Economic analysis of paliperidone long-acting injectable for chronic schizophrenia in Portugal

Abstract

Objective: Patients with chronic schizophrenia suffer a huge burden, as do their families/caregivers. Treating schizophrenia is costly for health systems. The European Medicines Agency has approved paliperidone palmitate (PP-LAI; Xeplion), an atypical antipsychotic depot; however, its pharmacoeconomic profile in Portugal is unknown. A cost-effectiveness analysis was conducted from the viewpoint of the Portuguese National Health Service.

Methods: PP-LAI was compared with long acting injectables risperidone (RIS-LAI) and haloperidol (HAL-LAI) and oral drugs (olanzapine; oral-OLZ) adapting a 1-year decision tree to Portugal, guided by local experts. Clinical information and costs were obtained from literature sources and published lists. Outcomes included relapses (both requiring and not requiring hospitalization) and quality-adjusted life-years (QALYs). Costs were expressed in 2014 euros. Economic outcomes were incremental cost-effectiveness ratios (ICERs); including cost-utility (outcome = QALYs) and cost-effectiveness analyses (outcomes = relapse/hospitalization/emergency room (ER) visit avoided).

Results: The base-case cost of oral-OLZ was 4447€ (20% drugs/20% medical/60% hospital); HAL-LAI cost 4474€ (13% drugs/13% medical/74% hospital); PP-LAI cost 5326€ (49% drugs/12% medical/39% hospital); RIS-LAI cost 6223€ (44% drugs/12% medical/44% hospital). Respective QALYs/hospitalizations/ER visits were oral-OLZ: 0.761/0.615/0.242; HAL-LAI: 0.758/0.623/0.250; PP-LAI: 0.823/0.288/0.122; RIS-LAI: 0.799/0.394/0.168. HAL-LAI was dominated by oral-OLZ and RIS-LAI by PP-LAI for all outcomes. The ICER of PP-LAI over oral-OLZ was 14,247€/QALY, well below NICE/Portuguese thresholds (≈24,800€/30,000€/QALY). ICERs were 1973€/relapse avoided and 2697€/hospitalization avoided. Analyses were robust against most variations in input values, as PP-LAI was cost-effective over oral-OLZ in >99% of 10,000 simulations.

Conclusion: In Portugal, PP-LAI dominated HAL-LAI and RIS-LAI and was cost-effective over oral-OLZ with respect to QALYs gained, relapses avoided, and hospitalizations avoided.

Keywords:

• Paliperidone palmitate
• Risperidone
• Schizophrenia
• Depot
• Long acting injectable
• Pharmacoeconomic analysis
• Cost-effectiveness
• Portugal

Introduction

The World Health Organization has listed schizophrenia among the top 10 causes of disability in the world and it is well known that health and social problems are worse in countries with lower GDP, such as Portugal^1,2. It exerts a tremendous negative impact on healthcare in terms of cost, service provision, and support systems^3,4. As well, the quality-of-life is substantially lower in patients with schizophrenia than in those without, and is highly correlated with psychopathology^5,6.

This disease has no known cure; many patients endure a chronic and erratic clinical path that often involves numerous psychotic relapses which can frequently result in hospital admission or incarceration⁷. Patients suffering from this form of schizophrenia have been referred to as “revolving door” patients due to their frequent hospitalizations⁸. Investigations have identified non-adherence to medication and lack of response to medication as the most common causes for this phenomenon^9,10. As a result, efforts have been made to find approaches to improve both adherence and response rates.

Two such innovations have been depot injections, also known as long-acting injectables (LAIs), and the development of atypical anti-psychotics. Depot forms help to decrease both intentional and unintentional non-adherence¹¹. Drugs of this type have been available for decades; however, until this century, only the “typical” anti-psychotics such as haloperidol (HAL-LAI) were available. The first atypical LAI was risperidone (RIS-LAI; Risperdal Consta)^12,13. The European Medicines Agency has also approved paliperidone palmitate (PP-LAI; Xeplion)^14,15 which has also been approved for reimbursement in Portugal.

