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Over the past 50 years, antipsychotic medications have emerged as the cornerstone in the management of schizophrenia. However, the unrivalled role of first- generation antipsychotics in use for almost 4 decades has constantly been challenged by their wide range of side effects. Prominent among these side effects are a wide range of extrapyramidal symptoms (EPS), lack of subjective toler- ability, and negative impact on quality of life and functional status (1). More recently, several new antipsychotics have been introduced into Canada. These include remoxipride (withdrawn as a result of serious side effects); risperidone, olanzapine, and quetiapine (introduced into Canada in this order); and ziprasidone and aripiprazole, for both of which approval is pending. Clozapine was initially introduced in the early 1970s and was reintroduced in the early 1990s with a specific indication for the management of treatment-resistant patients. Generally, second-generation antipsychotics have proven to be at least comparable in efficacy to first-generation antipsychotics. Further, they have a more favourable overall side effects profile, even though some may have produced their own side effects, such as metabolic or cardiac side effects (2–5). Because most published studies have focused mainly on demonstrating both short- and long-term efficacy, fewer studies have explored effectiveness in terms of other important outcomes, such as adherence to medications, quality of life, and overall better subjective tolerability. The premise here is to demonstrate that efficacy and improved side effects profiles can translate into more favourable outcomes. This review, based on our work as well as on a selective review of the most recent available literature, examines the impact of second-generation antipsychotics on less frequently researched but important outcomes, such as compliance, quality of life, and subjective tolerability. Second-Generation Antipsychotics and Adherence to MedicationsCompliance, also commonly referred to as treatment adherence, has been defined as “the extent to which patient behaviour, in terms of taking medications, following diets or executing life-style changes, coincides with the clinical prescription” (6). Nonadherence to medications or therapeutic regimens is a widespread and universal problem in all medical practices, and antipsychotic treatment in schizophrenia is no exception. Recent studies continue to show treatment nonadherence rates in schizophrenia as high as 74% (7,8). It is clear that adherence or nonadherence is not an all-or-none phenomenon: it encompasses a wide range of behaviours ranging from not taking medications to taking medications using an incorrect dosage or at the wrong time (9). Recent reviews (10–14) of factors identified as contributing to nonadherence behaviours have grouped them into 4 major categories. The first category comprises illness-related factors, such as delusional paranoid thinking, lack of motivation, depressive states, neurocognitive deficits, lack of insight, and unawareness of illness and the need for its treatment. The second category encompasses patient-related factors and includes sociodemographic characteristics such as young age, male sex, being single, having lower socioeconomic status, and lack of family involvement. This category also includes issues related to knowledge and health beliefs about the illness and the medications. The third group of factors includes issues related to the health care system itself, in terms of perceived poor quality of care and such barriers to treatment as complex dosing regimens and lack of reasonable access to medications. The last group of factors concerns the antipsychotic medications and includes issues related both to their positive effect, in terms of perceived benefits, and to their negative effects, in terms of distressing side effects. Prominent among side effects are a wide range of EPS and neuroleptic-induced dysphoria, and it is in this area that one hopes to find significant differences in treatment-adherence behaviour between the second and first generation of antipsychotics. Given the improved side effects profile of second-generation antipsychotics, one would expect improved treatment- adherence behaviour, compared with that observed for first- generation antipsychotics. Unfortunately, such a notion has not been adequately or systematically tested. Very few recent comparative clinical trials of second-generation antipsychotics have included treatment-adherence behaviour as an outcome. In a long-term study that involved switching patients with schizophrenia from first- to second-generation antipsychotics, 150 patients were switched from first- generation antipsychotics to either risperidone, olanzapine, or quetiapine and were followed up for a period of 2 to 3 years (15). Patients on the new antipsychotics demonstrated an average of 28% improvement in their medication- adherence behaviour. In another recent study, rates of medication adherence over a 1-year period were compared among patients treated with either first- or second-generation antipsychotics (16). Results demonstrated significantly less switching among second-generation medications, which the authors construed as an indication of better adherence. However, this finding does not necessarily indicate