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Meeting everyday challenges: Antipsychotic therapy in the real world
European Neuropsychopharmacology (2006) 16, S156 — S162
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Meeting everyday challenges: Antipsychotic therapy in the real world Philip Gorwood * AP-HP, Hopital Louis Mourier, Colombes, France INSERM U675, Faculty Paris VII, France
KEYWORDS Schizophrenia; Naturalistic; Atypical antipsychotics; Outcomes
Abstract Patients with schizophrenia and their physicians face a number of challenges, such as long-term control of symptoms, maintaining cognitive function and subjective well-being, and preventing relapse. While randomised, placebo-controlled trials and open-label extensions can provide valuable information about the long-term efficacy and tolerability of newer antipsychotic agents, they cannot address all the variables that may affect treatment outcome. Factors such as cognitive function, antipsychotic side effects, patients’ attitudes to medication and subjective well being can all affect the results of treatment in real-life clinical practice. Moreover, the patient cohorts enrolled in clinical trials are often not reflective of the wider population with schizophrenia. For example, patients with conditions such as anxiety and panic disorders or comorbid substance abuse, as well as those with severe illness and patients from certain ethnic or age groups, may often be excluded from clinical trials. In addition, patients themselves may refuse to participate in placebo-controlled studies because of a fear of being under-treated. Naturalistic studies are, therefore, an important means of providing additional data on the safety and effectiveness of antipsychotic agents in dreal-worldT settings. Studies such as the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) study, the Schizophrenia Outpatient Health Outcomes (SOHO) study and the Broad Effectiveness Trial with Aripiprazole (BETA) studies, together with large-scale database analyses, are now producing results supplementary to those observed in long-term, open-label extension studies. Such naturalistic studies will continue to provide important data on the real-world effectiveness of atypical antipsychotics with respect to key outcomes such as treatment continuation and prolonged recovery. D 2006 Elsevier B.V. and ECNP. All rights reserved.
1. Introduction * Hospital Louis Mourier (AP-HP, Paris VII), INSERM U675, 178 rue des Renouillers, 92701 Colombes Cedex, France. Tel.: +33 1 47 60 64 15; fax: +33 1 47 60 67 40. E-mail address: [email protected].
The incidence of mental health problems is currently increasing, accounting for up to 30% of general practitioner consultations in Europe (WHO, 2002). Overall, neuropsychiatric disorders have been estimated to represent 11.5% of
0924-977X/$ - see front matter D 2006 Elsevier B.V. and ECNP. All rights reserved. doi:10.1016/j.euroneuro.2006.06.002
Real-world antipsychotic therapy the global burden of disease, with schizophrenia, unipolar major depression, alcohol dependence, bipolar depression and obsessive-compulsive disorder among the 10 leading causes of disability worldwide. The incidence of schizophrenia itself is estimated at 1—2% and, unlike that of other mental disorders such as anxiety, is similar across different countries (WHO, 2002). Individuals with schizophrenia are at high risk of relapse, even with antipsychotic treatment, and studies have estimated that the risk of relapse is around 3.5% per month (Csernansky and Schuchart, 2002). In addition, schizophrenia is associated with a high degree of functional impairment. Notably, schizophrenia is associated with impaired cognitive function (Heinrichs and Zakzanis, 1998), which has been shown to have a substantial effect on daily functioning, including living autonomy, social competence and behavioural problems (Prouteau et al., 2005). As a result of the chronic, relapsing course of schizophrenia and the impairments in compliance, functioning and cognition, patients in real-life practice often behave differently to those in clinical trials. There is, therefore, a need to assess the benefits of long-term treatment outside the clinical trial setting. This review examines the evidence for the long-term efficacy of atypical antipsychotics within clinical trials and considers the many factors that can affect treatment outcomes in real-world clinical practice. Key studies that are being carried out to explore the full range of disease dimensions important in real-world clinical care are discussed.
S157 patients who received long-term treatment with aripiprazole (209 patients at 4 years). Effectiveness measures used in this study include the Positive and Negative Symptom Scale (PANSS) and the CGI-S scale. Improvement in PANSS score was observed at each timepoint, with continuous improvement over time. The recently proposed criteria for remission in schizophrenia (Andreasen et al., 2005) was reached by 334 of 442 patients (70%) who had previously completed 1 year of blinded treatment with aripiprazole. Over the course of long-term treatment, there was no evidence of increased serum total cholesterol or glucose levels, or prolonged QTc interval. Adverse events occurring during long-term treatment were similar to those previously reported in studies of aripiprazole (Carson et al., 2005 [Abstract]). While highly promising, these clinical trial results cannot fully predict the effects of atypical antipsychotics in reallife clinical practice, because a wide range of factors relating to the patient, their medication and their environment can have a substantial impact on treatment outcomes.
3. Factors affecting treatment outcomes Many of the factors that can play a role in determining outcomes are inter-related. For example, adverse effects of treatment can lead to a deterioration in subjective wellbeing, while patients’ relationships with physicians and nurses can play an important role in determining their attitude towards their condition and their medication.
