One year mirror-image study using paliperidone palmitate for relapse prevention of schizophrenia in four university hospitals in Canada

doi:10.1016/j.schres.2017.01.013

Schizophrenia Research

Volume 185, July 2017, Pages 96-100

https://doi.org/10.1016/j.schres.2017.01.013 Get rights and content

Abstract

Background

Superiority of long acting injectable antipsychotics (LAI) over oral antipsychotics remains controversial and dependent on study design and inclusion criteria. Meta-analysis of 21 RCTs demonstrated no difference in their effectiveness, but meta-analysis of 25 mirror-image studies did. None of these included paliperidone palmitate (PP). Methods: We challenged efficiency of PP in a multicentric mirror-image study. Primary outcome was total hospitalization days. Mirror periods were 365 days either side of the first injection in model-1, and either side of index admission in model-2. Inclusion criteria were: 18 to 65 years, schizophrenia spectrum disorder, ≥ 3 injections received, and oral antipsychotic prescriptions before PP trial. Exclusion criteria were: prior clozapine or LAI trial. Cost-effectiveness was calculated from a public payer's perspective.

Results

114 patients were recruited (77% males, mean 37 years, mean disease duration 10 years). Oral antipsychotics adherence was 43%. Mean PP treatment lasted 297 days (adherence 81%). Mean annual hospitalization days weren't significantly different in model-1 (45.8 days vs 38.5 days, p = 0.058), but were significantly lower in model-2, (14.4 days vs 24.2 days, p = 0.003). 1.9 admissions per patient-year fell to 0.64 on PP (p < 0.0001). PP was approximately cost-neutral: differences were -$326 and $1788 for model-1 and model-2.

Discussion

PP as a first LAI improved adherence, decreased hospital visits and duration was cost neutral. Drawbacks are the retrospective design and lack of comparator and safety data. Strengths are naturalistic design and adherence calculation. A subset of patients responds well to LAI, leading to meaningful reductions in hospital services requirements.

Introduction

Although schizophrenia only affects approximately 1% of the Canadian population, it still remains one of the costliest illnesses. Estimates from 2004 demonstrated that the total costs attributed to schizophrenia totaled $6.85 billion CAN including productivity losses (Goeree et al., 2005). When the later are removed, this represents 5% of Canadian healthcare expenditures (Goeree et al., 2005). This mental illness can be treated with varying degrees of success with a combination of medication, psychological and social interventions.

Nonetheless, non-adherence remains a major issue that complicates the treatment of schizophrenia. Among 10 studies published since 1980, it was reported that the mean rate of non-adherence to antipsychotic medication was 41% whereas 5 studies meeting stricter inclusion criteria demonstrated a mean non-adherence rate of 49.5% (Lacro et al., 2002). Non-compliance to psychiatric treatment has been associated with increased hospital utilization, increased relapses, decreased quality of life, disease chronicity, deterioration of social functioning and increased health costs (Ascher-Svanum et al., 2006).

Long-acting intramuscular delivery was hoped to resolve the issue of non-compliance to antipsychotic treatments. Attempts were made by several authors to determine whether long-acting injectable antipsychotics (LAI) are more clinically effective. A meta-analysis of 21 randomized controlled trials demonstrated no significant difference in the effectiveness of LAIs over oral antipsychotics (Kishimoto et al., 2012). Nonetheless, rigorous inclusion criteria and follow-ups may have biased the representation of the psychiatric population initiated on LAI antipsychotics. For instance, patients with dual diagnosis and/or patients under community treatment order (CTO, a mandatory treatment ordered by a judge) are often excluded. Furthermore, a meta-analysis of 25 mirror-image studies comparing oral antipsychotic treatment with a subsequent period of LAI treatment showed LAI superiority over oral antipsychotics in preventing hospitalizations with a risk ratio of 0.43 in 14 out of 16 studies (Kishimoto et al., 2013). The literature on the superiority of LAIs over oral antipsychotics therefore remains controversial and dependent on study design and inclusion criteria.

Paliperidone palmitate (PP), a long-acting injectable antipsychotic, was added in 2011 to Quebec's formulary. Since then, its use has grown in popularity given its advantages over its predecessors including quick onset of action and once-monthly administration. As of yet, no Canadian study has been designed to assess whether PP is more effective and cost-effective than oral antipsychotics. However, other groups have asked this question, and the answer varies depending on country (Bera et al., 2013, Bressington et al., 2015, Taylor and Olofinjana, 2014).