RIS-LAI is administered every 2 weeks¹³, while PP-LAI may be injected monthly¹⁵. This difference may have implications for the cost of patient management, since administration interval may affect adherence. Currently, it is not known whether clinical differences reflect economic differences in actual practice. Thus, the pharmacoeconomics of these drugs for treating “revolving door” patients have not been established in Portugal. Therefore, we undertook the present investigation.

The primary goal of this research was to determine the cost-effectiveness of PP-LAI as compared with other commonly used treatments for such patients, including RIS-LAI, HAL-LAI and oral anti-psychotics. Secondary goals were to determine the cost-effectiveness of these dug in preventing relapses of the symptoms of schizophrenia.

Methods

This pharmacoeconomic analysis was conducted according to the Portuguese Medicines Agency guidelines for economic drug evaluation studies¹⁶. We adapted a decision tree that had been previously validated and used in another European country¹⁷ for use in the Portuguese National Health Service (PNHS). The population of interest was the group of “revolving door” patients with schizophrenia. The term “revolving door” refers to patients who had longstanding disease with multiple recurrences of psychoses and hospitalizations⁸. A more recent paper defines them as “frequently admitted patients undergoing one or more admissions per year on average”¹⁸. Because these patients adhere poorly to both appointments and medication regimens, they are frequently prescribed LAIs. The atypical drugs compared in this analysis were RIS-LAI and PP-LAI. We used haloperidol decanoate (HAL-LAI) to represent the traditional depots, as it is the most widely used traditional LAI in Portugal and systematic reviews have found little clinical difference among the available traditional depots¹⁹. Also, we included one oral drug to represent all orals, olanzapine (oral-OLZ), as it is commonly used. Table 1 provides a summary of the doses used and sources for that information^{12,13,15,19–38}.

Table 1. Doses used to treat patients and data sources.

Reason for administration	Treatment	Dosing regimen	Source
Maintenance of stable schizophrenia	PP-LAI	69.3 mg monthly	Average of Gopal et al.^37, Fleischhacker et al.^21
	RIS-LAI	40.3 mg every 2 weeks	Average of Fleischhacker et al.^21, Kissling et al.^22, Lee et al.^23, Olivares et al.^24, Lindenmayer et al.^25
	HAL-LAI	122 mg monthly (55% every 4 weeks, 45% every 2 weeks)	Weighted average from 11 clinical trials reported by Adams et al.^19 and Quraishi et al.^26
	oral-OLZ	15.8 mg daily	Weighted average from 12 head-to-head trials reported by Komossa et al.^27
Treatment of relapsed outpatient	PP-LAI	84.9 mg monthly	Average of Gopal et al.^37, Pandina et al.^28, Hough et al.^29, Nasrallah et al.^30, Pandina et al.^31
	RIS-LAI	50 mg every 2 weeks*	Risperdal Consta summary of product characteristics^13
	HAL-LAI	150 mg per 4 weeks administered every 1–3 weeks	Pro-rated from PP-LAI dose
	oral-OLZ	15.9 mg daily	Average of 15 head-to-head trials from Komossa et al.^27, Jayaram et al.^32 and Lieberman et al.^33
Treatment of hospitalized patient	PP-LAI	150 mg week 1, 100 mg week 2, then 82.8 mg every 4 weeks’ maintenance	Xeplion summary of product characteristics^15, Hough et al.^29
	RIS-LAI	50 mg every 2 weeks*	Risperdal Consta summary of product characteristics^13; Meltzer et al.^34
	HAL-LAI	150 mg per 4 weeks administered every 1–3 weeks then 122 mg every 4 weeks	Pro-rated from PP-LAI dose; maintenance dose as above
	oral-OLZ	20.7 mg/day	Weighted average dose from nine trials as reported by Komossa et al.^27

LAI, long-acting injection; PP, paliperidone palmitate (Xeplion); RIS, risperidone microspheres (Risperdal Consta).

* The maximum allowable dose was used, since the average dose in three trials by Kane et al.¹², Chue et al.³⁵, and Eerdekens et al.³⁶ was 58.2 mg, but they included a dose of 75 mg, which is not commercially available.

