2015 April-June; 2(2): 48–58. ISSN: 2421-3349
Published online 2016 October 12.

May second generation long-acting injectable antipsychotics be prescribed as a first-line treatment of first episode in patients with schizophrenia? An overview

Domenico De Berardis,1,2,3 Nicola Serroni,1 Luigi Olivieri,1 Daniela Gianfelice,1 Felice Iasevoli,3,4 Carmine Tomasetti,3,4 Andrea de Bartolomeis,4 Monica Mazza,3,5 Alessandro Valchera,3,6 Michele Fornaro,3,7 Fabio Di Fabio,3,8 Paolo Cavedini,9 Giampaolo Perna,9,10,11 Monica Piersanti,12 Marco Di Nicola,13 Manuela Odorisio,14 Alessandro Carano,15 Federica Vellante,2 Ilaria Matarazzo,2 and Massimo Di Giannantonio2

1NHS, Department of Mental Health, Psychiatric Service of Diagnosis and Treatment, Hospital “G. Mazzini”, ASL 4 Teramo, Italy
2Department of Neuroscience, Imaging and Clinical Science, Chair of Psychiatry, University “G. d’Annunzio”, Chieti, Italy
3Polyedra Clinical Group, Teramo, Italy
4Laboratory of Molecular Psychiatry and Psychopharmacotherapeutics, Section of Psychiatry, Department of Neuroscience, University School of Medicine “Federico II”, Naples, Italy
5Department of Health Science, University of L’Aquila, Italy
6Villa S. Giuseppe Hospital, Hermanas Hospitalarias, Ascoli Piceno, Italy
7Department of “Scienze della Formazione”, University of Catania, Italy
8Department of Neurology and Psychiatry, “Sapienza” University of Rome, Italy
9Hermanas Hospitalarias, FoRiPsi, Department of Clinical Neurosciences, Villa San Benedetto Menni, Albese con Cassano, Como, Italy
10Department of Psychiatry and Neuropsychology, University of Maastricht, The Netherlands
11Department of Psychiatry and Behavioral Sciences, Leonard Miller School of Medicine, University of Miami, Florida, USA
12Hospital Farmacy, Hospital “G. Mazzini”, ASL 4 Teramo, Italy
13Institute of Psychiatry and Psychology, Catholic University of Sacred Heart, Rome, Italy
14NHS, Department of Mental Health, Mental Health Centre, Atri, ASL 4 Teramo, Italy
15NHS, Department of Mental Health, Psychiatric Service of Diagnosis and Treatment, Hospital “Madonna Del Soccorso”, ASUR 12, San Benedetto del Tronto, Italy

Address for correspondence: Domenico De Berardis, National Health Service, Department of Mental, Health, Psychiatric Service of Diagnosis and Treatment, “G. Mazzini” Hospital, P.zza Italia 1, 64100 Teramo, Italy, Tel.: +39 0861429708; fax: +39 0861429709, E-mail: dodebera@aliceposta.it

Abstract

Schizophrenia is a chronic and disabling disorder, characterized by positive, negative, cognitive and affective symptoms. The first episode of schizophrenia (FES) usually occurs after a variable period of prodromic symptoms and the importance of early detection and treatment of FES has been raised in psychiatric literature from long time. In fact, it has been suggested that the first years of the schizophrenic disorder may be a critical period for long-term prognosis, as the relationship between the poor medication adherence and poorer outcome is well demonstrated. Long-acting injectable formulations of second-generation antipsychotics (SGAs-LAIs) provide constant medication delivery and the potential for improved adherence. Currently, four SGAs-LAIs are available for the treatment of schizophrenia, risperidone long-acting injectable, olanzapine pamoate, paliperidone palmitate and aripiprazole. Several studies have also demonstrated efficacy and safety of such drugs in patients with schizophrenia. In the present paper the literature on SGAs-LAIs atypical antipsychotics in the treatment of FES will be reviewed and practical advice will be given concerning the use of this drug in the everyday clinical practice.