We aimed to evaluate whether adherence to PP is improved in comparison to oral antipsychotics on the Canadian market and whether its therapeutic advantages can result in decreased hospitalization. Despite its significant cost of acquisition, it remains to be determined whether it is a cost-effective treatment. Quebec guidelines recommend the use of LAI when poor treatment adherence is noted or when it's the patient's preference (Stip et al., 2011). We hypothesized that patients with problematic compliance and high hospitalization rate would benefit from introduction of PP, resulting in lower hospitalizations and healthcare cost savings.

Section snippets

Study design

A retrospective mirror-image study was designed (Fig. 1) to determine the efficiency of PP compared to standard oral antipsychotic treatment. We defined the date of the first injection of PP as the index event, thereby using this date as the cut-off point for determining the pre-initiation (AB) and post-initiation periods (CD). The study, being multi-centered, used data collected from four Canadian centers: the Institut universitaire en santé mentale de Montréal (IUSMM, Montreal, Quebec),

Patients

We gathered drug exposure and hospitalization periods for 328 patient-years in 114 patients. Approximately 550 patients were excluded from the study because of previous exposure to a LAI (30%) or to clozapine (15%), were lost to follow-up (12%), refused to participate (7%), were never prescribed oral antipsychotics (7%), or other reasons (11%). Seventy-seven percent were male, mean age 37 years old (18–64 years), mean duration of illness 10 years (0–42 years), of which 70% had schizophrenia, 30%

Discussion

This study has revealed that initiating PP as a first LAI in a cohort of Canadian schizophrenic and schizoaffective patients improved adherence to pharmacological treatment and decreased the frequency of hospital visits with an overall net effect in government health expenditures. These results suggest that in schizophrenic patients demonstrating low adherence to oral antipsychotics, PP remains an efficient and cost-neutral therapeutic strategy in comparison to the sole use of oral

Conclusion

We believe that a higher efficacy can be assumed from the increased drug exposure with LAI in our cohort. This led to a meaningful reduction in the patient's use of hospital services. Our study sheds light on another problem to investigate, which is the long delay before LAI are initiated. Our patients suffered from schizophrenia or schizoaffective disorder for a mean 10 years, had a mean adherence rate of 43% and still, PP was their first LAI trial. We believe that a better monitoring of

Role of the funding source

An unrestricted educational grant from Janssen Canada (JCAEDG00468) was used to support this study.

Contributors

Philippe Vincent designed and coordinated the research project, recruited patients, interpreted the data, did statistical analysis and wrote the manuscript. Alex Halme interpreted the data and helped with statistical analysis. Josée Duchesneau, Marie-France Demers and Violaine Masson helped recruit patients in their hospital. Venessa Doyon-Kemp recruited patients, wrote the manuscript draft, and helped with grammar and language. All authors read and approved of the final manuscript.

Conflicts of interest

P. D. Vincent reports personal fees from Apotex, personal fees from Eli Lilly, grants and personal fees from Janssen Canada, personal fees from Lundbeck/Otsuka, personal fees from Pfizer, personal fees from Uniprix, all outside the submitted work

M.-F. Demers reports grants from Lundbeck, personal fees from Otsuka, personal fees from Mylan, grants from Janssen, all outside the submitted work

V. Masson reports personal fees from Otsuka-Lundbeck, outside from the submitted work

A. Halme, J.

Acknowledgments

We wish to thank Ingrid Agbado, Sandra Bilodeau, Katy Lavoie and Akram Djouini for help recruiting patients and collecting data, all nurses and psychiatrists who referred patients in our hospitals, Chantal Vallières, research coordinator in IUSMQ, all pharmacists at IUSMQ, especially Catherine Lesueur, Nathalie Couillard, Esthel Malenfant and Guillaume Chalifour.