Figure 1 depicts the model used to analyze the data. Patients began with one of the LAIs or oral-OLZ, then followed clinical paths as determined by literature-based probabilities. Adherence to medication was first considered in the model and rates were adjusted accordingly using data from Weiden et al.³⁹. Patients could remain stable or could incur a relapse; some would be treated through the emergency room (i.e. the milder cases), while others would require hospitalization to stabilize their condition (i.e. the more severe cases). Those not successfully treated at the initial dose were titrated to its maximum dose. Patients receiving PP-LAI, RIS-LAI, or oral-OLZ who failed to respond to the maximum dose or who were unable to tolerate the drug were switched to a traditional depot anti-psychotic (i.e. HAL-LAI). After a subsequent failure or intolerance to HAL-LAI, they were given clozapine, as per the NICE guidelines³⁹. Patients initiating with HAL-LAI and failing to achieve resolution of symptoms or who were intolerant to the drug were switched to oral-OLZ. Table 2 provides a summary of the rates used as clinical inputs into the model^{29,37,40–57}.

Figure 1. Model used for the pharmacoeconomic analysis.

Table 2. Clinical input rates, utility scores, and their sources.

Clinical state	Treatment	Rate	Source
Adherence	PP-LAI	0.872	RIS rate from Olivares et al.^24 adjusted via Mehnert et al.^41
	RIS-LAI	0.823	Olivares et al.^40
	HAL-LAI	0.592	Average of rates from Bartkó et al.^42, Heyscue et al.^43, Ritmannsberger et al.^55, Valenstein et al.^56
	oral-OLZ	0.537	Average of 1-year rates reported by Ascher-Svanum et al.^47, Guo et al.^44, Hamilton et al.^45, Ritmannsberger et al.^55, Valenstein et al.^56, Yu et al.^46
Stable schizophrenia	PP-LAI	0.769	Calculation: 1 − (non-hospitalized exacerbations + hospitalization rates)
	RIS-LAI	0.712	Calculation: 1 − (non-hospitalized exacerbations + hospitalization rates)
	HAL-LAI	0.633	Calculation: 1 − (non-hospitalized exacerbations + hospitalization rates)
	oral-OLZ	0.605	Calculation: 1 − (non-hospitalized exacerbations + hospitalization rates)
Emergency room visits for relapse	PP-LAI	0.067	Hospitalization rate × ratio of ER visits:hospitalizations^47
	RIS-LAI	0.084	Hospitalization rate × ratio of ER visits:hospitalizations^47
	HAL-LAI	0.107	Hospitalization rate × ratio of ER visits:hospitalizations^47
	oral-OLZ	0.115	Hospitalization rate × ratio of ER visits:hospitalizations^47
Hospitalization for relapse	PP-LAI	0.164	Gopal et al.^20, Hough et al.^29
	RIS-LAI	0.204	Olivares et al.^24
	HAL-LAI	0.260	RIS rate x ratio HAL:RIS rates in Csernansky et al.^48
	oral-OLZ	0.280	Rabinowitz et al.^49
Utilities for health states	Stable disease	0.890	Average: Briggs et al.^50, Cummins et al.^51, Lenert et al.^52, Oh et al.^53, Revicki et al.^54
	Relapsed outpatient	0.659	Average: Briggs et al.^50, Cummins et al.^51, Lenert et al.^52
	Relapsed inpatient	0.490	Average: Lenert et al.^52, Revicki et al.^54

HAL, haloperidol; LAI, long-acting injection; OLZ, olanzapine; PP, paliperidone palmitate (Xeplion^®); RIS, risperidone microspheres (Risperdal Consta).

This model examined all direct costs of care that would be accrued by the PNHS in treating patients over a 1-year period of time. This time horizon precluded the need for discounting. Manufacturers’ price lists were used to determine drug costs; other costs were identified from the literature and expressed in 2014 euros, using the Consumer Price Index for Portugal as an inflator⁵⁸. Clinical rates were also obtained from literature sources. Table 3 lists the cost inputs⁵⁹.

