Model of Management (Mo.Ma) for the patient with schizophrenia: crisis control, maintenance, relapse prevention, and recovery with long-acting injectable antipsychotics (LAIs)
Modello di Management (Mo.Ma) del paziente affetto da schizofrenia: controllo della crisi, mantenimento, prevenzione delle ricadute e recovery
con gli antipsicotici LAI

ROBERTO BRUGNOLI1, CHIARA RAPINESI1, GEORGIOS D. KOTZALIDIS1, ANDREA MARCELLUSI2, FRANCESCO S. MENNINI2, SERGIO DE FILIPPIS1,3, DARIO CARRUS1,4, ANDREA BALLERINI5,
ANTONIO FRANCOMANO6, GIUSEPPE DUCCI7, ANTONIO DEL CASALE1,8, PAOLO GIRARDI1
E-mail: chiara.rapinesi@uniroma.it

1NESMOS Department (Neurosciences, Mental Health, and Sensory Organs), Sapienza University of Rome,
School of Medicine and Psychology; Sant’Andrea Hospital, Rome, Italy
2Faculty of Economics, Centre for Economic and International Studies (CEIS)-Economic Evaluation and HTA (EEHTA),
University of Rome, Italy
3Villa von Siebenthal Neuropsychiatric, Clinic and Hospital Rome, Italy
4ASL VT, Viterbo, Italy
5Department of Neuroscience, Psychology, Drug Research and Child Health, Section of Neuroscience, University of Florence, Italy
6Department of Experimental Biomedicine and Clinical Neuroscience, University of Palermo, Italy
7DSM ASL Roma 1, Rome, Italy
8Department of Psychiatric Rehabilitation, Fondazione ‘‘P. Alberto Mileno Onlus’’, Vasto (CH), Italy


summary. Schizophrenia is a severe mental disease that affects approximately 1% of the population with a relevant chronic impact on social and occupational functioning and daily activities. People with schizophrenia are 2-2.5 times more likely to die early than the general population. Non-adherence to antipsychotic medications, both in chronic and first episode schizophrenia, is one of the most important risk factors for relapse and hospitalization, that consequently contributes to increased costs due to psychiatric hospitalization. Atypical long-acting injectable (LAI) antipsychotics can improve treatment adherence and decrease re-hospitalization rates in patients with schizophrenia since its onset. The primary goals in the management of schizophrenia are directed not only at symptom reduction in the short and long term, but also at maintaining physical and mental functioning, improving quality of life, and promoting patient recovery. Aim. To propose a scientific evidence-based integrated model that provides an algorithm for recovery of patients with schizophrenia and to investigate the effectiveness and safety of antipsychotics LAI in the treatment, maintenance, relapse prevention, and recovery of schizophrenia. Methods. After an accurate literature review we identified, collected and analyzed the crucial points in taking care schizophrenia patients, through which we defined the steps described in the model of management and the choice of the better treatment option. Results. In the management model we propose, the choice of a second generation long acting antipsychotic, could allow from the earliest stages of illness better patient management, especially for young individuals with schizophrenia onset, a better recovery and significant reductions of relapse and health care costs. LAI formulations of antipsychotics are valuable, because they help patients to remain adherent to their medication through regular contact with healthcare professionals and to prevent covert non-adherence. Conclusion. The proposed schizophrenia model of management could allow better patient management and recovery, in which the treatment with LAI formulation is a safe and effective therapeutic option. This new therapeutic approach could change the cost structure of schizophrenia by decreasing costs with efficient economic resource allocation guaranteed from efficient diagnostic and therapeutic pathways.

KEY WORDS: Long-acting injectable antipsychotic drugs, LAIs, schizophrenia, recovery.