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Cited by (24)

A 10-year mirror-image study of effectiveness and cost of long-acting paliperidone palmitate injectable in patients with schizophrenia or schizoaffective disorder
2022, Psychiatry Research
Citation Excerpt :
In the literature, there is an interesting amount of mirror-studies evaluating these variables, with positive results. However, they have a shorter observation period, mostly 1 year (Bressington et al., 2015; Chan et al., 2021; di Lorenzo et al., 2019; Hodgson, 2019; Lee et al., 2020; Mahabaleshwarkar et al., 2021; Mahlich et al., 2020; Oh et al., 2019; Vincent et al., 2017), 2 years (Taylor et al., 2016) and 3 years (Nikolić et al., 2017; Pappa et al., 2019) of follow-up. To our knowledge, this is the first 1MPP mirror-study with a 10-year observation time.
Acute episodes of Schizophrenia and Schizoaffective Disorder often require hospitalizations and/or psychiatry emergency room (PER) visits, with significant economic burden. Long-acting injectables (LAI), such as the once-monthly Palmitate Paliperidone LAI (1MPP) are effective in suppressing symptoms and raise treatment adherence. This study is the first aimed at evaluating long-term efficacy of initiation of 1MPP. This was a mirror-image study with a total 10 year observational length. Sample was divided into five different groups according to time span of observation: 2,4,6,8, and 10 years. Number of participants per group was 162, 129, 95, 77 and 35, respectively. Main outcomes were number and length of hospitalizations and number of PER visit. Significant reductions in these outcomes after initiation of 1MPP were found in all groups. Subgroups consisting only of patients with full adherence were evaluated, and these had better outcomes. A cost evaluation was also performed, which demonstrated decreases every year, for all main outcomes. Sensitivity analysis in the 2-year group showed results in this time-frame are independent of gender, diagnosis, previous LAI or 1MPP initiation setting. Initiation of 1MPP reduces number and length of hospitalizations up to 5 years, decreasing associated costs. This study increases evidence supporting use of 1MPP in patients with Schizophrenia or Schizoaffective disorder.
Effect of 3-monthly paliperidone palmitate on hospitalisation in a naturalistic schizophrenia cohort – A five-year mirror image study
2022, Journal of Psychiatric Research
Citation Excerpt :
Perhaps because of this poorer tolerability, there is a higher risk of hospitalisation in patients prescribed FGA LAIs than those on SGA LAIs(Wu et al., 2016). Paliperidone palmitate once-monthly LAI (PP1M) is a SGA LAI that has been shown to reduce relapse and hospitalisation risk in patients with schizophrenia(Vincent et al., 2017). Mirror-image studies suggest significant reduction in hospital stay, relapse and bed days in patients prescribed PP1M(Nikolic et al., 2017; Taylor and Olofinjana, 2014; Taylor, D. M. et al., 2016).
Currently the longest-acting antipsychotic formulation widespread clinical use is paliperidone 3-monthly injection (PP3M). While its efficacy has been shown in rigorous trials, there are few data relating to its effect on hospitalisation in normal clinical practice.
This was a mirror-image study (3 years before; 2 years after) of hospitalisations before and after beginning paliperidone 1-monthly (PP1M) and switching to 3-monthly within 18 months. All consecutive patients prescribed paliperidone long-acting injections with its licence (F20 schizophrenia diagnosis; 18–65 years) were included. The setting was an urban, specialist mental health organisation In London, UK.
In total 378 patients were initiated on PP3M during the study period. After applying inclusion criteria, 76 patients were retained and followed-up for 2 years. Mean duration of PP1M use before starting 3-monthly injections was 6 months (range 3–18 months). Of the 76 patients initiated, 13 patients discontinued PP3M within 2 years of starting PP1M or were lost to follow-up. Mean hospitalisations per patient per year fell from 0.55 (SD 0.46) before paliperidone to 0.05 (SD 0.19) after initiation (p < 0.001). Only 5 of 76 PP1M/PP3M participants were hospitalised during the 2-year follow up. The mean number of bed days per year before paliperidone initiation was 32.2 (SD 44.3) and after paliperidone initiation it was 23.0 (SD 53.2) (p = 0.004). Almost all of the bed days after initiation were associated with the index admission during which PP1M was started.