Keywords: first-episode of schizophrenia, long-acting, second-generation antipsychotics, risperidone long-acting, olanzapine pamoate, paliperidone palmitate, schizophrenia, adherence, efficacy, tolerability

Introduction

Schizophrenia is a chronic and disabling disorder, characterized by positive, negative, cognitive, and affective symptoms (13). The course of schizophrenia may be complicated by the potential occurrence of suicidal and/or violent behaviors, substance abuse and medical comorbidity, with sustained morbidity and disability that may severely impair quality of life of patient and shorten their lives (46). The first episode of schizophrenia (FES) usually occurs after a variable period of prodromic symptoms and the importance of early detection and treatment of first-episode schizophrenia has been raised in psychiatric literature from long time (7). In fact, it has been suggested that the first years of the schizophrenic disorder may be a critical period for long-term prognosis, as the relationship between the delay in treatment of FES and poorer outcome is well demonstrated (8).

Long-acting injectable antipsychotics (LAIs) have been commonly considered as an adherence intervention for patients who are ‘non-compliant’ with the oral medication they have been prescribed (9). In particular, there are some concern of their use as a first-line treatment in FES, and this may be particularly true for first generation LAIs, that are burdened by several adverse effects (such as extrapyramidal side effects, tadive diskynesia and QT prolongation) (10). However, the availability of the second-generation long-acting injectable antipsychotics (SGAs-LAIs) represents an advance in the long-term management of schizophrenia, particularly regarding subjective tolerability (11). In fact, SGAs-LAIs have been shown to have at least equal or even superior efficacy and to be associated with less propensity to induce parkinsonism and tardive diskynesia compared with first generation LAIs, although some SGAs-LAIs may be associated with an increased incidence of metabolic side effects (12).

Interestingly, another point in favour of SGAs-LAIs could be their potential efficacy in problematic patients with schizophrenia such as those in comorbidity with alcohol and substance use disorder. This aspect has been recently reported in some studies. Risperidone long-acting injection (RLAI) was more effective than zuclopenthixol-depot in improving substance abuse and schizophrenia symptoms in subjects with dual diagnosis (13). This observation was confirmed also by Meredith et al. (14).

Currently, in Italy, there are four available SGAs-LAIs (Tab. 1): RLAI, paliperidone palmitate (PLAI), olanzapine pamoate (OLAI) and aripiprazole. In the present review the literature on SGAs-LAIs in the treatment of FES will be reviewed and practical advice will be given concerning the use of these drugs in the everyday “real world” clinical practice.

Table 1Table 1
SGA-LAIs currently available in Italy.

Schizophrenia is associated with poor medication adherence: is this mostly true for first episode?
It is generally recognized that treatment non-adherence is a remarkable problem in the management of patient with schizophrenic disorder, with reported discontinuation rates more than 50% in several studies (1517). It has been demonstrated that adherence with oral conventional and/or atypical antipsychotics is poor in both short and long term (18) and is associated with relapse, even if it is unclear whether non-adherence precedes the relapse or is a consequence of it (1921). In the Clinical Antipsychotic Trials for Intervention Effectiveness (CATIE) trial (22) the 74% of patients discontinued the treatment prematurely. Moreover, in the European First Episode Schizophrenia Trial (EUFEST) about 40% of patients discontinued their treatment within one year after the onset of the disorder (23).

In FES, there are a couple of variables that may cooperate in causing nonadherence (24, 25). The most common are the lack of insight, the sensation of a subjective distress as a result of side effects, the fear of potential side effects and the poor medication efficacy with symptoms’ persistence (2628). However, above all, one of the main factor associated with non adherence may be the wrong belief that treatment is no longer needed after few weeks or months, especially (and paradoxically) in presence of a perceived improvement (29). Furthermore, the comorbidity with substance abuse, the lack of a familiar and social effective support, the failure of therapeutic alliance, the complexity of some treatment regimens and, last but not least, the perceived stigma that is still associated with psychiatric disorders and antipsychotic treatment, may further contribute to non-adherence (3034).

It has been demonstrated that neurocognitive dysfunctions are important predictors for non-adherence in patient with schizophrenia (35). The importance of cognitive deficits in schizophrenia is highlighted by reports indicating that the severity of cognitive deficits is predictive of treatment compliance, adherence, and risk of relapse among FES individuals (3638). Moreover, social cognition appears to be compromised in all FES patients compared to healthy controls and this may be also a predictor of non adherence (39).