RIASSUNTO. La schizofrenia colpisce circa l’1% della popolazione e rappresenta un grave disturbo mentale con un notevole impatto anche sul funzionamento sociale, lavorativo e sulle attività della vita quotidiana. Le persone con schizofrenia hanno un tasso di mortalità superiore di 2-2,5 rispetto a quello della popolazione generale. La non aderenza ai farmaci antipsicotici è uno dei più importanti fattori di rischio per le ricadute e le ospedalizzazioni, sia nei pazienti con disturbo cronico sia al primo episodio, e conseguentemente contribuisce all’aumento dei costi sanitari. Gli antipsicotici atipici LAI possono migliorare l’aderenza al trattamento contribuendo a diminuire i tassi di ricaduta nei pazienti affetti da schizofrenia fin dall’esordio. Gli obiettivi primari nella gestione dei pazienti schizofrenici sono diretti, non solo alla riduzione dei sintomi nel breve termine, ma anche al mantenimento fisico e della funzionalità mentale, migliorando la qualità della vita e promuovendo il recupero del paziente. Scopo. Proporre un modello integrato, basato sulle evidenze, che fornisca un algoritmo efficace per il recupero del paziente schizofrenico e indagare l’efficacia e la sicurezza degli antipsicotici LAI nel trattamento, nel mantenimento, nella prevenzione delle ricadute e nella recovery dei pazienti affetti da schizofrenia. Metodi. Dopo un’accurata analisi di letteratura abbiamo identificato, raccolto e analizzato gli elementi qualificanti per un’ottimale gestione del paziente schizofrenico, definendo un modello di gestione e selezione delle alternative terapeutiche. Conclusioni. Il modello di gestione della schizofrenia proposto potrebbe consentire un migliore recupero funzionale del paziente grazie alla scelta di iniziare il percorso terapeutico, fin dalle prime fasi del disturbo soprattutto se in giovane età e al primo episodio, con un farmaco atipico LAI. All’interno dei farmaci antipsicotici atipici la formulazione LAI rappresenta una scelta terapeutica sicura ed efficace nella gestione della schizofrenia fin dall’inizio della malattia. Questo nuovo approccio terapeutico potrebbe modificare la struttura dei costi della schizofrenia attraverso la loro riduzione e la ricollocazione delle risorse economiche, che verrà garantita da efficienti algoritmi diagnostico-terapeutici.

PAROLE CHIAVE: Antipsicotici long-acting iniettabili, LAI, schizofrenia, recovery.