In patients stabilised on PP1M and switched to PP3M in normal clinical practice, rehospitalisation is very uncommon and much reduced compared with previous treatments.
Effectiveness of Paliperidone Palmitate on Treatment Adherence and Relapse in the Adult Schizophrenia Population: A One-Year Mirror-Image Study in a Colombian Mental Health Care Facility
2022, Revista Colombiana de Psiquiatria
Citation Excerpt :
Previous studies have also shown that the removal of the index hospitalization not only affected hospitalization rate but also accentuated the beneficial effect of PP1M on total LoS. It was therefore suggested that PP1M would be more cost-effective when started in an outpatient setting.12 To further elucidate this hypothesis, the effect of PP1M on hospitalization rate and LoS, stratification of findings according to initiation setting (inpatient or outpatient) would need to be conducted.
The benefits of long-acting injectable antipsychotics have been documented in several observational studies, but data remain scarce in Latin America. This study aimed at evaluating the effectiveness of paliperidone palmitate once monthly (PP1M) on treatment adherence and relapse in the schizophrenia population followed in a government-funded mental health care facility in Colombia.
A mirror-image study was conducted. Adult schizophrenia patients treated with oral antipsychotics who subsequently received ≥2 PP1M injections between Jan. 1^st, 2015 and Oct. 31^st, 2018 were included. The study consisted of two retrospective phases: 12 months before and after the first PP1M injection. Outcomes were treatment adherence (proportion of days covered ≥80%), hospitalized relapse, hospital length of stay, and non-hospitalised relapse. Effect of PP1M on outcomes was assessed through multivariable conditional Poisson regression.
123 patients were eligible (mean age, 30.3 years; 79.7% males). Adherence was 23.6% in the pre-phase and 89.4% in the post-phase (RR = 3.77; 95%CI, 2.75-5.17). The proportion of patients with hospitalised relapse decreased from 46.3% to 35.0% (RR = 0.76; 95%CI, 0.59-0.99). In the 75 (61.0%) patients who continued PP1M throughout post-phase, beneficial effect on hospitalised relapse was stronger (RR = 0.64; 95%CI, 0.42-0.98). The proportion of patients with non-hospitalised relapse symptoms increased from 6.5% to 18.7% (RR = 2.27; 95%CI, 1.11-4.64).
PP1M initiation led to a dramatic improvement in treatment adherence and a decrease in hospitalised relapse. Observed increase in non-hospitalised relapse may be explained by a decrease in severity. Limitations are absence of a parallel comparison group and a generalisability limited to the population treated at this facility. Study provides data for the Latin America region and strength is the assessment of non-hospitalised relapse symptoms.
Los beneficios de los antipsicóticos inyectables de acción prolongada se han documentado en varios estudios observacionales, pero los datos de América Latina siguen siendo escasos. El estudio se dirige a evaluar la efectividad del palmitato de paliperidona 1 vez al mes (PP1M) en la adherencia al tratamiento y las recaídas en la población con esquizofrenia seguida en un centro público de salud mental en Colombia.
Se realizó un estudio en imagen especular. Se incluyó a pacientes adultos con esquizofrenia tratados con antipsicóticos orales que posteriormente recibieron > 2 PP1M entre el 1 de enero de 2015 y el 31 de octubre de 2018. El estudio consistió en 2 fases retrospectivas: 12 meses antes y después de la primera inyección de PP1M. Se evaluó la adherencia al tratamiento (proporción de días cubiertos ≥ 80%), la recaída hospitalizada, la duración de la estancia hospitalaria y la recaída no hospitalizada. El efecto del PP1M se evaluó mediante la regresión de Poisson.
Fueron elegibles 123 pacientes (media de edad, 30,3 años; el 79,7% varones). La adherencia fue del 23,6% en la fase previa y del 89,4% en la segunda (RR = 3,77; IC95%, 2,75-5,17). La proporción de pacientes con recaída hospitalizada disminuyó del 46,3 al 35,0% (RR = 0,76; IC95%, 0,59-0,99). De los 75 pacientes (61,0%) que continuaron PP1M en la segunda fase, el efecto beneficioso en la recaída hospitalizada fue más fuerte (RR = 0,64; IC95%, 0,42-0,98). La proporción de pacientes con síntomas de recaída no hospitalizados aumentó del 6,5 al 18,7% (RR = 2,27; IC95%, 1,11-4,64).
La iniciación de PP1M llevó a una drástica mejora en la adherencia al tratamiento y a una disminución de la recaída hospitalizada. El aumento observado en la recaída no hospitalizada puede explicarse por una disminución de la gravedad. Las limitaciones son la ausencia de un grupo de comparación paralelo y que la generalizabilidad se limita a la población tratada en este centro. La fortaleza del estudio es la presentación de datos de la región de América Latina y la evaluación de síntomas de recaída no hospitalizada.