Even in case of successfully treatment of FES, the eventual non-adherence may be associated not only with relapse, but also with an increased mortality (40, 41). In fact, treatment nonadherence after the FES may be associated with increased suicide rates and death for consequences of medical illnessess such as diabetes, cardiovascular disorders, cancer and stroke (4244). As stated by Kane (45) “…clinicians should educate patients about adherence and consider treatment options that will improve adherence. Recovery is attained when patients experience symptom remission, vocational role fulfillment, independent living, and social relationships for at least 2 years”. Moreover, it has been demonstrated that SGAs-LAIs treatment may reduce the suicide risk in patient with schizophrenia, simply improving adherence. Ascher-Svanum et al. (46) demonstrated that OLAI was associated with a significantly lower incidence of psychiatric hospitalization due to suicide threats. However, most studies investigating incidence and predictors of suicide and mortality in patients with FES have relatively short follow-up intervals and, to date, no data have been published concerning the reduction of suicide risk with SGAs-LAIs treatment.

Therefore, the availability of SGAs-LAIs may be a favourable treatment option and should be considered since the first episode and not only at the last stages of schizophrenia (47). As argued by Stephen Stahl (48), “shall the last be first?”.

Current guidelines on LAIs use in first-episode Schizophrenia
In 1998, the first published guidelines recommended that conventional LAIs should be considered for any patients with schizophrenia when a long-term treatment was necessary (49).

More recently, the American Psychiatric Association (50) recommended LAIs for patients with recurrent relapses related to partial or full nonadherence, but not explicitally as a first-line treatment in FES. In line with APA guidelines, also the Canadian Psychiatric Association Clinical Practice Guidelines (51) recommended LAIs to lower nonadherence in patients with recurrent and multiple episodes and/or with persistent positive symptoms. Also the International Psychopharmacology Algorithm Projects (IPAPs) schizophrenia algorithm (http://www.ipap.org/schiz/) proposed the utilization of LAIs in patients with partial or complete noncompliance: again, there is no explicit recommendation on their use as a first-line treatment in FES, but one can argue that, implicitally, in case of non adherence, they may be accordingly used. On the other hand, the National Clinical Excellence (NICE) guidelines (52) recommend that LAIs (especially SGAs-LAIs) may be given after an acute episode of schizophrenia if the patient prefers and to avoid covert non-adherence to oral medication. This was also the advice of the World Federation of Societies of Biological Psychiatry (53). Also the PORT Recommendations (54) proposed that “long-acting injection antipsychotic medication maintenance treatment should be available and considered for persons who have a history of frequent relapse on oral medication, or a history of problems with adherence on oral medication, or who prefer the long-acting injection depot regimen”.

In general, the current guidelines on schizophrenia treatment consider LAIs as drugs of choice for long-term therapy in patients who are nonadherent with antipsychotic medication and the use of such medications, especially SGAs-LAIs, may represent a promising strategy that should be employed in such patients to achieve symptoms’ remission, prevent relapse and reduce all-causes mortality (55). Thus, even not formally declared, it can be argued that, implicitally, in all cases of non adherence in FES, the LAIs (preferably SGAs-LAIs) may be consequently used.

Psychiatrists’ attitude toward LAIs use in the first episode of schizophrenia
Despite the effectiveness of LAIs in the treatment of schizophrenia, sometimes psychiatrists’ attitude toward these agents is negative, especially in the treatment of FES (56, 57). In fact, concerning FES, some of the common reasons against early usage of LAIs are the long-established association of depot treatment as a coercive and stigmatizing therapy, the recommendation of guidelines to use first oral antipsychotics, the belief that a good therapeutic relationship may be a pro-adherence factor, the relative lack of long-term studies and the tolerability profile of LAIs (58). Although LAIs were recognized to be adherence-enhancing and strongly preventive of relapse, a great number of psychiatrists seemed to avoid prescribing depot antipsychotics especially for patients with FES (59). Psychiatrists frequently imagine that patients with FES would not accept depot antipsychotics and that depots are generally eligible for chronic patients (60). However, it should be argued that these belief are often not supported by scientific evidences that, instead, point out the need of ensuring adherence after FES even with the use of LAIs (61).