INTRODUCTION
Epidemiology of schizophrenia: impact on social and occupational functioning
Schizophrenia is a severe, chronic psychiatric disorder affecting about 1% of the general population1. It is associated with social and occupational functioning decline and characterized by positive symptoms, representing an excess or distortion of normal functions, negative symptoms, a reduction of normal functions, and cognitive symptoms2. Schizophrenia-associated impairment tends to persist in many patients, thus impacting considerably their independent personal, social, and occupational lives and constituting a major source of disability3,4. Cognitive impairment persistently reduces patients’ ability to engage and maintain social and professional relationships4-6. The main reason for unimproved functional outcome is that the treatment of those aspects that are most strongly related to it, i.e., cognitive dysfunction and negative symptoms, is currently unsuccessful7. The best predictor of poor long-term functioning is poor first-three-post-diagnosis-years functioning8. This is most prominent for unemployment, which is associated with duration of untreated psychosis (DUP) and prevalent negative symptoms9. Early intervention in psychosis is a comprehensive and evidence-based approach aimed at detection and treatment of psychotic symptoms in their early stages, so to reduce the long-term adverse impact of psychosis and prevent relapses. It focuses on people with ultra-high risk for psychosis and those with initial psychotic symptoms. Even incompletely recovered patients may achieve a sufficiently satisfactory quality of life, provided they receive adequate support. The switch from an oral to a LAI antipsychotic formulation may benefit patients’ quality of life, independently from initial response, thus paving the way to recovery 10. After the acute phase of treatment for a first psychotic episode, guidelines usually indicate that subsequent maintenance antipsychotic medication should continue for at least 1 year, but consensus is lacking regarding the total duration of treatment if the patient remains asymptomatic1,11. A 5-year observational study of patients with first-episode psychosis indicated that stopping antipsychotic medication increased relapse rates 5-fold compared with continued treatment12. Annual discontinuation rates for oral antipsychotics in first-episode schizophrenia were as high as 42% in the European First Episode Schizophrenia Trial (EUFEST)13. However, the risk of relapse needs to be weighed against the likelihood and severity of adverse effects caused by antipsychotic medication14 and the fact that about 20% of first-episode patients experience only a single episode of psychosis15. The commonest cause of relapse and hospitalization in schizophrenia is poor adherence to oral medication16.
The issue of the lack of adherence to antipsychotic medication
Non-adherence to medication is a major challenge for patients treated for schizophrenia; adherence problems are among the most frequent causes of relapse and rehospitalization17,18. Despite the availability of effective antipsychotic treatment, adherence to antipsychotic treatment in the long run is low13,19. Failure to comply with treatment is frequent in patients with schizophrenia. Between ½ to ¾ of patients do not comply with prescription13,20. Some non-adherence is not due to willful refusal to take medication21, but rather to patient forgetfulness, which can worsen by illness sequelae, such as disorganization or lack of insight. Cannabis use is a risk factor for non-adherence to medication and dropout from treatment22. It should be recalled that schizophrenia and cannabis abuse frequently co-exist, but the causality of their relationship is far from clear23. In addition, stigma can also play a role, as can adverse effects, cost and lack of perceived efficacy21. Also, given that adherence may decrease in 25-80% of patients during treatment24, non-adherence could substantially impact healthcare costs, an issue that still awaits accurate evaluation25.
Health Economics aspects
Epidemiological data show mental illness to occur both in more- and in less-economically developed countries26. Mental disorders are known to have major consequences for longevity, quality of life, and productivity for both patients and caregiver. Mental health disorders are inversely correlated with household income27; this might indicate that mental illness negatively affects patients’ and their families productivity or, as some authors discussed28, that a low socio-economic status increases the risk of mental health problems. Schizophrenia, the most chronic and disabling of major mental illnesses, is included among the first ten causes worldwide of long-term disability, with a wide ranging and long-lasting impact for people suffering from the illness, their families and society as a whole29-31. In the USA, its direct and indirect costs are estimated to amount to $ 62,700,000,00032. Similarly, in Europe the total cost related to schizophrenia and other psychotic disorders was estimated at € 93,900,000,000; 69% of this amount is due to indirect costs33. Direct and indirect costs are high because schizophrenia is a chronic, lifelong condition with frequent relapses after onset, that occurs most frequently in young age34,35. In terms of direct costs, their main drivers in Italy were estimated to be hospitalization and residential cost (71% of total direct cost per patient), followed by semi-residential services (13%), antipsychotic and other drugs (8%) and outpatient services (8%)29,36,37. Despite the availability of effective antipsychotic drugs for the treatment of acute and chronic treatment of schizophrenia, more than 80% of patients relapse within 5 years, and suicide occurs in about 10% of cases38,39. Increased relapse during the post-onset period (16% in the first year after diagnosis, 50% at 2 years and 70% at 5 years39,40) means, in clinical and management terms, high hospitalization rates and, in economic terms, increased costs per treated individual. The most common cause of relapse in treated schizophrenia is poor adherence to oral medication41,42. Non-adherence contributes to a substantial increase in the cost of schizophrenia43-45. It is estimated that non-adherence accounts for approximately 40% of re-hospitalization costs for patients with schizophrenia in the 2 years following their discharge from an inpatient treatment facility46. Consequently, efficacious interventions and a correct integrated management of schizophrenia patients are essential to increase adherence, prevent relapse, and restore social functioning, so to improve long-term prognosis and reduce costs.
Early treatment with Long Acting Injectable (LAI) antipsychotics represents an effective tool for improving adherence39,47 and should have a positive economic impact reducing the main important direct cost of the total economic burden of disease (hospitalization). For example, if an efficacious treatment with fair adherence reduces by only 5% re-hospitalization, the estimated mean cost reduction per patient in Italy would be € 146 per year36 that multiplied for approximately 180.000 patients treated48,49 would correspond to a total direct cost reduction of € 26.2 million per year. In Italy, it was estimated that the most important costs related to schizophrenia are indirect and correspond to 70% of the total economic burden per patient50. Unemployment rate in schizophrenia is more than double than the one in the general population51,52 and 51% of these subjects obtain a disability pension in Italy51. Indirect costs represents the key economic aspects in the management of schizophrenia patients. In fact, another important objective of pharmacological intervention in the stable phase of the disease is to prevent relapse and help keeping the patient stable enough to ensure a life as normal as possible; this would allow to continue to promote the process of recovery34,35. This would translate into reduced absenteeism and for patients with a job and increase the possibility to find a job for those who are unemployed.
Efficacy, adherence and good management are important not only from a clinical perspective, but also for their economic impact. A new treatment approach would change the cost structure of schizophrenia by decreasing costs (especially in terms of hospitalization and indirect costs) with efficient economic resource allocation guaranteed from efficient diagnostic and therapeutic pathways.
METHODS
We searched the PubMed database using the following search strategy “(antipsychotic* OR neuroleptic*) AND (long-acting OR depot OR LAI OR once monthly OR prolonged release) AND (“randomized controlled trial*” OR double-blind)”. Reference lists of identified articles were reviewed for additional relevant publications. Included were double-blind, randomized controlled trials (RCTs) of any LAI antipsychotic versus placebo or comparators.
RESULTS
Our search strategy yielded 271 records on April 6, 2016; of these, 30 were reviews and excluded, but their reference lists were hand-searched for the identification of other potential studies to include. We finally included in our discussion of the efficacy and safety of LAIs 16 studies that are cited in that section. Table 1 roughly summarizes the evidence obtained from these studies. No other papers emerged after having searched the reference lists of retrieved literature. For a thorough review we recommend the paper by Graffino et al. 53.