Long-acting injectable versus oral antipsychotics for the maintenance treatment of schizophrenia: a systematic review and comparative meta-analysis of randomised, cohort, and pre–post studies
2021, The Lancet Psychiatry
Citation Excerpt :
The initial search provided 14 687 records, of which 11 493 records were excluded after title screening because they were not relevant or duplicates. Of the remaining 3194 records, 3057 were excluded after screening and assessment of abstracts and full texts, yielding 137 studies (32 RCTs [23·4%; 8577 patients],21–51 65 cohort studies [47·4%; 377 447 patients],52–115 and 40 pre–post studies [29·2%; 11 295 patients]116–155; figure 1). For one cohort study we extracted all data from the published abstract.74
Evidence of comparative benefits of long-acting injectable antipsychotics (LAIs) versus oral antipsychotics for schizophrenia has been inconsistent across study designs. The aim of this study was to evaluate the comparative benefits of LAIs versus oral antipsychotics in three study designs to inform clinical decision making.
We did a comprehensive systematic review and meta-analysis comparing LAIs versus oral antipsychotics for schizophrenia covering three study designs: randomised controlled trials (RCTs), cohort studies, and pre–post studies. Our literature search was without language restrictions, in MEDLINE and PubMed, the Cochrane Library, Scopus, and Embase, for studies published from database inception up to a last search on March 13, 2020. We also searched for unpublished studies and ClinicalTrials.gov. We included studies lasting at least 6 months that targeted adults with schizophrenia and related disorders (>80% of participants). Studies on penfluridol (neither an LAI or daily oral antipsychotic), case reports, and case series with fewer than 20 patients were excluded. Two investigators independently extracted study-level data and resolved disagreement by consensus, or via a third investigator. Study authors were contacted to obtain additional information as needed. For our primary outcome we meta-analysed the risk ratio (RR) for hospitalisation or relapse with LAIs versus oral antipsychotics by a random-effects model, with hospitalisation used preferentially over relapse. As secondary analyses, we reversed the preferential order to relapse over hospitalisation, and assessed hospitalisation risk and relapse risk individually. Other secondary outcomes included all meta-analysable data, classed by relevance to effectiveness, efficacy, safety, quality of life, cognitive function, and other outcomes, and analysed by study design. Dichotomous outcomes were expressed as pooled RR and continuous outcomes as standardised mean difference (SMD). The protocol is registered with PROSPERO (CRD42019142094).
We identified 14 687 records, of which 137 studies (397 319 patients) met the inclusion criteria (32 RCTs [23·4%; 8577 patients], 65 cohort studies [47·4%; 377 447 patients], and 40 pre–post studies [29·2%; 11 295 patients]) and were analysed. The quality of studies in terms of risk of bias varied across study designs and within each study design from low to high. LAIs were associated with a lower risk of hospitalisation or relapse than oral antipsychotics in each of the three study designs (RCTs: 29 studies, 7833 patients, RR 0·88 [95% CI 0·79–0·99], p=0·033; cohort studies: 44 studies, 106 136 patients, RR 0·92 [0·88–0·98], p=0·0044; pre–post studies: 28 studies, 17 876 patients, RR 0·44 [0·39–0·51], p<0·0001). This association was maintained across the study designs when we reversed the preferential order to risk of relapse over hospitalisation, and in individual analysis of hospitalisation risk. The association was maintained only in pre–post studies for relapse risk alone. In all other outcomes related to effectiveness, efficacy, safety, quality of life, cognitive function, and other outcomes, LAIs were more beneficial than oral antipsychotics in 60 (18·3%) of 328 comparisons, not different in 252 (76·8%) comparisons, and less beneficial in 16 (4·9%) comparisons when analysed by study design. Significant heterogeneity was observed across all three study designs. Publication biases were apparent in cohort and pre-post studies, but effect sizes were similar after trim-and-fill analyses.