Moreover, lack of knowledge, misperceptions and stigma related to LAIs and other treatment options should be addressed by providing patients with accurate information (62). Psychiatrist should avoid making assumptions about patients’ attitudes to LAIs as even if these attitudes vary, some FES patients not prescribed LAIs are favorable to considering this treatment (63). However, depot antipsychotics prescribing should always result from a shared decisionmaking process in which clinicians and patients explicitly discuss the pros and cons of different formulations and drugs (57).

Llorca et al. (64) selected 53 French psychiatrists working in the “real world” clinical practice and considered to be experts in the use of LAIs and submitted to them a questionnaire consisting of 32 questions that covered 539 therapeutic options grouped into 3 areas that were judged as essential: 1) Target-population: Description of the different indications of the LAI antipsychotics and of the most appropriate period of the illness to introduce the treatment. 2) Prescription and use: Choice of the molecule, methods of introduction, specific strategies depending on the psychiatric disorder or co-morbidities, and treatment monitoring. 3) Specific population: Use of LAI antipsychotics in pregnant women, elderly patients, subjects in a precarious situation, and subjects having to be treated in a prison establishment. Results showed that, in an evidence-based clinical approach, psychiatrists, through shared decision-making, should be systematically offering to most patients that require long-term antipsychotic treatment an LAI antipsychotic as a first-line treatment. In particular, SGA-LAIs were recommended as maintenance treatment after the first episode of schizophrenia whereas first-generation LAIs were not recommended in the early course of schizophrenia.

However, it should be specified that, in some patients, a decision not to consider LAIs may be more suitable. As pointed out by Kane and Garcia-Ribera (65), this may be particularly true in: 1) patients who has consistently demonstrated his or her ability to take oral medication and chooses to continue doing so, 2) patients who regardless of adequate discussion of potential benefits and risks, and sufficient psychoeducation regarding the nature of the illness, obstinately refuses even to try a LAI and 3) patient unable to tolerate or unresponsive to the drugs available in LAI formulations.

SGAs-LAIs in the treatment of first episode in patients with schizophrenia
The successful treatment of FES is essential to improve long-term outcomes, as it has been demonstrated that the majority of clinical and psychosocial deterioration with cognitive impairment and increasing structural changes in brain volume take place within the first five years from the disorder’ onset (66). In FES, pharmacological intervention favourably affect symptomatic control and functional outcomes and, therefore, the primary objective of treatment during this phase is to prevent relapses, possibly restoring the socio-occupational functioning to the premorbid level (67).

However, as above described, poor medication adherence is particularly common in FES and the most important goal should be the improvement of medication adherence. In a Finnish cohort study (68) conducted on 2588 FES patients, it was demonstrated that fewer than 50% of patients in the Finnish healthcare system continued treatment for the first two months after their first hospitalization. Grippingly, the type of administration affected relapse and LAIs had a 64% lower relapse rate than the equivalent oral treatment. Regarding which LAI may be more appropriate for FES, there is, to date, a relative lacking of long-term RCTs comparing LAIs with oral medication regarding effectiveness, tolerability, relapse prevention and overall outcomes (69, 70). Research supporting the usefulness of SGA-LAIs in FES has been mainly performed using RLAI since RLAI was the first marketed SGA-LAI and, therefore, the most evidence in the treatment of FES concerns it (Tab. 2).

Table 2Table 2
Summary of studies that evaluated SGA-LAIs in the treatment of early schizophrenia and FES.

Risperidone long-acting injection (RLAI). RLAI represents the first long acting formulation of second-generation antipsychotic drugs, launched in North America in 2004, available for the treatment of schizophrenia and closely related psychiatric conditions (71). Several studies demostrated that RLAI administered once every 2 weeks, has notably efficacy and well tolerated in both schizophrenia and schizoaffective disorder patients (7277). Due to its tolerability, RLAI is an important antipsychotic treatment available for use in vulnerable groups of patients, as elderly patients with psychosis (78). Compared to oral atypical and conventional long-acting agents, RLAI reduced the numbers of relapses in schizophrenia patients (7982). In addiction, concomitant medications as anticholinergics, anxiolytics, hypnotics, sedatives, antipsychotics used in combination, antidepressants and mood stabilizers were reported to be reduced in use (38, 83). For its favourable profile, it may be a rational choice for patients with FES or in the early phases of schizophrenia as demonstrated by Parellada et al. (84), Lasser et al. (85), Napryeyenko et al. (86) and Malla et al. (87).