Strategies to prevent relapses and to reduce hospitalization by improving medication adherence
Relapse prevention is critical, as psychopathology and social functioning can worsen with psychotic episodes in schizophrenia54. Guidelines for the management of schizophrenia recommend improving medication adherence as a strategy to reduce hospitalization rates and costs in patients with schizophrenia55. Long-acting injectable anti-psychotics provide an opportunity to improve medication adherence21,56,57 and reduce hospitalization rates compared to treatment with oral formulations. Relapse prevention and identifying treatments to assist patients may reduce the risk of cognitive and functional declines across the lifespan in patients with schizophrenia.
The issue of recovery in schizophrenia: is it feasible in studies of recently introduced antipsychotics?
It is widely accepted that some patients with schizophrenia may have a favorable prognosis. Symptoms can abate over time, and some patients with schizophrenia may attain fair outcomes in some clinical and functioning outcomes. While remission is usually well defined in terms of clinical symptoms58, recovery involves also regaining the pre-onset functioning in the social interaction, physical activity/independence (autonomy), leisure and work domains. The benefits of an early intervention program for psychosis support higher recovery rates at substantially lower personal and economic costs59-61. Extensive scientific literature supports the clinical benefits of antipsychotics for early intervention or treatment of first-episode psychosis62. A recent systematic review and meta-analysis found that second-generation LAIs were superior to first-generation LAIs for relapse prevention63. In addition, LAIs are effective for treating first-episode psychosis and for early initiation of treatment for schizophrenia64.
We intend to propose a scientific evidence/guideline-based model that provides an algorithm for standard treatment, rehabilitation and recovery investigating the efficacy and safety of antipsychotics LAI in treatment, maintenance, relapse prevention and recovery in schizophrenia.
Efficacy and safety of atypical LAI antipsychotics
Some investigations showed significant reductions in recurrence rates with the risperidone LAI formulation compared to the oral one65-67, while others failed to confirm this superiority68,69. The efficacy and tolerability of olanzapine LAI (olanzapine pamoate) was assessed in two randomized, double-blind, controlled trials, one compared to placebo70, the other to oral olanzapine71. In the placebo-controlled, randomized, double-blind trial72, olanzapine LAI improved the level of functioning in acutely ill patients with schizophrenia after 8-weeks. In a recent 2-year, open-label, randomized study of olanzapine LAI, outpatients with schizophrenia maintained or improved their baseline level of functioning over time, but results did not significantly differ between olanzapine LAI and oral olanzapine73. Several studies have demonstrated the greater efficacy of paliperidone LAI (paliperidone palmitate) compared to placebo and its non-inferiority compared to risperidone LAI in improving the PANSS scores in schizophrenia patients with acute symptomatology and in inducing a delay in time to recurrence in stabilized patients74. Paliperidone LAI has a relatively neutral metabolic profile, resulting in only limited weight gain and no effects on glucose and lipid metabolism, both in short and long-term studies75. More recently, the LAI formulation of aripiprazole has been approved by EMA for the maintenance treatment of schizophrenia in adult patients stabilized with oral aripiprazole76. Found aripiprazole LAI to be not inferior to its oral counterpart, while a further study, carried-out in Asian countries established that the two formulations were comparably well tolerated77. The clinical efficacy of aripiprazole LAI was established in two randomized, double-blind, controlled studies conducted in patients with schizophrenia in an acute78 and in a maintenance setting79. The efficacy and safety of aripiprazole LAI in the maintenance of stabilized schizophrenia were comparable to those of oral aripiprazole79. Aripiprazole LAI was also found to be efficacious and safe for patients experiencing an acute schizophrenia episode78. Superior improvements on clinician-rated health-related quality of life and a favorable tolerability profile suggest greater overall effectiveness for aripiprazole vs. PP80. Pharmacological (dynamic/kinetic) and dosage-related measures of LAI antipsychotic drugs are compared in Table 2.