2. The value of long-term antipsychotic treatment
3.1. Patients’ attitudes to medication
In the majority of patients, schizophrenia is a life-long condition requiring long-term antipsychotic treatment for control of symptoms and maintenance of functioning. Data are now available from open-label extension studies showing long-term symptomatic improvements lasting up to 4—5 years. Kasper et al. (2004) combined data from four open-label extension studies of quetiapine, following 674 patients with schizophrenia for up to a total of 4 years. The effectiveness of treatment was assessed using a number of rating scales, including the Brief Psychiatric Rating Scale (BPRS), the Clinical Global Impression-Severity of Illness (CGI-S) scale and the Scale for Assessment of Negative Symptoms (SANS). At each timepoint, the changes from baseline on each effectiveness measure were statistically significant ( p V 0.01). The greatest improvement occurred over the first 13 weeks of the study, with slower, consistent changes over weeks 14—78 and maintenance of effectiveness thereafter, although the authors do note that the proportion of evaluable patients after week 78 had decreased to around 10%. This is an important point, as treatment continuation in clinical practice is often a limiting factor. Treatment-related adverse events occurred in 38% of patients and the most common events (somnolence, postural hypotension and dizziness) were generally nervous system-related (Kasper et al., 2004). Carson et al. (2005 [Abstract]) recently presented pooled data from open-label extension studies involving 639
The attitude of an individual patient towards their medication can play an important role in treatment, particularly with regard to medication adherence. The attitudes of patients (n = 228) with psychosis towards antipsychotic medication were assessed by Day et al. (2005), who created a model to determine the relationships between patient attitudes and clinical and service variables. Parameters assessed included psychotic symptoms, antipsychotic side effects, attitudes towards medication (including the Drug Attitude Inventory [DAI] and Van Putten Dysphoria Scale), medication knowledge, insight (Birchwood Insight Scale), patients’ perceptions of expression of emotion by medical staff, the therapeutic alliance (California Pharmacotherapy Alliance Scale) and the admission procedure. Patients’ attitudes to medication were highly correlated both with insight (r = 0.54) and positive relationships with staff (r = 0.43). Using the information gained from the correlations, the authors constructed a best fit model that included admission experience, insight, relationship with staff and medication knowledge (Day et al., 2005). They concluded, therefore, that the quality of patients’ relationships with clinicians during acute admissions is critical in determining their attitudes towards their medication and their adherence to treatment. The latter is particularly important in real-world practice, as clinical studies can often incorrectly estimate the true level of medication non-adherence in the wider patient population.
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3.2. Subjective well-being While control of symptoms is undoubtedly important in determining a patient’s overall health, a number of studies have shown that patients’ subjective well-being does not necessarily correlate with treatment effectiveness. In a randomised, double-blind study of olanzapine versus clozapine in 114 patients with schizophrenia, both treatments improved PANSS and BPRS scores over 26 weeks of treatment (Naber et al., 2005). In addition, subjective well-being (Subjective Well-being under Neuroleptic treatment [SWN]) and quality of life (Munich Life Dimension List [MLDL]) also improved in both groups. Changes in SWN score were, however, only moderately correlated with improvement in PANSS score, while MLDL scores showed no correlation with improvement in PANSS scores. The authors conclude therefore that assessments of subjective well-being provide important information about patients’ health that cannot be gained from symptomatic measures (Naber et al., 2005). Importantly, studies have shown that treatment with atypical antipsychotics can lead to a high level of satisfaction with medication, subjective well-being and healthrelated quality of life (McGrath and Tempier, 2005), in addition to their widely reported benefits in terms of positive and negative symptom control. When treating patients with schizophrenia, it is therefore important that quality of life is assessed directly using appropriate instruments, as patient well-being cannot be assumed from measurements of effectiveness.
3.3. Adverse events Drug side effects can modify study-determined outcomes, particularly effectiveness, in everyday practice. Adverse events related to antipsychotic medication can also have important effects on patients’ attitudes to their medication, and may also affect daily functioning and long-term health. Motor symptoms in particular are highly unpleasant and are
P. Gorwood associated with fear, pain, severe suffering and stigma, while antipsychotics may also be responsible for subjective effects such as anhedonia or dysphoria (Naber and Karow, 2001). Sedation is a common adverse event during antipsychotic therapy and has been shown to have a significant negative impact on patients’ satisfaction with medication, as determined by the drug attitude inventory ( p = 0.002) (Hofer et al., 2002). Patients experiencing sedation as an adverse effect were also significantly more likely to believe that they did not need medication if they felt that they were asymptomatic ( p = 0.03) (Hofer et al., 2002). Thus, sedation may have a negative effect on adherence, leading to a reduction in the amount of medication received. In the longterm, sedation and associated reductions in treatment adherence may also affect social functioning, ability to work and participation in psychosocial training and rehabilitation programmes and, particularly in older patients, may increase the risk of falls and other accidents (Miller, 2004). Recently, attention has focused on the potential for atypical antipsychotics to induce symptoms of metabolic syndrome, including weight gain and insulin resistance. For example, many antipsychotics, notably olanzapine and clozapine, lead to substantial increases in body weight, while others such as ziprasidone, aripiprazole or fluphenazine are associated with little or no weight change (Allison et al., 1999; Marder et al., 2003). Issues relating to the metabolic syndrome and antipsychotic treatment are reviewed in detail by Haupt in this supplement (Haupt, 2006). In everyday practice, weight gain may have important effects on patients’ quality of life and may also affect functioning. Patients who feel that their medication is causing them to gain weight may also be at increased risk of non-adherence with their medication regimen.
3.4. Cognitive function Many patients with schizophrenia experience some form of cognitive impairment, and estimates of the prevalence of
Figure 1 Change in cognitive function in patients with schizophrenia (n = 77) switched from conventional to atypical antipsychotics and following the subsequent discontinuation of anticholinergics. Cognitive function was measured by the change in the percentage of correct answers given on the 6-Digit neutral test score to assess immediate memory (Mori et al., 2004).