better medication adherence, because there are several reasons apart from lack of adherence that may necessitate a medication switch. Conversely, Cabeza and others undertook a retrospective inpatient study using psychiatrist interviews and applying the Drug Attitude Inventory prior to discharge from hospital (17); they found no difference in adherence behaviour between patients receiving first- or second-generation antipsychotics. However, a recent prospective study with a large sample of outpatients followed up 3 months after discharge reported a trend toward improved medication-adherence behaviour for those patients on second-generation antipsychotics, compared with those on first-generation medications (18). This trend was confirmed by another study that included out- patients in supported residential housing facilities (19). Improved medication-adherence behaviour has been more consistently endorsed by studies of patients receiving clozapine (20,21). Although several authors have proposed specific pharmacologic mechanisms related to clozapine, one cannot ignore the contribution of the close monitoring, frequent visits, and support required during clozapine therapy. In essence, the few available studies seem to be inconsistent in demonstrating that second-generation medications are superior in terms of improving adherence behaviour. Most of the published data suffer from significant methodological issues related to design, length of follow-up, and how adherence to medications has been ascertained. Presently, one can only conclude from the available literature that there is a possible trend supporting the relative superiority of second-generation antipsychotics in improving medication-adherence behaviour—a conclusion that awaits well-designed and systematic studies. Second-Generation Antipsychotics and Quality of LifeOver the last few years, the concept of quality of life has become a new paradigm for representing the ideal of modern medicine emphasizing biopsychosocial approaches (22,23). In other words, the concept has come to represent the ultimate outcome of the interaction between the patient and the illness, its treatment, its psychosocial impact, and its consequences. In that context applied to schizophrenia, the impact of antipsychotics is considerable, not only because of their ability to alleviate symptoms but also because of the impact of side effects on how patients feel and function. A recent conceptual model for quality of life in medicated persons with schizophrenia has identified medications as major contributors to quality of life, owing to their impact on symptoms, side effects, and eventual psychosocial performance (24). Several reports have demonstrated compromised quality of life on first-generation antipsychotics (24,25–28). The introduction of second-generation antipsychotics has provided the opportunity to test whether their improved side effects profile translates into better quality of life and improved psychosocial performance. It is understood that medications alone are not capable of improving psychosocial performance; they must be coupled with enhanced resources for rehabilitation and psychosocial support. Nevertheless, medication can play a significant role as a positive or negative mediator for subjective constructs such as feelings of well-being and satisfaction. Although studies have reported the favourable impact of second-generation antipsychotics on quality of life, many studies suffered from several methodological and design shortcomings, including lack of a control group, the choice of quality-of-life instruments, the length of follow-up, and the significant heterogeneity of the populations studied— limitations that make comparison among studies rather difficult (29). Most published studies involved comparing risperidone, olanzapine, and clozapine either with first- generation antipsychotics or among themselves with regard to their impact on quality of life. So far, few or no comparisons have been reported involving quetiapine, aripiprazole, and ziprasidone. A large noncomparative postmarketing study of schizophrenia patients treated with risperidone reported significant improvement in quality of life (58% of patients) by week 10, compared with only 25% at baseline (30). In another long-term study, 362 schizophrenia patients were switched from other antipsychotics to risperidone (31). Improvement in quality of life was reported following 8 months of treatment. Several studies comparing the impact of risperidone and olanzapine on quality of life indicated similar improvement in both groups (32–34). Other comparative studies concluded that patients taking olanzapine demonstrated more improvement in quality of life, compared with those taking haloperidol (35). Several studies reported the superiority of clozapine to first-generation antipsychotics in improving quality of life for treatment-refractory schizophrenia patients (21,36–38). We recently reported the results of a large cross-sectional study comparing first- and second-generation antipsychotics with the reference to their impact on quality of life (28). A single-blind, naturalistic study included 230 patients in 5 groups treated with monotherapy of either first-generation antipsychotics or risperidone, olanzapine, quetiapine, or clozapine for a period of 6 months or longer. Patients receiving