DISCUSSION
Schizophrenia is a chronic and disabling condition that requires long-term pharmacological and nonpharmacological management. This is multidimensional and can involve integrated psychosocial interventions, including family therapy and individual psychotherapy, social interventions like case management and psychosocial support, professional rehabilitation, establishing a network of social relations and motivation to engage in pleasurable activities. This may require a team working in harmony with the same aim, i.e., to benefit the patient and increase his/her quality of life.
Efficacy, adherence and good management are important not only from a clinical perspective, but also for their economic impact. A new treatment approach would change the cost structure of schizophrenia by decreasing costs (especially in terms of hospitalization and indirect costs) with efficient economic resource allocation guaranteed from efficient diagnostic and therapeutic pathways.
Integrated care pathways (PDTA) and management models (Mo.Ma) are government tools that can enhance the different actors to define the best pathway for the schizophrenia patients optimizing clinical and the healthcare outcomes and resources.
In mental health and schizophrenia disease these aspects are particularly important due to the complexity of the diagnosis, treatment and case management. The complexity of the diagnosis is related to the presence of a variety of signs and symptoms, the treatment needs to be coordinated between the clinical and psychosocial aspects, and lastly the case management requires to structure processes in which different actors take part (various specialties, professions and hospital-territory).
The clinical pathway reported in Fig. 1 has been recently proposed to summarize current Guidelines and optimize resources and costs81. Our proposed model focuses on the right part of the algorithm, marked as Mo.Ma intervention area and will be detailed further on.






Current treatment clinical practice
In the current treatment practice, after being prescribed an oral, classical or atypical antipsychotic, the patient is initially monitored for response and has his/her treatment adjusted according to needs. Once efficacy has been established, the patient is usually monitored for side effects that may be subtle and insidious in onset, such as dysmetabolism and weight gain. Side effects, like suboptimal efficacy, are likely to be associated with subsequent development of non-adherence, hence the switch to another oral antipsychotic should include the possibility to consider switching to a LAI formulation (classical/atypical). During the course of schizophrenia, which may be exacerbating and remitting even in the face of previously effective drug treatment, hospitalization is always an option. While in the hospital adherence is easier to assess, problems arise as soon as the patient is discharged when he/she should be taken care by his/her reference community service and followed-up for adherence. It is not uncommon in this phase to switch from an oral to an atypical antipsychotic LAI formulation to ensure adherence, which in turn is related to better outcomes. The same considerations of the post-first episode discharge hold true even for the post-discharge period of subsequent episodes of schizophrenia. However, with repeated episodes, the likelihood to deal with people needing first generation LAI antipsychotics or hyperprolactinising atypical LAI antipsychotics increases, thus reducing the possibility to benefit from the better quality of life associated with the use of aripiprazole LAI (Figure 2).