Real-world antipsychotic therapy neurocognitive deficits vary from 40% to 78% (Peuskens et al., 2005). Studies have shown that, although impairments in memory, particularly working memory, and processing speed may be more pronounced compared with those in verbal comprehension and perceptual organisation, a generalised cognitive deficit can be considered as a core feature of schizophrenia (Dickinson et al., 2004). Treatment with the newer antipsychotics has been shown in numerous studies to improve cognitive function in patients with schizophrenia (Peuskens et al., 2005). This may be related to direct effects on cerebral functioning, but may also be a result of the improved efficacy and safety profile of the atypical agents and reduced need for concomitant medications that may affect cognition (Peuskens et al., 2005). For example, a study by Mori et al. (2004) examined the effects of switching from a conventional antipsychotic to one of four atypical agents, combined with a reduction in anticholinergic (anti-Parkinsonian) medication. This was associated with significant improvements in immediate and working memory in patients switched to olanzapine or risperidone (Fig. 1), while risperidone was also associated with improvements in verbal memory. Based on results with quetiapine and perospirone, the authors caution against concomitant prescription of quetiapine and anticholinergic agents, while anticholinergic withdrawal in patients receiving perospirone was associated with a deterioration in immediate memory (Mori et al., 2004). Cognitive dysfunction has an important impact on outcomes in schizophrenia, and up to 60% of the variance in functional outcomes can be explained by neurocognitive deficits; deficits in working memory, in particular, are an important predictor of social reintegration and tendency to relapse (Peuskens et al., 2005).
4. The challenges of assessing dreal-worldT effectiveness Evaluation of the efficacy and tolerability of antipsychotics in controlled clinical trials is, of course, a critical part of the development of new agents. Results from such studies are not, however, the only data that are required for a thorough evaluation. As discussed above, a large number of variables can affect patients’ responses to antipsychotic therapy, and it is extremely difficult, if not impossible, to account for all of these in randomised, double-blind, clinical studies. The problem is compounded by the fact that patients with schizophrenia enrolled into clinical trials are not representative of the wide range of patient and disease types seen in clinical practice. Patients with comorbidities, such as social anxiety disorder, panic disorder and other anxiety disorders, are generally excluded from clinical trials, although these patients may have been enrolled in studies in the past, when the diagnostic criteria used were less well developed (Stahl, 2001). A list of patient types who are often excluded from clinical trials is given in Table 1. A study of the reasons for selective sampling of patients with schizophrenia in clinical trials was carried out by Hofer et al. (2000), who included 200 consecutive patients admitted to inpatient psychiatric units over a 33-month period. Of these patients, 27 were recruited for a clinical trial; on average, these patients were younger, with a more recent onset of illness and fewer
S159 Table 1 Patient types who are often excluded from clinical studies of antipsychotic therapy (Stahl, 2001) Conditions/demographic variables Depression and psychosis Bipolar disorder Suicidal patients Comorbid medical illness Concomitant medication use Known resistance to antipsychotic medication Illness too severe to provide consent History of drug or alcohol abuse, or comorbid substance abuse Children and adolescents Women receiving oestrogen replacement therapy Some ethnic groups
previous psychotic episodes. Overall, the most common reasons for not including otherwise eligible patients in a clinical trial were non-compliance with previous treatment and refusal of consent (Hofer et al., 2000). A high level of refusal to participate in a placebo-controlled trial was also found in a cross-sectional study by Hummer and colleagues (2003), who interviewed 100 patients with schizophrenia using a questionnaire designed to assess attitudes towards participation in placebo-controlled trials. They found that 56% of patients would be unwilling to participate in such a study, for reasons including a fear of deterioration if given a placebo. Nevertheless, only 16% of patients were against clinical trials in principle, and 76% of patients stated that being asked to participate in a study would not affect their trust in their physician (Hummer et al., 2003). Real-world studies, in which there is no interruption to treatment, may therefore be more acceptable to patients, leading to greater enrolment and thus increasing the value of such studies to refining psychiatric practice.
5. Naturalistic studies An important supplement to controlled clinical trials are naturalistic studies, which have a number of important advantages, including the ability to enrol a wide range of patients and to focus on real-life outcome measures, such as relapse, re-hospitalisation rates and treatment continuation. Apart from these clear advantages, it is important to bear in mind that observational, naturalistic open studies also have a set of limitations, such as potential treatment selection bias, larger impact of different confusing factors, such as co-prescription or associated psychotherapy, and absence of control of the placebo effect. The CATIE (Clinical Antipsychotic Trials of Intervention Effectiveness) study, conducted by the US National Institutes of Mental Health, assessed the effectiveness of atypical antipsychotics in comparison with perphenazine (Lieberman et al., 2005). Patients (n = 1493) were initially randomised to perphenazine, olanzapine, quetiapine or risperidone for up to 18 months. Overall, 74% of patients discontinued treatment within 18 months, ranging from 64% in the olanzapine group to 82% in the quetiapine group. Rates of discontinuation because of side effects were similar across the groups, although weight gain and metabolic effects were
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P. Gorwood
Figure 2 Percentage of patients with schizophrenia (n = 833) rated as very much improved or much improved on the Clinical Global Impression-Improvement (CGI-I) scale after 8 weeks of aripiprazole treatment (n = 680), compared with standard of care (SOC) treatment (n = 153) with other antipsychotic agents in the Broad Effectiveness Trial with Aripiprazole (BETA) in Europe (Beuzen et al., 2006). OC = observed case, LOCF = last observation carried forward.
