Costs and effects of paliperidone extended release compared with alternative oral antipsychotic agents in patients with schizophrenia in Greece: A cost effectiveness study
© Geitona et al; licensee BioMed Central Ltd. 2008
Received: 04 February 2008
Accepted: 28 August 2008
Published: 28 August 2008
To compare the costs and effects of paliperidone extended release (ER), a new pharmaceutical treatment for the management of schizophrenia, with the most frequently prescribed oral treatments in Greece (namely risperidone, olanzapine, quetiapine, aripiprazole and ziprasidone) over a 1-year time period.
A decision tree was developed and tailored to the specific circumstances of the Greek healthcare system. Therapeutic effectiveness was defined as the annual number of stable days and the clinical data was collected from international clinical trials and published sources. The study population was patients who suffer from schizophrenia with acute exacerbation. During a consensus panel of 10 psychiatrists and 6 health economists, data were collected on the clinical practice and medical resource utilisation. Unit costs were derived from public sources and official reimbursement tariffs. For the comparators official retail prices were used. Since a price had not yet been granted for paliperidone ER at the time of the study, the conservative assumption of including the average of the highest targeted European prices was used, overestimating the price of paliperidone ER in Greece. The study was conducted from the perspective of the National Healthcare System.
The data indicate that paliperidone ER might offer an increased number of stable days (272.5 compared to 272.2 for olanzapine, 265.5 f risperidone, 260.7 for quetiapine, 260.5 for ziprasidone and 258.6 for aripiprazole) with a lower cost compared to the other therapies examined (€7,030 compared to €7,034 for olanzapine, €7,082 for risperidone, €8,321 for quetiapine, €7,713 for ziprasidone and €7,807 for aripiprazole). During the sensitivity analysis, a ± 10% change in the duration and frequency of relapses and the economic parameters did not lead to significant changes in the results.
Treatment with paliperidone ER can lead to lower total cost and higher number of stable days in most of the cases examined.
Healthcare costs in developed countries attributed to schizophrenia account for 1.5–3% of total healthcare spending . Given the fact that the prevalence of the disease across populations is approximately 1.0% of the adult population, the economic burden of schizophrenia is significant, especially since it involves both healthcare and societal costs [1–6]. Although indirect non-medical costs dominate the financial burden of schizophrenia, since patients with schizophrenia usually are unable to find and keep paid employment, direct medical costs are comparable with other chronic conditions [7, 8].
Schizophrenia persists throughout life and does not distinguish between social classes . The usual age of onset is the late teens for men and mid-twenties to early thirties for women. However, this age may vary between puberty and 45 years . The illness is characterised by the occurrence of positive, negative and cognitive symptoms, and a definite cure for schizophrenia has not yet been found [11, 12]. Positive symptoms are associated with acute psychotic episodes, negative symptoms are linked to long-standing illness and cognitive symptoms are those that create a high degree of impairment in the everyday life of the patient . Patients with schizophrenia are known to have higher mortality rates than the general population that are most frequently associated with higher incidence of suicides and accidents and also with the physical and psychiatric comorbidities related to schizophrenia, such as cardiovascular disease, depression and anxiety . Only 20–30% of patients will experience full remission within 5 years of the first episode, 10–20% will never experience a remission and 60–70% will have further relapses [13, 14].
The therapeutic approach for symptoms of schizophrenia is mainly based around pharmaceutical treatment. Atypical antipsychotics could offer particular advantages over typical antipsychotics and more specifically have been found to control both positive and negative symptoms with lower incidence of side effects. However, there are still unmet therapeutic needs for more effective and tolerable pharmaceutical options, as was indicated in the first phase of the recent Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) study, in which only 26% of patients were still on their allocated medication at 18 months .
Paliperidone Extended Release (ER), a new oral atypical antipsychotic treatment registered in Europe and USA for the management of schizophrenia, has been shown to reduce the Positive and Negative Syndrome Scale (PANSS) total and subscales scores and was generally well tolerated by adults with schizophrenia, while improving their personal and social functioning, during the phase III trials [16–25]. The overall incidence of adverse events in the phase III trials was similar for the combined 3 mg/12 mg paliperidone ER groups (72%) and the olanzapine 10 mg/day group (69%) and the events were of mild to moderate severity [20–22]. During longer-term open-label treatment with paliperidone ER, <1% of subjects discontinued treatment due to extrapyramidal symptom (EPS)-related adverse events and only two patients experienced tardive dyskinesia [21–23]. It is believed that the improved tolerability is achieved through the use of the delivery system based on osmotic-controlled release oral delivery system (OROS) technology, that facilitates the avoidance of peaks and troughs in plasma concentration [26, 27]. It is also suggested that the once per day administration of paliperidone ER, the lack of the need of dose titration [16–25], the early realisation of the therapeutic effect that occurs at least by day 4 [21–23] and the continued improvement of patients could lead to improved compliance to treatment  and the prevention of relapses, and therefore potentially to treatment cost minimisation .