Table 3. Resources consumed and their costs.*

Resource	Item	Cost
Hospital/institutional care	Psychiatric hospitalization(5–89 days)	3069.95€†
	Psychiatric rehab ward/day	87.56€
	Day hospital	30.49€
	Psychiatric outpatient visit	99.32€
	Emergency room visit	112.07€
Medical care	Psychiatrist – outpatient visit	34.50€
	Psychiatrist – follow-up	24.50€
	Psychiatric nurse	3.70€
	Primary care physician	31.00€
Drugs	Xeplion	3.564€/mg
	Risperdal Consta	3.433€/mg
	haloperidol decanoate	0.068€/mg
	haloperidol tablets	0.026€/mg
	paliperidone tablets	0.715€/mg
	risperidone tablets	0.081€/mg
	clozapine tablets	0.005€/mg
	olanzapine tablets	0.122€/mg

* All costs are expressed in 2014 euros; Data source for all costs: Ministério da Saúde⁵⁹.

† Flat rate for 4–89 days, after which the cost is 87.56€/day.

The decision tree generated a set of clinical and economic outcomes for the average patient treated using standard approaches. The first outcome was the average (expected) cost per patient treated. Clinical events measured were relapses (including both those requiring hospitalization and those treated in the emergency room as out-patients), numbers of days in remission and relapse, and quality-adjusted life years (QALYs) associated with each LAI. QALYs were determined using utilities derived from the literature, as presented in Table 2^50–54.

We conducted two types of analyses, including cost-utility and cost-effectiveness. As recommended by the CHEERS Statement⁶⁰, the economic outcome for these analyses was the incremental cost-effectiveness ratio (ICER), which is the amount needed to pay to produce one unit of outcome. In accordance with the Portuguese guidelines for pharmacoeconomic studies, the primary economic outcome (ICER) was expressed in terms of the incremental cost per QALY gained¹⁶. NICE has established a threshold for cost-effectiveness of £20,000/QALY⁶¹, which would be ∼24,800€/QALY at the average exchange rate for 2014 (£1 = 1.240 17€)⁶². Also, Yazdanpanah et al.⁶³ have suggested that the Portuguese National Authority of Medicines (INFARMED) customarily adopts an informal threshold of 30,000€/QALY to indicate cost-effectiveness. These values were considered when assessing cost-effectiveness results.

In the secondary cost-effectiveness analyses, we determined the incremental cost per relapse, hospitalization, and emergency room (ER) visit avoided. Results were tested for sensitivity using 1-way analyses on all major inputs. Also, probabilistic analyses with 10,000 pairwise replications between LAIs was performed involving all inputs varied across plausible ranges using standard distributions such as gamma for costs and beta for rates.

Results

Overall results of the cost-utility analysis for the base case are presented in Table 4. Oral-OLZ had the lowest expect cost per patient treated. PP-LAI had the most QALYs, followed by RIS-LAI, then oral-OLZ, with HAL-LAI having the least. HAL-LAI was dominated by oral-OLZ since it had a higher cost and generated fewer QALYs. Similarly, RIS-LAI was dominated by PP-LAI. Thus, those two options were eliminated from consideration and the final two choices were compared (Table 5). The ICER for PP-LAI over oral-OLZ was 14,247€, which falls well below the usually accepted Portuguese threshold of 30,000€/QALY and the NICE threshold for cost-effectiveness of £20,000 (24,800€)/QALY.

Table 4. Results of the overall cost-utility analysis.

Drug	Cost*/patient	QALYs/patient	Incremental cost	Incremental QALYs	Economic outcome
oral-OLZ	4447€	0.7609	–	–	lowest cost
HAL-LAI	4474€	0.7585	27€	−0.0024	dominated
PP-LAI	5326€	0.8227	852€	0.0642	cost-effective (see Table 5)
RIS-LAI	6223€	0.7985	897€	−0.0242	dominated

HAL, haloperidol; ICER, Incremental Cost Effectiveness Ratio; LAI, long acting injectable; OLZ, olanzapine; PP, paliperidone palmitate; RIS, risperidone microspheres; QALY, quality adjusted life year.