Specifically concerning FES, Kim et al. (88) conducted a prospective, naturalistic, controlled, and open-label study over two years in 50 patients with FES. 22 patients with schizophrenia were assigned to the RLAI group and 28 patients with schizophrenia to the oral risperidone group as control. RLAI group showed significantly lower relapse rate and higher medication adherence than the control group. On the other hand, Emsley et al. (89, 90) evaluated the efficacy of RLAI (25–50 mg per every two weeks) among 50 patients with FES and 36 of these (72%) completed the trial, suggesting a relatively low discontinuation rate. A reduction of at least 50% on the PANSS total score was obtained by 42 of the 50 FES patients (84%) and 32 patients (64%) met the Remission in Schizophrenia Working Group (RSWG) remission criteria. 31 patients (97%) among that 32, maintained this remission status for two years until the completion of the study. Weiden et al. (91) conducted a prospective randomized controlled trial to compare acceptance and adherence between RLAI and continued oral antipsychotics (such as haloperidol, olanzapine, quetiapine and risperidone) in FES. Patients who were treated with RLAI were significantly more adherent than patients who were taking oral antipsychotics.

More recently, Bartzokis et al. (92) evaluated the treatment effects of RLAI on frontal lobe white matter volume in FES patients in a randomized 6-month trial. Researchers, using inversion recovery magnetic resonance imaging, showed that the frontal lobe white matter volume was stable in the RLAI group whereas it significantly decreased in the oral risperidone group. This finding suggests that RLAI can improve the trajectory of myelination in FES patients and may be related with positive effects on cognitive functions and processes. Moreover, Tiihonen et al. (65) conducted a nationwide cohort study in Finland between 2000 and 2007 and evaluated 2588 patients with schizophrenia hospitalized for the first time. They found the RLAI or depot formulations were associated with a 50–65% reduced rehospitalisation rate compared to the identical medication in oral form. On the other hand, Weiden et al. (93) have also demonstrated that acceptance of RLAI was associated with an initial adherence benefit that was not sustained over time. However, they also observed that. Even if non-adherence was almost universal in first-episode cohort, nonadherence was more easily detected among FES patients treated with RLAI therapy than it was with oral antipsychotics.

Other SGAs-LAIs. Fu et al. (94), in a post-hoc, subgroup analysis of a 13-week, double-blind, double-dummy, multicenter study, evaluated patients recently diagnosed with schizophrenia (≤ 5 years) who were administered PLAI or RLAI. They found that the tolerability and efficacy of PLAI and RLAI were generally similar over 13 weeks.

To date, no studies were present concerning OLAI and aripiprazole long-acting in the treatment of early schizophrenia or FES.

Conclusions

All SGA-LAIs have been approved for long-term treatment of patients with schizophrenia (95). Potential advantages and disvantages of SGA-LAIs in the treatment of FES in everyday clinical practice are summarized in Table 3. On the basis of existing literature, it can be argued that the usage of SGA-LAIs in first-episode schizophrenia may have beneficial impacts on treatment outcomes, but, to date, evidences are limited to RLAI. Due to its efficacy and tolerability, RLAI is an important antipsychotic treatment available for use in at-risk group of patients, such as FES patients. Especially in terms of adherence and relapse prevention, prescribing other SGA-LAIs might be another treatment option even in FES, when RLAI is not indicated, but no evidences still exist. In fact, there is limited research data (focused only on RLAI) for clinical trials in FES. More well-designed, randomized controlled clinical trials for the use of SGA-LAIs in FES are undoubtely needed.

Table 3Table 3
Summary of potential pros and cons of SGA-LAIs in FES as compared to oral antipsychotics.