Literature on studies on economic evaluation comparing the cost and effectiveness of different treatments options in Greece is limited, however, one cost of illness study was identified . The scope of this study is to examine the cost effectiveness of paliperidone ER compared with alternative oral antipsychotic agents available in Greece.
The decision tree for the cost effectiveness evaluation incorporated different scenarios depending on the response of the patients to oral atypical antipsychotics and the experience of relapses (Figure 1). Patients enter the model at an acute exacerbation and they initiate treatment with an oral antipsychotic. Patients who respond at 6 weeks may either continue to 1 year or discontinue prior to the end of the year. Patients who continue either remain stable or experience a relapse. Patients who discontinue prior to the end of the year may switch to another oral atypical antipsychotic or discontinue antipsychotic medication altogether. If they discontinue antipsychotic medication altogether, they will suffer a relapse. If they switch, they may either respond or not respond to the second medication. Responders will either remain stable or experience a relapse. Non-responders are assumed to discontinue medication altogether and experience relapse.
The sub-tree emanating from the 'Discontinue paliperidone ER before 1-year' branch follows the ' [+]' symbol at the 'Discontinue paliperidone ER before 6 weeks' branch and the 'No Response at 6 weeks – Discontinue paliperidone ER' branch. Branches of the other five oral atypical antipsychotics are identical to the paliperidone ER.
The measure of effectiveness used in the study was the number of stable days (days with no symptoms). Due to the lack of national data on resource utilisation of schizophrenia, information was acquired from a 10-member expert panel of Greek psychiatrists and 6 health economists (a list of the participants is included in the acknowledgement section). The selection of the experts was based on the geographic distribution of the psychiatric units across Greece, covering more than 65% of all psychiatric beds in Greece, the representation of all types of public mental healthcare providers and the academic status of the experts and/or their managerial position in the relevant units.
The analysis was carried out under the perspective of the Greek National Health System (NHS) and therefore, only direct costs related to treatment of schizophrenia were considered in the model using the tariffs reimbursed by the Social Insurance Fund. Indirect costs, such as cost due to lost productivity of the patients and the caregivers and any non-reimbursed out of pocket payments by the patient were not included. The time course of the study was 1 year.
Placebo and atypical antipsychotic response rates of selected comparator trials
Definition of response
Placebo response rate (%)
Atypical response rate (%)
6 week study, patients with schizophrenia and acute exacerbation, olanzapine comparator
3, 6, 9, and 12
≥ 30% decrease in PANSS from baseline to study endpoint
4 week study, patients with schizophrenia or schizoaffective disorder and acute exacerbation, aripiprazole comparator
≥ 30% decrease in PANSS from baseline to study endpoint or CGI-I ≤ 2
6 week study, patients with schizophrenia and acute exacerbation, paliperidone ER comparator
≥ 30% decrease in PANSS from baseline to study endpoint
6 week study, inpatients with chronic or subchronic schizophrenia and acute exacerbation
≥ 30% decrease in BPRS at any time during treatment
6 week study, patients with schizophrenia or schizoaffective disorder and acute exacerbation
80 and 160
≥ 30% decrease in PANSS from baseline to study endpoint
4 week study, patients with schizophrenia or schizoaffective disorder and acute exacerbation, risperidone comparator
20 and 30
≥ 30% decrease in PANSS from baseline to study endpoint or CGI-I ≤ 2
Treated EPS and clinically significant weight gain (≥7% increase of body weight compared to baseline), which are frequent side effects of oral treatment were considered in the study. Other side effects, such as galactorrhea, amenorrhea, gynecomastia and impotence were excluded from the analysis since they lead to minor medical resource utilisation, as was indicated by the expert panel. Additionally, although these side effects have been reported with prolactin-elevating compounds, the clinical significance of elevated serum prolactin is unknown in asymptomatic patients . In an analysis by Conley and Mahmoud , raw clinical trial data from an 8-week, double-blind comparison of risperidone and olanzapine showed the incidence of moderate/severe symptoms potentially related to prolactin was 5.4% in the risperidone group and 2.2% in the olanzapine group . When these rates were implemented into a recently published economic model, the impact on 1-year outcomes was not significant .