* All costs are in 2014 euros.

Table 5. Results of the final incremental analysis of PP-LAI over oral-OLZ.

Drug	Cost*/patient	QALYs/patient	Incremental cost	Incremental QALYs	Economic outcome
oral-OLZ	4447€	0.7609	–	–	lowest cost
PP-LAI	5326€	0.8227	880€	0.062	14,247€†

ICER, Incremental Cost Effectiveness Ratio; LAI, long acting injectable; OLZ, olanzapine; PP, paliperidone palmitate; QALY, quality adjusted life year.

* All costs are in 2014 euros.

† Incremental Cost-Effectiveness Ratio as compared with oral-OLZ; NICE threshold for cost-effectiveness ≈24,800€ (approximate equivalent of £20,000 using the average 2014 exchange rate)⁶¹.

Table 6. Clinical outcomes.

Drug	Remission days	Relapse days	Emergencyroom visits	Hospitalizations
PP-LAI	326.6	37.4	0.122	0.288
RIS-LAI	312.8	51.2	0.168	0.394
HAL-LAI	284.5	79.5	0.250	0.623
oral-OLZ	286.0	78.0	0.242	0.615

HAL, haloperidol; LAI, long acting injectable; OLZ, olanzapine; PP, paliperidone palmitate; RIS, risperidone microspheres.

In the cost-effectiveness analyses, similar results were obtained. PP-LAI had the lowest rates of hospitalization, ER visits, and days in relapse (Table 6). As with QALYs, RIS-LAI was second lowest, oral-OLZ third lowest, and HAL-LAI had the highest rates for those outcomes. Both HAL-LAI and RIS-LAI were dominated, leaving oral-OLZ and PP-LAI for analysis. The ICER for PP-LAI over oral-OLZ was 1973€/relapse avoided and 2697€/hospitalization avoided.

One-way sensitivity analyses were robust for all parameters (see the Appendix for break-even values). PP-LAI would always cost the most, but would remain cost-effective over a very wide range of assumptions. When all inputs were varied across plausible ranges of values, PP-LAI was cost-effective over oral-OLZ in >99% of the 10 000 simulations. Overall, oral-OLZ cost significantly less (p = 0.006), as PP-LAI was less costly in only 12 simulations. On the other hand, PP-LAI generated more QALYs more than 99.8% of the time (p < 0.001).

Discussion

This analysis has demonstrated that PP-LAI is a cost-effective alternative for chronic schizophrenia in Portugal. According to these results, only oral drugs and PP-LAI should be considered as alternatives. Results were similar for both the cost-utility analysis and cost-effectiveness analysis which used relapses as its primary outcomes. The other choices considered (RIS-LAI and oral-OLZ) were found not to be cost-effective and, therefore, should not be considered further.

Results were robust, as demonstrated by the many sensitivity analyses performed. Although PP-LAI had a higher cost, it was cost-effective when judged by the prevailing standards. The cost-effectiveness was largely due to PP-LAI having a greater number of QALYs, which was statistically significant (p < 0.001).

An important factor in this model was adherence. The rates of adherence that were input into the model were 82.3% for RIS-LAI and 87.2% for PP-LAI. These rates are very close to the self-reported adherence rate of 89% in a study in which 125 Portuguese patients with schizophrenia were interviewed⁶⁴. Similarly, Lambert et al.⁶⁵ reported that the remission rate in patients who started in remission on conversion to RIS-LAI was 85% after 1 year of treatment. In our analysis, patients receiving RIS-LAI were in remission for 313.1 days or 85.8% of the time. Finally, the QALYs experienced by patients (i.e. 0.823 for PP-LAI and 0.799 for RIS-LAI) were comparable to what was reported by Lambert et al.⁶⁵, who stated that quality-of-life was rated adequate in 81.5% of 526 patients. These similarities provide a measure of external validation of the model.

As well, our estimated costs are remarkably lower than those previously found in European countries with stronger economies^66,67. However, they were quite similar to the costs estimated for other European countries having similar economic situations^68,69.