References
1.
Insel TR. Rethinking schizophrenia. Nature. 2010;468:187–93.
2.
Ferri F, Salone A, Ebisch SJ, De Berardis D, Romani GL, Ferro FM, Gallese V. Action verb understanding in first-episode schizophrenia: is there evidence for a simulation deficit? Neuropsychologia. 2012;50:988–96.
3.
Ebisch SJ, Salone A, Ferri F, De Berardis D, Romani GL, Ferro FM, Gallese V. Out of touch with reality? Social perception in first-episode schizophrenia. Soc Cogn Affect Neurosci. 2013;8:394–403.
4.
Lieberman JA. Is schizophrenia a neurodegenerative disorder?: a clinical and pathophysiological perspective. Biol Psychiatry. 1999;46:729–739.
5.
Jarskog LF, Miyamoto S, Lieberman JA. Schizophrenia: new pathological insights and therapies. Annu Rev Med. 2007;58:49–61.
6.
Marasco V, De Berardis D, Serroni N, Campanella D, Acciavatti T, Caltabiano M, Olivieri L, Rapini G, Cicconetti A, Carano A, La Rovere R, Di Iorio G, Moschetta FS, Di Giannantonio M. Alexithymia and suicide risk among patients with schizophrenia: preliminary findings of a cross-sectional study. Riv Psichiatr. 2011;46:31–7.
7.
Chien WT, Yip AL. Current approaches to treatments for schizophrenia spectrum disorders, part I: an overview and medical treatments. Neuropsychiatr Dis Treat. 2013;9:1311–1332.
8.
Robinson D, Woerner MG, Alvir JM, Bilder R, Goldman R, Geisler S, et al. Predictors of relapse following response from a first episode of schizophrenia or schizoaffective disorder. Arch Gen Psychiatry. 1999;56:241–247.
9.
Kane JM, Garcia-Ribera C. Clinical guideline recommendations for antipsychotic long-acting injections. Br J Psychiatry. 2009;2:S63–7.
10.
Barnes TR, Curson DA. Long-term depot antipsychotics. A risk-benefit assessment. Drug Saf. 1994;10:464–479.
11.
Citrome L. New second-generation long-acting injectable antipsychotics for the treatment of schizophrenia. Expert Rev Neurother. 2013;13:767–783.
12.
Fleischhacker WW. Second-generation antipsychotic long-acting injections: systematic review. Br J Psychiatry. 2009;52:S29–36.
13.
Rubio G, Martínez I, Ponce G, Jiménez-Arriero MA, López-Muñoz F, Alamo C. Long-acting injectable risperidone compared with zuclopenthixol in the treatment of schizophrenia with substance abuse comorbidity. Can J Psychiatry. 2006;51:531–9.
14.
Meredith CW, Jaffe C, Cherrier M, Robinson JP, Malte CA, Yanasak EV, Kennedy A, Ferguson LC, Tapp AM, Saxon AJ. Open trial of injectable risperidone for methamphetamine dependence. J Addict Med. 2009;3:55–65.
15.
Kane JM, Quitkin F, Rifkin A, Ramos-Lorenzi JR, Nayak DV. Fluphenazine versus placebo in patients with remitted acute first episode schizophrenia. Arch Gen Psychiatry. 1982;39:70–73.
16.
Crow TJ, MacMillan JF, Johnson AL, Johnstone EC. A randomised controlled trial of prophylactic neuroleptic treatment. Br J Psychiatry. 1986;148:120–127.
17.
Lehman AF, Steinwachs DM. Survey Co-Investigators of the PORT Project. Patterns of usual care for schizophrenia. Initial results from the Schizophrenia Patient Outcomes Research Team (PORT) Client Survey. Schizophr Bull. 1998;24:11–20.
18.
Chan TC, Chang WC, Hui CL, Chan SK, Lee EH, Chen EY. Rate and predictors of disengagement from a 2-year early intervention program for psychosis in Hong Kong. Schizophr Res. 2014;153:204–208.
19.
Fenton WS, Blyler CR, Heinssen RK. Determinants of medication compliance in schizophrenia: empirical and clinical findings. Schizophr Bull. 1997;23:637–651.
20.
Robinson D, Woerner MG, Alvir JM, Bilder R, Goldman R, Geisler S, Koreen A, Sheitman B, Chakos M, Mayerhoff D, Lieberman JA. Predictors of relapse following response from a first episode of schizophrenia or schizoaffective disorder. Arch Gen Psychiatry. 1999;56:241–247.