The data used to populate the decision analytic model were primarily obtained from the published literature. The literature in the therapeutic area of schizophrenia is vast and growing rapidly, and was helpful in developing a solid and definitive model. Information that was not available in the literature was obtained from clinical expert opinion.
A literature search from 1997 to the present day was conducted by searching the Medline/PubMed databases to identify articles reporting response rates for the comparators. Since there were no trials directly comparing all of the treatment options, it was necessary to compare them through a common comparator (i.e. placebo). The search terms used in the PubMed search were 'schizophrenia' AND 'risperidone' OR 'olanzapine' OR 'quetiapine' OR 'ziprasidone' OR 'aripiprazole'. The search was limited to 'HUMAN' publications and 'CLINICAL TRIALS'. The criteria that were utilised in the selection of studies for comparator response rates included the following: included a placebo control arm, duration matched paliperidone ER data (approximately 6 weeks), evaluated the appropriate patient population (diagnosis of schizophrenia and experiencing acute exacerbation), used an adequate sample size, evaluated and reported response rates of patients, the definition of response rate matched paliperidone ER trial definition (≥30% decrease in PANSS score from baseline), and used appropriate dose of antipsychotic (dosing comparable to that seen in clinical practice and according to product labelling). The selected studies used are summarised in Table 1.
Through the literature search three double-blind, randomised, placebo-controlled published studies evaluating risperidone were identified [33–35], from which, Potkin et al. was selected as the source of response rate data, since its design and definition of response most closely resembled the paliperidone ER trials and it was the most recently conducted study . The first risperidone placebo-controlled trial had a sample size of only 36 patients randomised to either risperidone (n = 12), haloperidol (n = 12), or placebo (n = 12) and response was defined as 20% change in Brief Psychiatric Rating Scale (BPRS) from baseline . The second risperidone study had a large sample size but defined response as 20% change in PANSS from baseline .
For olanzapine, three multi-centre, double-blind, randomised, placebo controlled trials were identified. Only two of the trials reported the proportion of patients responding to treatment, defined however as threshold decreases in BPRS scores from baseline [36, 37]. Therefore, the data for olanzapine response from the paliperidone ER pivotal trials, in which olanzapine was included as an active control, was regarded suitable for this economic evaluation [21–23]. The response was defined as ≥30% decrease in PANSS score from baseline.
From the four identified quetiapine trials [38–41], the study that was selected was conducted by Arvanitis et al. . This study had an adequate sample size and utilised appropriate doses of quetiapine. Unfortunately, their definition of response was ≥30% decrease in BPRS from baseline and no alternative source was found. This was not considered ideal, since four of the six comparator response rates included in the analysis were based on changes in PANSS scores, but it was considered a reasonable approach since evidence has shown that the syndrome scale scores of the two instruments have been found to be highly correlated .
Ziprasidone has been studied in three multi-centre, double-blind, randomised, placebo-controlled trials [43–45]. Two of these trials were short-term studies and one was a long-term study. The Daniel et al. study was selected as the best source of response rate data for ziprasidone because the duration of this trial matched that of the paliperidone ER studies and the average dose of ziprasidone used in clinical practice .
Finally, Aripiprazole has been studied in three multi-centre, double-blind, randomised, placebo-controlled studies [35, 46, 47]. One of these trials included a haloperidol comparator arm, one trial included a risperidone comparator arm, and one only had a placebo control arm. The first two studies were short-term studies and the third study was a long-term study of efficacy and safety. The Potkin et al. study was selected as the source of response rate data for aripiprazole 20 and 30 mg/day because the design and definition of response most closely resembled the paliperidone ER trials, it was the most recently conducted study, and was the source of data for risperidone response rates . An overall response rate for aripiprazole was obtained by weighting the response rates at the two doses by the number of patients randomised to the two doses.
Since the placebo response rates amongst the six selected trials differed significantly (Table 1), they had to be normalised in order to compare response rates across atypical antipsychotic products. This, in turn, was done by subtracting the placebo response rate from the respective rate of each product (absolute response rate) and then adding the latter to the average (of all agents) placebo rate.
