviour. Research into neuroleptic dysphoria represents an interesting chapter in psychiatric research: it took almost 25 years of persistent clinical research to finally unravel the pathophysiological basis and the role of dopamine in its genesis. Dr Lakshmi Voruganti, the principle investigator of our team in Toronto and a contributor to this special section, has successfully managed to experimentally induce dysphoria in medication-free schizophrenia patients by manipulating dopamine activities in the striatal– accumbens complex, thereby linking dysphoria to dopamine- binding ratio as well as demonstrating the variability of dopamine activities in schizophrenia (5). In this issue, Dr Vorunganti and I review serial assessments of emerging subjective, affective, cognitive, and extrapyramidal symptoms induced by dopamine depletion that have revived the notion of whether neuroleptic-induced dysphoria can be a variant of extrapyramidal side effects (6). Dr Lieuwe de Haan and his group in Amsterdam have used positron emission tomography studies to demonstrate the association between striatal dopamine receptor occupancy and dysphoria (7). In his contribution to this issue (8), Dr de Haan concludes that schizophrenia patients with lower baseline dopamine function are at an increased risk for dysphoric response.
These discoveries are by themselves significant, not only in terms of finally clarifying the origins of neuroleptic dysphoria but also because they open a research window: exploring the role of dopamine in other conditions such as drug abuse, which is frequently comorbid with schizophrenia and has been linked to the emergence of dysphoria. Significant preclinical data have pointed to a major role for dopamine in pleasurable experiences and reinforcement behaviour. Despite the prevailing belief that the self-medication hypothesis can explain frequent drug abuse in medicated schizophrenia patients (seen as an effort to overcome dysphoric anhedonic feelings), new evidence points in a different direction. Extensive existing data raise the possibility that the schizophrenia disease process can create a state of dopamine dysregulation, particularly in the nucleus accumbens (9). This can be manifested as enhanced vulnerability to drug abuse. Conversely, dopamine dysregulation is responsible for the development of psychotic symptoms, as well as for the vulnerability for development of dysphoric and affective symptoms.
These new insights into dopamine’s role in the genesis of neuroleptic dysphoria and drug addiction not only point to the need to reconceptualize schizophrenia and its varied clinical picture but also can prove useful in the development of new antipsychotics. They can already explain the relatively lower dysphoria reported with second-generation antipsychotics (11). The third paper (12) in this section selectively reviews recent clinical studies comparing second- and first-generation antipsychotics in terms of their impact on subjective tolerability, medication adherence behaviour, and quality of life. Significant improvements in these domains can translate into much better overall satisfaction, which contributes to a much more positive long-term outcome (2). Obviously, we need better-designed, controlled, and adequately powered studies to make definitive conclusions about the superiority of the new antipsychotics in such domains. I believe the present accelerated research and the new neurobiological insights about the role of dopamine in neuroleptic dysphoria and drug addictions open vistas that may expand our knowledge beyond schizophrenia into mood states. I also believe that, with new insights, we are on the verge of a new science that can be appropriately designated as “disorders of subjective tolerability.”
References
1. Awad AG, Voruganti LNP, Heslegrave RJ. The aim of antipsychotic medications: what are they and are they being achieved? CNS Drugs 1995:4:8–16.
2. Awad AG. Antipsychotic medications in schizophrenia: how satisfied are our patients? In: Clear perspectives—management issues in schizophrenia: patient satisfaction, compliance and outcomes in schizophrenia. London (UK): Shire Hall Ltd; 1999. p 1–6.
3. Awad AG. Antipsychotic medications: compliance and attitudes towards treatment. Curr Opin Psychiatry. Forthcoming.
4. Awad AG, Voruganti LNP. Quality of life and new antipsychotics in schizophrenia: are patients better off? Int J Soc Psychiatry 1999;45:268–75.
5. Voruganti LNP, Slomka P, Zabel P, Costa G, So A, Matter A, Awad AG. Subjective effects of AMPT-induced dopamine depletion in schizophrenia: the correlation between D2 binding ratio and dysphoric responses. Neuropsychopharmacology 2001;25:642–50.
6. Voruganti LNP, Awad AG. Neuroleptic dysphoria as a variant of extrapyramidal side-effects of antipsychotic medications. Can J Psychiatry 2004;49:285–9.
7. de Haan L, Lavalaye J, Linszen D, Dingemans PMAJ, Booij J. Subjective experience and striatal dopamine D2 receptor occupancy in patients with schizophrenia stabilized by olanzapine or risperidone. Am J Psychiatry 2000;157:1019–20.
8. de Haan L, Lavalaye J, van Bruggen M, Van Nimwegen L, Booij J, Amelsvoort T, and others. Subjective experiences and dopamine D2 receptor occupancy in patients treated with antipsychotics: clinical implications. Can J Psychiatry 2004;49:290–6.
9. Chambers A, Krystal J, Self D. A neurobiological basis for substance abuse comorbidity in schizophrenia. Biol Psychiatry 2001;50:71–83.
10. Voruganti LNP, Cortese L, Owyeumi L, Kotteda V, Chernovsky Z, Zirul S, and others. Switching from conventional to novel antipsychotic drugs: results of a prospective naturalistic study. Schizophr Res 2002;57:201–8.
11. Awad AG, Voruganti LNP. New antipsychotics, compliance, quality of life and subjective tolerability: are patients better off? Can J Psychiatry 2004;49:297–302.
Author
1. Professor Emeritus, University of Toronto and The Institute of Medical Science; Chief of Psychiatry, Humber River Regional Hospital, Toronto, Ontario.
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