Although study designs have strengths and weaknesses, including potential low quality of observational studies, we consistently identified significant benefit with LAIs versus oral antipsychotics in preventing hospitalisation or relapse, in settings ranging from restricted research (RCTs) to real-word application (cohort and pre–post studies). Our findings suggest that increased clinical use of LAIs could improve outcomes in schizophrenia.
None.
For the Chinese, French, German, Italian, Japanese, Portugese and Spanish translations of the abstract see Supplementary Materials section.
Second-generation LAI are associated to favorable outcome in a cohort of incident patients diagnosed with schizophrenia
2018, Schizophrenia Research
Citation Excerpt :
The results from the current study showing a reduction in number of hospitalizations of approximately 0.57 is in line with a meta-analysis from Kishimoto et al. (2013) based on 25 mirror-image studies, which showed a reduction in number of hospitalizations of 0.38. A recent small study by Vincent et al. (2017)) investigating paliperidone palmitate showed a reduction in admissions to approximately one third after LAI initiation, but with no difference in days hospitalized. Similarly Mesones-Peral et al. (2017) also recently found reductions in admissions and bed days associated with paliperidone palmitate.
Investigate the associations of long-acting injectable (LAI) second generation antipsychotic drugs with number of relapses, psychiatric admissions, days hospitalized, intentional self-harm events, and costs linked to hospitalizations in incident patients diagnosed with schizophrenia.
A nationwide, population-based, retrospective study utilizing mirror-image models before and after initiation of LAI SGA.
10,509 patients were included as study population, with analyses being conducted on 2223 patients in a six-month period, 1383 in a 12-month period, 713 in a 24-month period. After initiation of LAI antipsychotics, patients experienced a reduction in number of relapses with an incidence rate ratio (IRR) of 0.60 for the first six months, IRR 0.64 for the first 12 months and IRR 0.64 for the first 24 months following initiation of LAI, all P < 0.001. The number of psychiatric admissions was reduced in a similar manner with respective IRR of 0.59, 0.60 and 0.64, all P < 0.001. Psychiatric bed-days were reduced with 58, 100 and 164 days for the respective periods after LAI initiation, all P < 0.001. In a Cox regression model in patients initiated on LAI, higher age at diagnosis, hazard rate ratio (HR) 0.99, 95%CI(0.98–0.99), P < 0.001, and a later calendar year of diagnosis, HR 0.99, 95%CI(0.98–1.00), P < 0.05, were associated with a lower risk of relapse, whereas mainly psychiatric comorbidity, HR 1.07, 95% CI (1.04–1.11), P < 0.001, and cardiovascular disease, HR 1.12, 95%CI(1.01–1.26), P < 0.05, were associated with relapse.
Even though the design does not allow inferences regarding causality, these population-based findings support the use of second generation LAI antipsychotics.
Effectiveness of Paliperidone Palmitate in Reducing Acute Psychiatric Service Use for Patients Suffering from Psychosis—A Retrospective Mirror-Image Study
2023, International Journal of Environmental Research and Public Health

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¹: Present address: Pharmacie Paul St-Onge, André St-Onge et Clément Pelletier, Brossard, Canada.

²: Present address: Mcgill University Health Center, Montreal, Canada.

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One year mirror-image study using paliperidone palmitate for relapse prevention of schizophrenia in four university hospitals in Canada

Abstract

Background

Results

Discussion

Introduction

Section snippets

Study design

Patients

Discussion

Conclusion

Role of the funding source

Contributors

Conflicts of interest

Acknowledgments

Medication adherence and long-term functional outcomes in the treatment of schizophrenia in usual care

J. Clin. Psychiatr.

Impact on healthcare resource usage and costs among Medicaid-insured schizophrenia patients after initiation of treatment with long-acting injectable antipsychotics

J. Med. Econ.

A retrospective observational study of the effectiveness of paliperidone palmitate on acute inpatient hospitalization rates

Int. Clin. Psychopharmacol.

Patient cost estimator

Pharmacoeconomics of depot antipsychotics for treating chronic schizophrenia in Sweden

Nord. J. Psychiatry

Nouvelles échelles salariales incluant le PIB

The economic burden of schizophrenia in Canada in 2004

Curr. Med. Res. Opin.