more common in the olanzapine group, while perphenazine was associated with more discontinuations as a result of extrapyramidal symptoms (Lieberman et al., 2005). Patients who discontinued medication in the initial phase of the CATIE study will be eligible for future phases in which patients will be randomised to ziprasidone, clozapine or any atypical agent they did not receive in the initial phase (Stroup et al., 2003). This will be followed by an open-label extension phase in which clinicians and patients will select medication based on the results of the earlier phases. The SOHO (Schizophrenia Outpatient Health Outcomes) study is a 3-year, prospective, open-label, observational study to assess health outcomes in over 10,000 European patients with schizophrenia who were enrolled at the time of initiating or changing their antipsychotic medication (Haro et al., 2005). Treatment decisions were made by the investigators independently of the study, and data collection occurred within the normal course of therapy. Outcome measures included the CGI schizophrenia (CGI-SCH) scale and the EuroQoL-5 Dimensions quality of life instrument. At baseline, approximately half of the patients were prescribed olanzapine, while those receiving clozapine or combination antipsychotics tended to be younger, and to have more severe illness with a lower level of social functioning. After 6
Figure 3
months of treatment, CGI-SCH and quality of life scores improved in all treatment cohorts, notably in patients receiving clozapine or olanzapine (Haro et al., 2005). After 12 months, CGI-SCH scores were analysed in patients who remained on olanzapine, risperidone, quetiapine or haloperidol monotherapy (Dossenbach et al., 2005). The results showed that, after 12 months of treatment, olanzapine- and risperidone-treated patients had a significantly greater response rate than those receiving haloperidol ( p b 0.001), and olanzapine-treated patients also had significantly lower rate of relapse ( p b 0.001). Thus, atypical antipsychotics offer the potential to improve response rates and reduce relapse rates in real-world clinical practice. To evaluate the overall effectiveness of aripiprazole, the BETA (Broad Effectiveness Trial with Aripiprazole) study has been established in Europe (Beuzen et al., 2006). In total, 833 patients with schizophrenia who required initiation or switching of antipsychotic medication were enrolled. Patients were randomised 4:1 to receive aripiprazole or standard of care for 8 weeks, and the primary endpoint was the score on the CGI-Global Improvement (CGI-I) scale. Over the course of the studies, patients receiving aripiprazole achieved continual improvement as assessed by CGI-I, with a greater proportion of responders (i.e. patients scoring 1
Risk of re-hospitalisation in antipsychotic-treated patients with schizophrenia (Carrigan et al., 2005 [Abstract]).
Real-world antipsychotic therapy [bvery much improvedQ] or 2 [bmuch improvedQ] on the CGI-I) than with other antipsychotic agents (Fig. 2). After 8 weeks, more patients receiving aripiprazole rated their medication as bmuch betterQ than their previous antipsychotic (Beuzen et al., 2006).
6. Database analyses An alternative to naturalistic studies is the use of large-scale patient databases, which allow retrospective analysis of a wide range of parameters, particularly those relating to outcomes such as hospitalisation. Olfson et al. (2005 [Abstract]) used a large managed care database to assess treatment discontinuation rates among patients with schizophrenia, with a 3-year enrolment period. Their results showed that the hazard ratios for discontinuation with atypical agents were significantly lower when compared with conventional agents ( p V 0.037). Of all the agents prescribed, aripiprazole was associated with the lowest rate of discontinuation and the longest mean time to discontinuation compared with conventional agents (Olfson et al., 2005 [Abstract]). Further analysis of the database, involving 576 patients receiving antipsychotic monotherapy, showed that atypical agents were associated with lower rates of rehospitalisation than conventional agents (Fig. 3) (Carrigan et al., 2005 [Abstract]). Results for aripiprazole (71% risk reduction) and olanzapine (57% risk reduction) were statistically significantly better compared with conventional agents, while those for risperidone, quetiapine and ziprasidone did not achieve significance. Thus, these analyses of large numbers of patients can confirm results seen in smaller studies, while also providing information that may not otherwise be obtained.
7. Conclusion Randomised, double-bind, placebo-controlled studies of atypical antipsychotic agents have provided invaluable evidence of the efficacy and tolerability of these drugs, and long-term extension data covering up to 4 years of treatment are now becoming available. There are many variables that affect patients’ responses to treatment, however, and clinical trials often enrol a highly selective patient cohort that is not representative of the wider population of patients with schizophrenia. Naturalistic studies and database analyses provide an important means of gathering data on patients in real-world settings and are a key part of the evaluation of any new antipsychotic agent.