Mo.Ma evidence-based model algorithm for standard treatment, rehabilitation and recovery
People with schizophrenia face a number of challenges in managing their lives and disease, including lack of insight into their illness and cognitive deficits that interfere with treatment adherence – both psychosocial and pharmacologic. These challenges increase the risk of relapse, with each relapse resulting in significant personal and economic costs.
A wide variety of antipsychotic agents is available, with the drugs having broadly similar efficacies in terms of producing reductions in symptoms and in the risk of relapse. Therefore, antipsychotic choice is commonly guided by tolerability issues and individual patient factors, including past medical history, past response to drugs, past experience of adverse events, concurrent medical conditions or comorbidities, and individual patient preference. However, their success depends also on treatment adherence. The use of atypical LAI formulations of antipsychotic drugs is suitable to overcome medication non-adherence. Relapse prevention is considered a major treatment aim in schizophrenia. Relapse itself represents an important predictor of subsequent relapse, while multiple relapses have been associated with poorer long-term outcome 13. Relapse rates decrease by over 50% after maintenance antipsychotic treatment78. Three RCTs support relapse prevention by LAI aripiprazole in schizophrenia, two versus oral76,77 and one versus placebo79. The latter has also shown efficacy in the acute treatment of schizophrenia78. Psychiatric hospitalization rates were significantly lower when patients were treated with aripiprazole LAI, compared with oral anti-psychotic therapy82. In a head-to-head comparison study80, treatment with aripiprazole LAI showed superior improvements to paliperidone palmitate (PP) on health-related quality of life, improvements in symptoms and functioning, and a favorable tolerability profile, as shown by fewer important AEs and lower all-cause discontinuation rates; taken together, these data suggest greater overall effectiveness for aripiprazole LAI vs. paliperidone palmitate. In predefined analyses, significantly greater improvements with aripiprazole LAI vs. PP were consistently shown in patients ≤35 years, indicating that younger patients may be particularly responsive to aripiprazole LAI. aripiprazole LAI may show a favorable metabolic profile and was generally well tolerated. Of 12 analyzable drugs, aripiprazole ranked fourth for limiting weight gain and fifth for limiting EPS and sedation, best for limiting prolactin increase and prolactin levels, and second best drug for limiting QTc prolongation83. The better tolerability profile of aripiprazole regarding metabolic alterations and prolactin increase suggests that aripiprazole LAI may target those patients for which these issues are a particular concern. The safety profile of aripiprazole LAI was comparable to that of oral aripiprazole76,77 and consistent with the one reported for oral aripiprazole in previous registration maintenance studies84,85.
Studies confirm that aripiprazole LAI choice is reasonable for younger, first episode patients, who showed more benefit than multi episode patients with schizophrenia80. Patients with obesity are also likely to benefit more from aripiprazole LAI86. For patients with a chronic disorder that had previously responded to other antipsychotics and who have florid positive symptoms, other LAIs may be preferable.
We are tempted to conclude that the sooner you intervene, the better (Figure 3). So we propose a model that integrates all current notions about schizophrenia, its insidious onset and prodrome, the worsening course in the absence of timely treatment, and the negative impact of hospitalizations and nonadherence, we call this Mo.Ma (Model of Management). The model in current psychiatric practice may be implemented according to the algorithm found in Figure 2. Considering both clinical and pharmacoeconomic aspects 82,87 we here propose this updated treatment algorithm, by which the choice of a LAI antipsychotic may occur soon after diagnosis of schizophrenia, especially for patients with poor awareness of illness and poor insight; this algorithm will allow us to deal with patients from the very first presentation of psychosis to full-blown schizophrenia. LAIs are traditionally reserved for patients at later stages of psychosis; however their use is currently advocated for early episodes of schizophrenia, so to further improve outcomes like recurrence, hospitalization rate, and consequences of lack or less than optimal treatment 88,89.
The above model is already in place in the Mental Health centers of the scientific board of this article, but in order to be validated it needs to be tested against current practices to determine its validity in other centers. Possible study designs could compare outcomes of LAIs vs. their respective oral medications, LAIs vs. other LAIs and/or placebo in LAI-like formulation, or the algorithms in Figure 2 vs. Figure 3. The results of a similar study will tell us whether there is a need for change in our current practices. Outcomes should include efficacy and safety matters, but also patient-focused measures such as quality of life, functioning, satisfaction with treatment and attitudes towards the use of drugs.
A set of indicators (KPI) can be selected to validate organization quality and process, so to monitor the correct adoption of clinical pathways (Figure 4)90.
PERSPECTIVES
Applying the model we propose is desirable to obtain:
• Reducing hospitalizations by increasing adherence
• Reduction medication dosages
• Improve compliance to other drugs
• Increase subjective well-being
• Improve social functioning (recovery)
• Reducing health care costs
• Reducing Social costs