risperidone, olanzapine, quetiapine, or clozapine demonstrated more improvement in self-rated quality of life, compared with those receiving first-generation anti- psychotics. In another recent study, we examined the long-term consequences of switching patients from first- to second-generation medications (15). We included 150 patients diagnosed with schizophrenia or schizoaffective disorder who were switched from first-generation antipsychotics to risperidone, olanzapine, or quetiapine and monitored for a period of at least 1 year. Several quality-of-life measures demonstrated that second-generation antipsychotics had a more favourable impact. Similar conclusions were reported by another study demonstrating the benefits of switching from typical to atypical antipsychotic medications in a community-based setting (39). Conversely, few studies have failed to observe a difference in quality of life between groups of patients with schizophrenia treated with either first- or second-generation antipsychotics (40–42). On balance, and notwithstanding the many methodological and design limitations in the published studies, one can detect a strong trend toward a more favourable impact of second-generation antipsychotics on quality of life. Obviously, the challenging question is not only to document improved quality of life with second-generation antipsychotics but also to demonstrate that this improved quality of life can translate into better functional states, less utilization of resources, and greater overall satisfaction (43). Second-Generation Antipsychotics, Subjective Tolerability, and Attitudes Toward MedicationNot long after the introduction of the first antipsychotic, chlorpromazine, many patients complained of an altered subjective state that could occur following even a few doses of the medication (44–47). Patients complained about feeling, “fuzzy or dull,” of being “unable to think straight,” and of feeling “like a zombie.” Some patients even believed that the medication made their conditions worse. Not surprisingly, many patients pressured their clinicians for frequent changes of medication, and some discontinued medication altogether. Despite these serious complaints, it took some time for clinicians and researchers to recognize the phenomena, which eventually were collectively labelled neuroleptic dysphoria (48). As clinical and research interest eventually focused on this issue, the consequences of neuroleptic dysphoria and lack of subjective tolerability were increasingly recognized: their negative impact on adherence behaviour and on eventual outcome includes frequent relapses, excessive utilization of resources, hospitalizations, and compromised quality of life (49–53). Although medication- induced dysphoria proved to be unrelated to the dosage or type of first-generation antipsychotic, we reported correlations with aspects of symptomatology such as positive and negative symptoms, general psychopathology, depression, impaired insight, and side effects, particularly akathisia (47). Similar data were also reported by Bartko and others (54) and Weiden and others (55). Since second-generation antipsychotics lack many of the side effects, particularly the extrapyramidal side effects, of the first-generation antipsychotics, they can be expected to be subjectively better tolerated. Again, however, a survey of the recent literature indicates that few studies have explored the impact of second-generation antipsychotics on subjective tolerability and attitudes of patients toward medications. In our longitudinal switch study (15), data confirmed that, at 1-year follow-up, patients switched to either risperidone, olanzapine or quetiapine demonstrated better subjective tolerability, significantly less dysphoria, and more positive subjective responses and attitudes toward medication. In another study involving quetiapine, most patients reported a high level of satisfaction and expressed readiness to continue taking the medication (56). Similar conclusions were reported by Rabinowitz and others, who studied patient satisfaction and burden of adverse effects with second-generation, compared with first-generation, antipsychotics (57). In a recent study of satisfaction and subjective experiences of patients with schizophrenia who switched from first- to second- generation antipsychotics, Bartko and others concluded that most patients experienced higher levels of satisfaction (58). This high level of satisfaction contributed to more favourable attitudes toward medication. Of interest is that most patients in that study perceived benefits related to quality of life rather than to efficacy. Data from a recent survey showed that, among 66 psychiatrists in a defined geographical area in Germany, most would prefer a new antipsychotic if they themselves or a family member required antipsychotic treatment (59). Although the construct of neuroleptic dysphoria, together with its clinical consequences, has received clinical and research attention over the past 3 decades, its genesis and pathophysiological basis continues to be unclear. Since the phenomenon has been connected with the use of various antipsychotics, regardless of the clinical condition, the general notion has been that it is somehow related to dopamine functioning in the brain. Recent neuroimaging techniques have allowed us to test such hypotheses in a recent single photon emission