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S162 McGrath, B.M., Tempier, R.P., 2005. Patients’ opinions of olanzapine and risperidone following long-term treatment: results from a cross-sectional survey. Pharmacopsychiatry 38, 147 – 157. Miller, D., 2004. Atypical antipsychotics: sleep, sedation, and efficacy. Prim. Care Companion J. Clin. Psychiat. 6, 3 – 7. Mori, K., Nagao, M., Yamashita, H., Morinobu, S., Yamawaki, S., 2004. Effect of switching to atypical antipsychotics on memory in patients with chronic schizophrenia. Prog. Neuropsychopharmacol. Biol. Psychiatry 28, 659 – 665. Naber, D., Karow, A., 2001. Good tolerability equals good results: the patient’s perspective. Eur. Neuropsychopharmacol. 11 (Suppl 4), S391 – S396. Naber, D., Riedel, M., Klimke, A., Vorbach, E.U., Lambert, M., Kuhn, K.U., Bender, S., Bandelow, B., Lemmer, W., Moritz, S., Dittmann, R.W., 2005. Randomized double blind comparison of olanzapine vs. clozapine on subjective well-being and clinical outcome in patients with schizophrenia. Acta Psychiatr. Scand. 111, 106 – 115. Olfson, M., Carrigan, G., Corey-Lisle, P., Cislo, P., Ray, S., 2005. Discontinuation rates among treated schizophrenia patients in managed care. Abstract Presented at the 158th Annual Meeting
P. Gorwood of the American Psychiatric Association, Atlanta, GA. (http:// www.psych.org/public_info/libr_publ/abstracts.cfm accessed 12 May 2006). Peuskens, J., Demily, C., Thibaut, F., 2005. Treatment of cognitive dysfunction in schizophrenia. Clin. Ther. 27 (Suppl A), S25 – S37. Prouteau, A., Verdoux, H., Briand, C., Lesage, A., Lalonde, P., Nicole, L., Reinharz, D., Stip, E., 2005. Cognitive predictors of psychosocial functioning outcome in schizophrenia: a follow-up study of subjects participating in a rehabilitation program. Schizophr. Res. 77, 343 – 353. Stahl, S.M., 2001. Does evidence from clinical trials in psychopharmacology apply in clinical practice? J. Clin. Psychiatry 62, 6 – 7. Stroup, T.S., McEvoy, J.P., Swartz, M.S., Byerly, M.J., Glick, I.D., Canive, J.M., McGee, M.F., Simpson, G.M., Stevens, M.C., Lieberman, J.A., 2003. The National Institute of Mental Health Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) project: schizophrenia trial design and protocol development. Schizophr. Bull. 29, 15 – 31. WHO, 2002. World Health Organization Regional Office for Europe, Copenhagen, Denmark.
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Meeting everyday challenges: Antipsychotic therapy in the real world Philip Gorwood * AP-HP, Hopital Louis Mourier, Colombes, France INSERM U675, Faculty Paris VII, France
KEYWORDS Schizophrenia; Naturalistic; Atypical antipsychotics; Outcomes
Abstract Patients with schizophrenia and their physicians face a number of challenges, such as long-term control of symptoms, maintaining cognitive function and subjective well-being, and preventing relapse. While randomised, placebo-controlled trials and open-label extensions can provide valuable information about the long-term efficacy and tolerability of newer antipsychotic agents, they cannot address all the variables that may affect treatment outcome. Factors such as cognitive function, antipsychotic side effects, patients’ attitudes to medication and subjective well being can all affect the results of treatment in real-life clinical practice. Moreover, the patient cohorts enrolled in clinical trials are often not reflective of the wider population with schizophrenia. For example, patients with conditions such as anxiety and panic disorders or comorbid substance abuse, as well as those with severe illness and patients from certain ethnic or age groups, may often be excluded from clinical trials. In addition, patients themselves may refuse to participate in placebo-controlled studies because of a fear of being under-treated. Naturalistic studies are, therefore, an important means of providing additional data on the safety and effectiveness of antipsychotic agents in dreal-worldT settings. Studies such as the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) study, the Schizophrenia Outpatient Health Outcomes (SOHO) study and the Broad Effectiveness Trial with Aripiprazole (BETA) studies, together with large-scale database analyses, are now producing results supplementary to those observed in long-term, open-label extension studies. Such naturalistic studies will continue to provide important data on the real-world effectiveness of atypical antipsychotics with respect to key outcomes such as treatment continuation and prolonged recovery. D 2006 Elsevier B.V. and ECNP. All rights reserved.
1. Introduction * Hospital Louis Mourier (AP-HP, Paris VII), INSERM U675, 178 rue des Renouillers, 92701 Colombes Cedex, France. Tel.: +33 1 47 60 64 15; fax: +33 1 47 60 67 40. E-mail address: [email protected].
The incidence of mental health problems is currently increasing, accounting for up to 30% of general practitioner consultations in Europe (WHO, 2002). Overall, neuropsychiatric disorders have been estimated to represent 11.5% of
0924-977X/$ - see front matter D 2006 Elsevier B.V. and ECNP. All rights reserved. doi:10.1016/j.euroneuro.2006.06.002
Real-world antipsychotic therapy the global burden of disease, with schizophrenia, unipolar major depression, alcohol dependence, bipolar depression and obsessive-compulsive disorder among the 10 leading causes of disability worldwide. The incidence of schizophrenia itself is estimated at 1—2% and, unlike that of other mental disorders such as anxiety, is similar across different countries (WHO, 2002). Individuals with schizophrenia are at high risk of relapse, even with antipsychotic treatment, and studies have estimated that the risk of relapse is around 3.5% per month (Csernansky and Schuchart, 2002). In addition, schizophrenia is associated with a high degree of functional impairment. Notably, schizophrenia is associated with impaired cognitive function (Heinrichs and Zakzanis, 1998), which has been shown to have a substantial effect on daily functioning, including living autonomy, social competence and behavioural problems (Prouteau et al., 2005). As a result of the chronic, relapsing course of schizophrenia and the impairments in compliance, functioning and cognition, patients in real-life practice often behave differently to those in clinical trials. There is, therefore, a need to assess the benefits of long-term treatment outside the clinical trial setting. This review examines the evidence for the long-term efficacy of atypical antipsychotics within clinical trials and considers the many factors that can affect treatment outcomes in real-world clinical practice. Key studies that are being carried out to explore the full range of disease dimensions important in real-world clinical care are discussed.