A search of both Medline and Embase located only two studies of the cost of anti-psychotics in Portugal^70–72. The abstract by Garrido et al.⁷⁰ indicated that they compared first and second generation drugs, but they did not present any actual results. The other study appeared both as an abstract⁷¹ and a full text article⁷². Heeg et al.⁷² reported that RIS-LAI dominated HAL-LAI and also oral drugs when used with this type of patient. Over a 5-year time horizon, RIS-LAI saved 3603€ and avoided 0.44 relapses compared with HAL-LAI. With respect to oral risperidone, RIS-LAI saved 4682€ and avoided 0.59 relapses.

The results from that study are similar to those from the present analysis in that the newer LAIs were cost-effective when compared with traditional LAIs or oral atypical anti-psychotics. However, there were a number of differences between these analyses. Different oral drugs were used by Heeg et al.⁷² for both second and third line. Since that time, NICE has recommended that clozapine be used as third line in all cases⁷³. Heeg et al.⁷² did not calculate QALYs; however, they did determine the number of outpatient days. Their calculations were very close to those in our model, which differed by 3.6% for RIS-LAI and 11% for HAL-LAI. The greatest difference was in the cost outcomes. The largest cost centers were drugs and hospitalization. In the analysis by Heeg et al., the price of RIS-LAI was 67% higher than the current price and HAL-LAI was 38% higher. Also, there has been a change in the method of reimbursement for acute care in the hospital in Portugal. They now have a fixed payment for hospital stays ranging from 5–89 days, much like a Diagnosis Related Group (DRG) payment as done in the US⁷⁴ and other countries⁷⁵. Decreases in overall costs have similarly been observed after the introduction of DRGs in the US⁷⁶. To our knowledge, no other study has addressed the issue of the economics of anti-psychotics in Portugal.

The results found in this analysis parallel those we recently obtained in a similar analysis in Finland in that PP1M was the cost-effective choice over the same time frame⁷⁷. However, there were many differences in that study with respect to outcomes. For example, the costs were dramatically higher in Finland and the QALYs were much lower. Costs were higher for several reasons. First, all patients entered the model in acute relapse and were hospitalized, which also accounts for lower QALYs. Therefore, all patients incurred at least one hospitalization, which is quite costly, whereas most patients in Portugal remained stable as outpatients. Second, the costs of healthcare are much higher in Finland than in Portugal. Third, patients remain in hospital longer in Finland. Finally, as already mentioned, Portugal has implemented a DRG system to limit hospital costs. Another differences is that only LAIs were studies in Finland. In another economic analysis from France, Druais et al.⁷⁸ used a 5-year Markov model comparing six anti-psychotics. They also found oral-OLZ to have the lowest cost, with three of the comparison drugs being dominated. In their final analysis, only three drugs were considered. PP-LAI was cost-effective compared with oral-OLZ and RIS-LAI had an ICER per QALY (>4 million euros) that was far beyond the accepted threshold for cost-effectiveness. With respect to relapses, PP-LAI had an ICER of 1782€per relapse avoided, which approximates our ICER of 1973€.

Recently, there have been several clinical trials comparing PP-LAI to other atypical anti-psychotics, which adds clinical support to our findings. In the PROSIPAL Study, Schreiner et al.⁷⁹ found a 44% reduction in relapses between PP-LAI and oral drugs over a 2-year period. Similarly, Alphs et al.^80,81 reported a 26% reduction over 15 months in the PRIDE Study. In our model, relapses were 48% lower with PP-LAI. In another study by Schreiner et al.’s⁸² group, patients who did not respond to other depot anti-psychotics were switched to PP-LAI. Among those switched from RIS-LAI, 61.1% incurred a reduction in PANSS total score ≥20% within 6 months and 31.5% experienced a reduction ≥50%. That group reported similar results in patients unsuccessfully treated with oral drugs who were switched to PP-LAI, with ≥64% showing 20% improvement in PANSS total score⁸³. Finally, in a head-to-head comparison between PP1M (n = 381) and risperidone LAI (n = 366), efficacy results were similar, but slightly favored PP1M⁸⁴. Responder rates (i.e. ≥30% improvement in PANSS total score) were numerically higher with PP1M (56.7%) than for risperidone LAI (52.2%). These findings are similar to those in the present study.