computed tomography dopamine depletion study. In it, we were able to induce dysphoria in a sample of medication-free patients with the diagnosis of schizophrenia (60). We demonstrated a significant correlation between dysphoric responses and dopamine binding ratio in the striatal-accumbens complex. This study had another important finding: the demonstration of variability in basal dopamine activities, which probably explains why not every patient receiving antipsychotics develops dysphoria. Patients who have relatively lower dopamine activities are likely to develop dysphoria when given a potent D2 receptor antagonist. This in turn can explain, at least in part, why patients taking second-generation antipsychotics develop less dysphoria and are able to subjectively tolerate the medications better, since their impact on the dopamine receptor is much less pronounced or transient in nature (61). Our data have received confirmation from a series of PET studies comparing dopamine receptor occupancy in patients receiving either first- or second-generation antipsychotics (62). Despite such recent breakthroughs in understanding the neurobiology of neuroleptic dysphoria, only limited clinical data indicate a strong trend toward more positive attitudes toward medication and a more favourable impact of second-generation antipsychotics on subjective tolerability. ConclusionsGiven their more favourable overall side effects profile, the introduction of second-generation antipsychotics has ushered in an era of optimism and higher expectations of better outcomes. Unfortunately, these better outcomes have not yet been fully demonstrated. One can only conclude, from the few available studies, that there is a possible trend for superiority of second-generation antipsychotics in improving medication- adherence behaviour and quality of life. However, there seems to be stronger evidence indicating a more favourable impact on subjective tolerability and overall satisfaction. To reach definitive conclusions, there is a pressing need for well-designed, controlled, and adequately powered studies. Further comparative studies are required, not only between first- and second- generation antipsychotics but also between second-generation antipsychotics themselves. Particularly in terms of their side effects profile, there may be individual differences in weight gain, sexual dysfunction, and metabolic side effects that can specifically affect certain outcomes. Based on this selective review and on our experiences in the field, our answer to the question that we posed for ourselves— “Are our patients better off on the second-generation antipsychotics?”—is at this time only a qualified “Yes, pending further studies.” References1. Awad AG, Voruganti LNP, Heslegrave RJ. 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Self-rating scale to measure subjective effects of neuroleptic drugs, relationship to objective psychopathology, quality of life and other clinical variables. Int Clin Psychopharmacol 1995;10(Suppl 3):133–8. 52. Voruganti LNP, Heslegrave RJ, Awad AG. Quality of life measurement during antipsychotic drug therapy of schizophrenia. J Psychiatry Neurosci 1997;22:267–74. 53. Brownie S, Gervan J, Gervin M, Roe M, Larkin C, O’Callaghan E. Quality of life in schizophrenia: insight and subjective response in schizophrenia. J Nerv Ment Dis 1998;186:74–8. 54. Bartko G, Herczeg I, Bekesy M. Predicting outcome of neuroleptic therapy on the basis of subjective response and early clinical improvement. J Clin Psychiatry 1987;48:363–5. 55. Weiden PJ, Mann JJ, Dixon L, Haas G, DeChillo N, Francis AJ. Is neuroleptic dysphoria a healthy response? Compr Psychiatry 1989;30:546–52. 56. Hellewell JS, Kalali AH, Langham SJ, Awad AG. Patient satisfaction and acceptability of long-term treatment with quetiapine. Int J Psychiatry Clin Pract 1999;3:105–13. 57. Rabinowitz J, Bromet EJ, Davidson M. Comparison of patient satisfaction and burden of adverse effects with novel and conventional neuroleptics: a naturalistic study. Schizophr Bull 2001;27:597–600. 58. Bartko G, Varadi H, Simon L, Linka E, Tuske T, Szabo T, and others. Patient satisfaction after switching from conventional to new atypical antipsychotics in schizophrenia. Int J Psychiatry Clin Pract 2002;6:9–14. 59. Steinert T. Which neuroleptic would psychiatrists take for themselves or their relatives? Eur Psychiatry 2003;18:40–1. 60. Voruganti L, Slomka P, Zabel P, Costa G, So A, Matter A, and others. Subjective effects of AMPT-induced dopamine depletion in schizophrenia: the correlation between D2 binding ratio and dysphoric responses. Neuropsychopharmacology 2001;25:642–50. 61. Kapur S, Seeman P. Does fast dissociation from the D2 receptor explain the action of atypical antipsychotics? A new hypothesis. Am J Psychiatry 2001;158:360–9. 62. 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. Author(s)Manuscript received and accepted February 2004. 1. Professor Emeritus, University of Toronto and The Institute of Medical Science; Chief of Psychiatry, Humber River Regional Hospital, Toronto, Ontario. 2. Associate Professor and Head, Schizophrenia Research Program, McMaster University, Hamilton, Ontario. Address for correspondence: Dr AG Awad, Department of Psychiatry, 2175 Keele Street, Suite 243A, Toronto, ON M6M 3Z4 e-mail: gawad@hrrh.on.ca
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