S157 patients who received long-term treatment with aripiprazole (209 patients at 4 years). Effectiveness measures used in this study include the Positive and Negative Symptom Scale (PANSS) and the CGI-S scale. Improvement in PANSS score was observed at each timepoint, with continuous improvement over time. The recently proposed criteria for remission in schizophrenia (Andreasen et al., 2005) was reached by 334 of 442 patients (70%) who had previously completed 1 year of blinded treatment with aripiprazole. Over the course of long-term treatment, there was no evidence of increased serum total cholesterol or glucose levels, or prolonged QTc interval. Adverse events occurring during long-term treatment were similar to those previously reported in studies of aripiprazole (Carson et al., 2005 [Abstract]). While highly promising, these clinical trial results cannot fully predict the effects of atypical antipsychotics in reallife clinical practice, because a wide range of factors relating to the patient, their medication and their environment can have a substantial impact on treatment outcomes.
3. Factors affecting treatment outcomes Many of the factors that can play a role in determining outcomes are inter-related. For example, adverse effects of treatment can lead to a deterioration in subjective wellbeing, while patients’ relationships with physicians and nurses can play an important role in determining their attitude towards their condition and their medication.
2. The value of long-term antipsychotic treatment
3.1. Patients’ attitudes to medication
In the majority of patients, schizophrenia is a life-long condition requiring long-term antipsychotic treatment for control of symptoms and maintenance of functioning. Data are now available from open-label extension studies showing long-term symptomatic improvements lasting up to 4—5 years. Kasper et al. (2004) combined data from four open-label extension studies of quetiapine, following 674 patients with schizophrenia for up to a total of 4 years. The effectiveness of treatment was assessed using a number of rating scales, including the Brief Psychiatric Rating Scale (BPRS), the Clinical Global Impression-Severity of Illness (CGI-S) scale and the Scale for Assessment of Negative Symptoms (SANS). At each timepoint, the changes from baseline on each effectiveness measure were statistically significant ( p V 0.01). The greatest improvement occurred over the first 13 weeks of the study, with slower, consistent changes over weeks 14—78 and maintenance of effectiveness thereafter, although the authors do note that the proportion of evaluable patients after week 78 had decreased to around 10%. This is an important point, as treatment continuation in clinical practice is often a limiting factor. Treatment-related adverse events occurred in 38% of patients and the most common events (somnolence, postural hypotension and dizziness) were generally nervous system-related (Kasper et al., 2004). Carson et al. (2005 [Abstract]) recently presented pooled data from open-label extension studies involving 639
The attitude of an individual patient towards their medication can play an important role in treatment, particularly with regard to medication adherence. The attitudes of patients (n = 228) with psychosis towards antipsychotic medication were assessed by Day et al. (2005), who created a model to determine the relationships between patient attitudes and clinical and service variables. Parameters assessed included psychotic symptoms, antipsychotic side effects, attitudes towards medication (including the Drug Attitude Inventory [DAI] and Van Putten Dysphoria Scale), medication knowledge, insight (Birchwood Insight Scale), patients’ perceptions of expression of emotion by medical staff, the therapeutic alliance (California Pharmacotherapy Alliance Scale) and the admission procedure. Patients’ attitudes to medication were highly correlated both with insight (r = 0.54) and positive relationships with staff (r = 0.43). Using the information gained from the correlations, the authors constructed a best fit model that included admission experience, insight, relationship with staff and medication knowledge (Day et al., 2005). They concluded, therefore, that the quality of patients’ relationships with clinicians during acute admissions is critical in determining their attitudes towards their medication and their adherence to treatment. The latter is particularly important in real-world practice, as clinical studies can often incorrectly estimate the true level of medication non-adherence in the wider patient population.
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3.2. Subjective well-being While control of symptoms is undoubtedly important in determining a patient’s overall health, a number of studies have shown that patients’ subjective well-being does not necessarily correlate with treatment effectiveness. In a randomised, double-blind study of olanzapine versus clozapine in 114 patients with schizophrenia, both treatments improved PANSS and BPRS scores over 26 weeks of treatment (Naber et al., 2005). In addition, subjective well-being (Subjective Well-being under Neuroleptic treatment [SWN]) and quality of life (Munich Life Dimension List [MLDL]) also improved in both groups. Changes in SWN score were, however, only moderately correlated with improvement in PANSS score, while MLDL scores showed no correlation with improvement in PANSS scores. The authors conclude therefore that assessments of subjective well-being provide important information about patients’ health that cannot be gained from symptomatic measures (Naber et al., 2005). Importantly, studies have shown that treatment with atypical antipsychotics can lead to a high level of satisfaction with medication, subjective well-being and healthrelated quality of life (McGrath and Tempier, 2005), in addition to their widely reported benefits in terms of positive and negative symptom control. When treating patients with schizophrenia, it is therefore important that quality of life is assessed directly using appropriate instruments, as patient well-being cannot be assumed from measurements of effectiveness.
3.3. Adverse events Drug side effects can modify study-determined outcomes, particularly effectiveness, in everyday practice. Adverse events related to antipsychotic medication can also have important effects on patients’ attitudes to their medication, and may also affect daily functioning and long-term health. Motor symptoms in particular are highly unpleasant and are
P. Gorwood associated with fear, pain, severe suffering and stigma, while antipsychotics may also be responsible for subjective effects such as anhedonia or dysphoria (Naber and Karow, 2001). Sedation is a common adverse event during antipsychotic therapy and has been shown to have a significant negative impact on patients’ satisfaction with medication, as determined by the drug attitude inventory ( p = 0.002) (Hofer et al., 2002). Patients experiencing sedation as an adverse effect were also significantly more likely to believe that they did not need medication if they felt that they were asymptomatic ( p = 0.03) (Hofer et al., 2002). Thus, sedation may have a negative effect on adherence, leading to a reduction in the amount of medication received. In the longterm, sedation and associated reductions in treatment adherence may also affect social functioning, ability to work and participation in psychosocial training and rehabilitation programmes and, particularly in older patients, may increase the risk of falls and other accidents (Miller, 2004). Recently, attention has focused on the potential for atypical antipsychotics to induce symptoms of metabolic syndrome, including weight gain and insulin resistance. For example, many antipsychotics, notably olanzapine and clozapine, lead to substantial increases in body weight, while others such as ziprasidone, aripiprazole or fluphenazine are associated with little or no weight change (Allison et al., 1999; Marder et al., 2003). Issues relating to the metabolic syndrome and antipsychotic treatment are reviewed in detail by Haupt in this supplement (Haupt, 2006). In everyday practice, weight gain may have important effects on patients’ quality of life and may also affect functioning. Patients who feel that their medication is causing them to gain weight may also be at increased risk of non-adherence with their medication regimen.