6-week discontinuation rate (%)
Responder 1-year discontinuation rate (%)
15.0 (assumed equal to risperidone and olanzapine)
26.7 (average of risperidone and olanzapine)
40.0 (assumed equal to quetiapine)
20.0 (assumed equal to ziprasidone)
40.0 (assumed equal to quetiapine)
Frequency and duration of relapses
Relapse requiring hospitalisation, weighted average (min, max)
Relapse not requiring hospitalisation, weighted average (min, max)
Lead to early discontinuation
1.20 (1, 2)
Lead to later discontinuation
1.20 (0, 2)
1.20 (1, 2)
Duration (mean, days)
Lead to early discontinuation
100.00 (80, 120)
90.00 (80, 110)
Lead to later discontinuation
60.00 (40, 80)
44.00 (34, 66)
Incidence rate of both clinically significant weight gain and extrapyramidal symptoms (EPS) on patients with antipsychotic treatment
% Patients experiencing clinically significant weight gain
% Patients experiencing EPS
Invega PI, Janssen-Cilag International NV Turnhoutseweg 30 BE-2340 Beerse Belgium
Risperdal PI, Janssen-Cilag Pharmaceutical SACI, Eirinis Avenue 56, 15121, Pefki, Athens, Greece
Zyprexa PI, Eli Lilly Nederland B.V., Grootslag 1–5, NL-3991 RA Houten, The Netherlands.
Seroquel PI, AstraZeneca Pharmaceuticals LP, Wilmington, DE 19850, USA
Geodon PI, Pfizer Hellas, Ltd, Mesogeion Avenue 243, 15451 Athens, Greece
Abilify PI, Otsuka Pharmaceutical Europe Ltd Hunton House Highbridge Business Park Oxford Road Uxbridge, Middlesex UB8 1HU United Kingdom
Assumed equal to ziprasidone
Market share of the alternative treatments
Resource utilisation data
Results from the consensus panel on resource utilization
Type of mental healthcare
Stable days (per month)
Relapse with hospitalization (per episode)
Relapse without hospitalization (per episode)
Extrapyramidal symptoms (per episode)
Weight increase (per episode)
Days of Hospitalisation
Visits to day hospital
Visits to Emergency room
Visits to mental health clinic
Hours of home care
Visits to social/group therapy
Visits to nutritionist
Daily antipsychotic costs
Average daily dose (mg/day)
Cost per day (€)
Mental healthcare unit costs (€)
Type of mental healthcare
Unit costs (€)
Hospitalisation (cost per day)
Day hospital visits
Emergency room visits
Mental health clinic visits
Hours of home care
Social/group therapy visits
Sensitivity analysis was conducted to test the robustness of the model, by examining the changes in the results when one parameter was allowed to vary at a time. The parameters that were associated with the highest degree of uncertainty in the present model were those derived from the expert panel, namely the frequency and duration of relapses, adverse events resource utilisation for stable days (weight gain and EPS). All the parameters were allowed to vary within a range of ± 10% from the base case scenario values.
Cost effectiveness results
Mean annual cost of treatment per patient (€)
Cost categories (€)
Emergency room visit
Outpatient physician visit
Outpatient mental health clinic visit
Home health care
Social/group therapy meeting
Other: (e.g. nutritionist visits)
Mean annual number of stable days and cost per patient by pharmaceutical treatment
Incremental cost and effectiveness compared with paliperidone ER:
Sensitivity analysis results
Sensitivity analysis confirmed the robustness of the model, as the results did not change significantly when allowing different parameters to vary.
Model results when frequency and duration of relapses are increased by 10%
+10% in frequency of relapses:
+10% in duration of relapses:
Model results when frequency and duration of relapses are decreased by 10%
-10% in frequency of relapses:
ICER (€/stable day)
-10% in duration of relapses:
ICER (€/stable day)
Another set of parameters tested were those referring to resource utilisation (days of hospitalisation, physician visits, emergency room visits etc). Similarly, ± 10% variation was allowed for patients in stable days, relapses (requiring hospitalisation and not) and the two types of adverse events (EPS and weight gain), but did not affect the number of stable days. Paliperidone ER proved to be the dominant strategy in all tests except in the case of a 10% increase in the resource utilisation of patients in stable days and 10% decrease in resource utilisation of relapses. In both cases paliperidone ER was ranked second after risperidone with a minimum additional cost (ICER of €0.8 per stable day and €2.5 per stable day, respectively).
The purpose of this study was to apply pharmacoeconomic modelling to the process of choosing a cost-effective oral treatment strategy for patients with schizophrenia in Greece. Within the 1-year time period, the results of the study indicated that paliperidone ER might be the least expensive treatment compared to risperidone, olanzapine, quetiapine, ziprasidone and aripiprazole, achieving at the same time the best clinical outcomes measured in number of stable days. The results held true when tested through a multitude of sensitivity analyses indicating the robustness of the model.