Limitations

One limitation to this analysis is that the model had a 1-year analytic time horizon, whereas schizophrenia is a chronic, incurable disease with an erratic path over time. An analysis over the expected lifetime may provide further insights into long-term outcomes. To do so would require longitudinal data which are not often available.

Also, results are limited to the specific patients under study, who had chronic relapsing schizophrenia and required depot medications. They may not apply to persons with less severe symptoms who constitute the majority of those with the disease.

Furthermore, we are limited by the fact that the data were derived from RCTs conducted with highly selected patients under closely monitored conditions. Also, trials are often of limited duration (e.g. we used mostly trials with a 1-year duration). They may not entirely reflect what happens in real life. We did try to address this issue to some degree by incorporating such factors as patient adherence to treatment regimens. In addition, there is inherent uncertainty in modeling; hence, the application of numerous sensitivity analyses. Thus, these limitations should be kept in mind when interpreting these results or applying them to clinical practice. A need exists for real world data observed over time in these patients.

Finally, we did not conduct a budget impact analysis. Since the acquisition cost of PP1M is higher than that of oral drugs, its adoption would likely increase the drug budget. On the other hand, some of that increase would be offset by reduced hospitalizations and emergency room visits.

Conclusions

In this analysis, PP-LAI was cost-effective over oral-OLZ from the point of view of the PNHS; RIS-LAI and HAL-LAI were dominated. This and other factors, such as the impact on the drug budget (which would probably increase), should be considered when selecting drugs for patients with chronic relapsing schizophrenia.

Transparency

Declaration of funding

This research was funded by Janssen A/S, Beerse, Belgium.

Declaration of financial/other relationships

TRE and BGB received funding from the sponsor for this research. SML, PG, and KvI are employees of Janssen. JME peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Acknowledgements

Supported by Janssen Pharmaceutica NV, Beerse, Belgium.

Appendix

Results of the one-way (break-even) sensitivity analyses

Table

Parameter	Drug rate changed	Base case	Value where PP-LAI is cost saving	% difference	Value where PP-LAI not cost-effective	% difference	Value where PP-LAI QALYs not highest	% difference
Adherence	PP-LAI	0.872	Resistant	n/a	0.65	−22%	0.164	−71%
(primary)	oral-OLZ	0.380	Resistant	n/a	Resistant	n/a	Resistant	n/a
Adherence	PP-LAI	0.400	Resistant	n/a	Resistant	n/a	Resistant	n/a
(2nd line)	oral-OLZ	0.400	Resistant	n/a	Resistant	n/a	Resistant	n/a
relapse rate	PP-LAI	0.166	Resistant	n/a	0.31	−14%	0.77	+60%
	oral-OLZ	0.473	Resistant	n/a	Resistant	n/a	Resistant	n/a
Stable + non-adherent	PP-LAI	0.148	Resistant	n/a	Resistant	n/a	Resistant	n/a
	oral-OLZ	0.071	Resistant	n/a	Resistant	n/a	Resistant	n/a
Dropout rate	PP-LAI	0.202	Resistant	n/a	0.32	+12%	0.65	+45%
	oral-OLZ	0.343	Resistant	n/a	Resistant	n/a	Resistant	n/a
Clozapine relapse	clozapine	0.402	Resistant	n/a	Resistant	n/a	Resistant	n/a
Drug cost/mg	PP-LAI	3.564€	2.3€	−35%	4.74€	+33%	n/a
	oral-OLZ	0.122€	0.475€	+289%	Resistant	n/a	n/a
Hospital cost/stay	n/a	3069.95€	5700€	+86%	800€	−74%	n/a

n/a, not applicable; resistant means that results do not change to favor the other drug, even if the rates are at the extremes (i.e. either 0% or 100%). For example, in the case of secondary adherence, all results will always favor PP-LAI over oral-OLZ, even if the rate for PP-LAI is 0% or the oral-OLZ rate is 100%.