3.4. Cognitive function Many patients with schizophrenia experience some form of cognitive impairment, and estimates of the prevalence of
Figure 1 Change in cognitive function in patients with schizophrenia (n = 77) switched from conventional to atypical antipsychotics and following the subsequent discontinuation of anticholinergics. Cognitive function was measured by the change in the percentage of correct answers given on the 6-Digit neutral test score to assess immediate memory (Mori et al., 2004).
Real-world antipsychotic therapy neurocognitive deficits vary from 40% to 78% (Peuskens et al., 2005). Studies have shown that, although impairments in memory, particularly working memory, and processing speed may be more pronounced compared with those in verbal comprehension and perceptual organisation, a generalised cognitive deficit can be considered as a core feature of schizophrenia (Dickinson et al., 2004). Treatment with the newer antipsychotics has been shown in numerous studies to improve cognitive function in patients with schizophrenia (Peuskens et al., 2005). This may be related to direct effects on cerebral functioning, but may also be a result of the improved efficacy and safety profile of the atypical agents and reduced need for concomitant medications that may affect cognition (Peuskens et al., 2005). For example, a study by Mori et al. (2004) examined the effects of switching from a conventional antipsychotic to one of four atypical agents, combined with a reduction in anticholinergic (anti-Parkinsonian) medication. This was associated with significant improvements in immediate and working memory in patients switched to olanzapine or risperidone (Fig. 1), while risperidone was also associated with improvements in verbal memory. Based on results with quetiapine and perospirone, the authors caution against concomitant prescription of quetiapine and anticholinergic agents, while anticholinergic withdrawal in patients receiving perospirone was associated with a deterioration in immediate memory (Mori et al., 2004). Cognitive dysfunction has an important impact on outcomes in schizophrenia, and up to 60% of the variance in functional outcomes can be explained by neurocognitive deficits; deficits in working memory, in particular, are an important predictor of social reintegration and tendency to relapse (Peuskens et al., 2005).
4. The challenges of assessing dreal-worldT effectiveness Evaluation of the efficacy and tolerability of antipsychotics in controlled clinical trials is, of course, a critical part of the development of new agents. Results from such studies are not, however, the only data that are required for a thorough evaluation. As discussed above, a large number of variables can affect patients’ responses to antipsychotic therapy, and it is extremely difficult, if not impossible, to account for all of these in randomised, double-blind, clinical studies. The problem is compounded by the fact that patients with schizophrenia enrolled into clinical trials are not representative of the wide range of patient and disease types seen in clinical practice. Patients with comorbidities, such as social anxiety disorder, panic disorder and other anxiety disorders, are generally excluded from clinical trials, although these patients may have been enrolled in studies in the past, when the diagnostic criteria used were less well developed (Stahl, 2001). A list of patient types who are often excluded from clinical trials is given in Table 1. A study of the reasons for selective sampling of patients with schizophrenia in clinical trials was carried out by Hofer et al. (2000), who included 200 consecutive patients admitted to inpatient psychiatric units over a 33-month period. Of these patients, 27 were recruited for a clinical trial; on average, these patients were younger, with a more recent onset of illness and fewer
S159 Table 1 Patient types who are often excluded from clinical studies of antipsychotic therapy (Stahl, 2001) Conditions/demographic variables Depression and psychosis Bipolar disorder Suicidal patients Comorbid medical illness Concomitant medication use Known resistance to antipsychotic medication Illness too severe to provide consent History of drug or alcohol abuse, or comorbid substance abuse Children and adolescents Women receiving oestrogen replacement therapy Some ethnic groups
previous psychotic episodes. Overall, the most common reasons for not including otherwise eligible patients in a clinical trial were non-compliance with previous treatment and refusal of consent (Hofer et al., 2000). A high level of refusal to participate in a placebo-controlled trial was also found in a cross-sectional study by Hummer and colleagues (2003), who interviewed 100 patients with schizophrenia using a questionnaire designed to assess attitudes towards participation in placebo-controlled trials. They found that 56% of patients would be unwilling to participate in such a study, for reasons including a fear of deterioration if given a placebo. Nevertheless, only 16% of patients were against clinical trials in principle, and 76% of patients stated that being asked to participate in a study would not affect their trust in their physician (Hummer et al., 2003). Real-world studies, in which there is no interruption to treatment, may therefore be more acceptable to patients, leading to greater enrolment and thus increasing the value of such studies to refining psychiatric practice.