The economic analysis results showed a lower cost in hospitalisation and outpatient visits with treatment with paliperidone ER that could in turn attribute to the lower total annual cost. Patients with greater medication compliance have a decreased probability of suffering a relapse, which in turn reduces the likelihood of needing more intensive and costly treatment [28, 53]. A reduced rate and duration of hospitalisation could have a major impact on the total treatment cost, since hospitalisation is shown to be the largest contributor to the total healthcare cost of schizophrenia management [29, 54].
Despite the fact that the analysis was based on the best available clinical and economic data, there are some methodological limitations that should be considered. The choice of methodology was limited by the lack of long-term comparative data from clinical or observational studies and therefore, individual placebo-controlled studies of the comparators were used to derive comparative response rates. The availability of clinical studies directly comparing the treatment alternatives could serve as a more reliable source of data for our model. When such data are lacking, modelling techniques are appropriate for estimating costs and benefits of different modalities. In order to account for this limitation, a simple and transparent model was designed based on 'real world' conditions and scientifically sound published research data, as well as expert opinion.
The approach of collecting information by an expert panel has been frequently used before in economic evaluation studies [55–58], but could present potential areas of bias since the decisions may be reached by persuasion rather than consensus . Moreover, due to the diversity of disease management and the lack of databases reporting treatment patterns in Greece, the opinion of the expert panel could reflect the personal experience of the panellists. However, previous research has found that consensus panel decisions have a degree of consistency and validity when compared with clinical practice [58, 59]. The consensus panel was chosen to provide some of the information for this study, due to the lack of any alternative sources of information available in Greece.
Other possible limitations of the study that might influence the economic analysis results could be the lack of a societal perspective as only direct costs are taken into consideration and the use of EPS and weight gain as the only adverse events. In addition, since an official price for paliperidone ER was not available at the time of study conduction, the use of maximum allowed prices in EU may lead to an overestimation of the total treatment cost for paliperidone ER. Given that official pharmaceutical prices in Greece are defined by the average of the lowest prices in two EU15 countries and Switzerland and one in EU10 countries , the final cost of treatment could be expected to be lower. Finally, the hypothesised dose distribution for paliperidone ER that influence the final cost estimates would need to be confirmed once the product is in the market.
Over a 1-year period the use of paliperidone ER has been shown to result in better clinical outcomes for patients and lower total healthcare costs than the oral comparators considered in this study. Experience with paliperidone ER in the Greek marketplace would help in the accumulation of clinical outcomes and health economic evidence validating the results of the study. Future research efforts could focus on 'real-world' effectiveness data and the conduction of additional economic evaluation studies in Greece and other countries. This would enable data collection on clinical practice, definition of related treatment and economic outcomes and eventually cross-country comparisons. The findings of such studies could have clear relevance to both disease management and formulary decision making.
List of abbreviations
Brief Psychiatric Rating Scale
Clinical Antipsychotic Trials of Intervention Effectiveness
Clinical Global Impression – Improvement
Clinical Global Impression schizophrenia scale
incremental cost effectiveness ratio
National Health System (Greece)
Positive and Negative Syndrome Scale.
The authors would like to thank the members of the expert panel for their help in conducting this study: Nikiforos Aggelopoulos (Prof. of Psychiatry, University of Thessaly), Elias Aggelopoulos, (Assistant Prof. of Psychiatry, University of Athens), Alexandros Chaidemenos (Neurologist/Psychiatrist, Director of the 8th Clinic of Psychiatric Hospital of Athens), Theodosios Christodoulakis (Psychiatrist, Psychoanalyst, Director Of EOPS), Ioannis Diakogiannis (Assistant Prof. of Psychiatry, University of Thessaloniki), Vasiliki Karpouza (Psychiatrist, Psychiatric Hospital of Thessaloniki), Ioannis Kogeorgos (Assistant Prof of Psychiatry, Director of Psychiatric Unit of Agia Olga, Athens), George Kokkinakos (Psychiatrist, Director of Centre of Mental Health, Chania, Crete), Nikolaos Mpilanakis (Psychiatrist, Assistant Prof. University of Ioannina), Periklis Paterakis, (Psychiatrist, Director of Psychiatric Clinic, Dromokaitio Psychiatric Hospital, Athens). The authors also wish to recognise the contribution of Mr Efthimios Zouzoulas in the conduction of the analysis. Oral presentation of this work was made at the 3rd Panhellenic Congress on Health Management, Economics and Policies, Athens, Greece, 12–15 December 2007. The study results have not been previously published in a peer review journal. The study was supported by funding from Janssen-Cilag Pharmaceutical SACI.
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