LIMITATIONS
Since this was a selective, nonsystematic review, we might have not included in our discussion some significant papers. Furthermore, since we endorse a strong, ground-breaking viewpoint, we might not concord with the bulk of literature; however, we identified some papers that are in line with this viewpoint, so this paper may be added to theirs and constitute the core of a new approach to the early treatment of schizophrenia.
CONCLUSIONS
Schizophrenia affects approximately 1% of the population, and is a severe mental illness with a chronic impact on social and occupational functioning and daily activities. Schizophrenia, is the most chronic and disabling of mental illnesses and is included among the first ten causes worldwide of long-term disability, with a wide ranging and long-lasting impact for people suffering from the illness, their families and society as a whole29-31.
The primary goals in the management of schizophrenia are directed not only at symptom reduction in the short and long term, but also at maintaining physical and mental functioning, improving quality of life, and promoting patient recovery57,91.
Efficacious interventions and a correct integrated management of schizophrenia patients are essential to increase adherence, prevent relapse, and restore social functioning, so to improve long-term prognosis and reduce costs. Early treatment with LAI antipsychotics represents an effective tool for improving adherence39,47 and should have a positive economic impact reducing the main important direct cost of the total economic burden of disease (hospitalization).
The proposed schizophrenia model of management, already in place in the Mental department of the board members, allowed better patient management and recovery, where aripiprazole LAI formulation represents a new safe and effective long-acting treatment option for the management of schizophrenia. The efficacy of aripiprazole LAI as maintenance treatment for schizophrenia has been demonstrated in three RCTs. Aripiprazole LAI was superior to placebo, and non-inferior to oral aripiprazole, in delaying the time to (impending) relapse, as well as in reducing relapse rates. The actual benefit of aripiprazole LAI over oral medications in clinical practice may even be greater than the one shown in RCTs, since patient willingness to participate and a protected research environment can increase treatment adherence. Since patients seen in everyday practice are likely to show poor adherence, the increased compliance fostered by LAI formulations will probably increase the gap between LAI and oral aripiprazole.
In the model of management we propose, the cost structure of schizophrenia could also change by decreasing costs with efficient economic resource allocation guaranteed from efficient diagnostic and therapeutic pathways. The cost-saving effect of aripiprazole LAI compared to other antipsychotics has to be investigated in a real life setting; however, data emerging from recent publications and congress abstracts suggest that the use of aripiprazole LAI will lower health care costs more than other antipsychotics and other LAI at least compared to paliperidone palmitate.

Acknowledgments: The authors wish to thank Ms Mimma Ariano, Ms Ales Casciaro, Ms Teresa Prioreschi, and Ms Susanna Rospo, Librarians of the Sant’Andrea Hospital, School of Medicine and Psychology, Sapienza University, Rome, for rendering precious bibliographical material accessible, as well as their Secretary Lucilla Martinelli for her assistance during the writing of the manuscript.

Financial & Competing Interests Disclosure: In the past three years, Paolo Girardi has received research support from Lilly, Janssen, Angelini, and Springer Healthcare, and has participated in Advisory Boards for Lilly, Otsuka, Pfizer, Schering, and Springer Healthcare and received honoraria from Lilly and Springer Healthcare. All other authors of this paper have no relevant affiliations or financial involvement with any organization or entity with a financial interest in, or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.
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