5. Naturalistic studies An important supplement to controlled clinical trials are naturalistic studies, which have a number of important advantages, including the ability to enrol a wide range of patients and to focus on real-life outcome measures, such as relapse, re-hospitalisation rates and treatment continuation. Apart from these clear advantages, it is important to bear in mind that observational, naturalistic open studies also have a set of limitations, such as potential treatment selection bias, larger impact of different confusing factors, such as co-prescription or associated psychotherapy, and absence of control of the placebo effect. The CATIE (Clinical Antipsychotic Trials of Intervention Effectiveness) study, conducted by the US National Institutes of Mental Health, assessed the effectiveness of atypical antipsychotics in comparison with perphenazine (Lieberman et al., 2005). Patients (n = 1493) were initially randomised to perphenazine, olanzapine, quetiapine or risperidone for up to 18 months. Overall, 74% of patients discontinued treatment within 18 months, ranging from 64% in the olanzapine group to 82% in the quetiapine group. Rates of discontinuation because of side effects were similar across the groups, although weight gain and metabolic effects were
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Figure 2 Percentage of patients with schizophrenia (n = 833) rated as very much improved or much improved on the Clinical Global Impression-Improvement (CGI-I) scale after 8 weeks of aripiprazole treatment (n = 680), compared with standard of care (SOC) treatment (n = 153) with other antipsychotic agents in the Broad Effectiveness Trial with Aripiprazole (BETA) in Europe (Beuzen et al., 2006). OC = observed case, LOCF = last observation carried forward.
more common in the olanzapine group, while perphenazine was associated with more discontinuations as a result of extrapyramidal symptoms (Lieberman et al., 2005). Patients who discontinued medication in the initial phase of the CATIE study will be eligible for future phases in which patients will be randomised to ziprasidone, clozapine or any atypical agent they did not receive in the initial phase (Stroup et al., 2003). This will be followed by an open-label extension phase in which clinicians and patients will select medication based on the results of the earlier phases. The SOHO (Schizophrenia Outpatient Health Outcomes) study is a 3-year, prospective, open-label, observational study to assess health outcomes in over 10,000 European patients with schizophrenia who were enrolled at the time of initiating or changing their antipsychotic medication (Haro et al., 2005). Treatment decisions were made by the investigators independently of the study, and data collection occurred within the normal course of therapy. Outcome measures included the CGI schizophrenia (CGI-SCH) scale and the EuroQoL-5 Dimensions quality of life instrument. At baseline, approximately half of the patients were prescribed olanzapine, while those receiving clozapine or combination antipsychotics tended to be younger, and to have more severe illness with a lower level of social functioning. After 6
Figure 3
months of treatment, CGI-SCH and quality of life scores improved in all treatment cohorts, notably in patients receiving clozapine or olanzapine (Haro et al., 2005). After 12 months, CGI-SCH scores were analysed in patients who remained on olanzapine, risperidone, quetiapine or haloperidol monotherapy (Dossenbach et al., 2005). The results showed that, after 12 months of treatment, olanzapine- and risperidone-treated patients had a significantly greater response rate than those receiving haloperidol ( p b 0.001), and olanzapine-treated patients also had significantly lower rate of relapse ( p b 0.001). Thus, atypical antipsychotics offer the potential to improve response rates and reduce relapse rates in real-world clinical practice. To evaluate the overall effectiveness of aripiprazole, the BETA (Broad Effectiveness Trial with Aripiprazole) study has been established in Europe (Beuzen et al., 2006). In total, 833 patients with schizophrenia who required initiation or switching of antipsychotic medication were enrolled. Patients were randomised 4:1 to receive aripiprazole or standard of care for 8 weeks, and the primary endpoint was the score on the CGI-Global Improvement (CGI-I) scale. Over the course of the studies, patients receiving aripiprazole achieved continual improvement as assessed by CGI-I, with a greater proportion of responders (i.e. patients scoring 1
Risk of re-hospitalisation in antipsychotic-treated patients with schizophrenia (Carrigan et al., 2005 [Abstract]).
Real-world antipsychotic therapy [bvery much improvedQ] or 2 [bmuch improvedQ] on the CGI-I) than with other antipsychotic agents (Fig. 2). After 8 weeks, more patients receiving aripiprazole rated their medication as bmuch betterQ than their previous antipsychotic (Beuzen et al., 2006).
6. Database analyses An alternative to naturalistic studies is the use of large-scale patient databases, which allow retrospective analysis of a wide range of parameters, particularly those relating to outcomes such as hospitalisation. Olfson et al. (2005 [Abstract]) used a large managed care database to assess treatment discontinuation rates among patients with schizophrenia, with a 3-year enrolment period. Their results showed that the hazard ratios for discontinuation with atypical agents were significantly lower when compared with conventional agents ( p V 0.037). Of all the agents prescribed, aripiprazole was associated with the lowest rate of discontinuation and the longest mean time to discontinuation compared with conventional agents (Olfson et al., 2005 [Abstract]). Further analysis of the database, involving 576 patients receiving antipsychotic monotherapy, showed that atypical agents were associated with lower rates of rehospitalisation than conventional agents (Fig. 3) (Carrigan et al., 2005 [Abstract]). Results for aripiprazole (71% risk reduction) and olanzapine (57% risk reduction) were statistically significantly better compared with conventional agents, while those for risperidone, quetiapine and ziprasidone did not achieve significance. Thus, these analyses of large numbers of patients can confirm results seen in smaller studies, while also providing information that may not otherwise be obtained.
7. Conclusion Randomised, double-bind, placebo-controlled studies of atypical antipsychotic agents have provided invaluable evidence of the efficacy and tolerability of these drugs, and long-term extension data covering up to 4 years of treatment are now becoming available. There are many variables that affect patients’ responses to treatment, however, and clinical trials often enrol a highly selective patient cohort that is not representative of the wider population of patients with schizophrenia. Naturalistic studies and database analyses provide an important means of gathering data on patients in real-world settings and are a key part of the evaluation of any new antipsychotic agent.
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