21.
De Berardis D, Serroni N, Campanella D, Olivieri L, Marini S, Moschetta FS, Martinotti G, Di Giannantonio M. Safety and efficacy of combined clozapine-azathioprine treatment in a case of resistant schizophrenia associated with Behçet’s disease: a 2-year follow-up. Gen Hosp Psychiatry. 2013;35:213.e9–11.
22.
Lieberman JA, Stroup TS, McEvoy JP, Swartz MS, Rosenheck RA, Perkins DO, Keefe RS, Davis SM, Davis CE, Lebowitz BD, Severe J, Hsiao JK. Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) Investigators. Effectiveness of antipsychotic drugs in patients with chronic schizophrenia. N Engl J Med. 2005;353:1209–1223.
23.
Kahn RS, Fleischhacker WW, Boter H, Davidson M, Vergouwe Y, Keet IP, Gheorghe MD, Rybakowski JK, Galderisi S, Libiger J, Hummer M, Dollfus S, López-Ibor JJ, Hranov LG, Gaebel W, Peuskens J, Lindefors N, Riecher-Rössler A, Grobbee DE. EUFEST study group. Effectiveness of antipsychotic drugs in first-episode schizophrenia and schizophreniform disorder: an open randomised clinical trial. Lancet. 2008;371:1085–1089.
24.
Macaluso M, McKnight S. Overcoming medication nonadherence in schizophrenia: Strategies that can reduce harm. Current Psychiatry. 2013;12:14–20.
25.
Acosta FJ, Bosch E, Sarmiento G, Juanes N, Caballero-Hidalgo A, Mayans T. Evaluation of noncompliance in schizophrenia patients using electronic monitoring (MEMS) and its relationship to sociodemographic, clinical and psychopathological variables. Schizophr Res. 2009;107:213–217.
26.
Byerly MJ, Nakonezny PA, Lescouflair E. Antipsychotic medication adherence in schizophrenia. Psychiatr Clin North Am. 2007;30:437–452.
27.
Roberts DL, Velligan DI. Medication adherence in schizophrenia. Drug Discov Today Ther Strateg. 2011;8:11–15.
28.
De Berardis D, Serroni N, Campanella D, Olivieri L, Ferri F, Carano A, Cavuto M, Martinotti G, Cicconetti A, Piersanti M, Saverio Moschetta F, Di Giannantonio M. Update on the adverse effects of clozapine: focus on myocarditis. Curr Drug Saf. 2012;7:55–62.
29.
Gibson S, Brand SL, Burt S, Boden ZV, Benson O. Understanding treatment non-adherence in schizophrenia and bipolar disorder: a survey of what service users do and why. BMC Psychiatry. 2013;13:153.
30.
Dibonaventura M, Gabriel S, Dupclay L, Gupta S, Kim E. A patient perspective of the impact of medication side effects on adherence: results of a cross-sectional nationwide survey of patients with schizophrenia. BMC Psychiatry. 2012;12:20.
31.
Misdrahi D, Petit M, Blanc O, Bayle F, Llorca PM. The influence of therapeutic alliance and insight on medication adherence in schizophrenia. Nord J Psychiatry. 2012;66:49–54.
32.
Sapra M, Weiden PJ, Schooler NR, Sunakawa-McMillan A, Uzenoff S, Burkholder P. Reasons for adherence and nonadherence: a pilot study comparing first- and multi-episode schizophrenia patients. Clin Schizophr Relat Psychoses. 2014;7:199–206.
33.
Yang J, Ko YH, Paik JW, Lee MS, Han C, Joe SH, Jung IK, Jung HG, Kim SH. Symptom severity and attitudes toward medication: impacts on adherence in outpatients with schizophrenia. Schizophr Res. 2012;134:226–231.
34.
Mwansisya TE, Yi W, Wang Z, Yang B, Li L, Wang P, Liu C, Wu G, Xue Z, Liu Z. Comparison of psychosocial determinants in inpatients with first-episode and chronic schizophrenia in china. Arch Psychiatr Nurs. 2013;27:32–41.
35.
Kucukalić A, Dzubur-Kulenović A, Mehmedika-Suljić E. Relapse prevention in schizophrenia - new therapeutic challenges. Psychiatr Danub. 2007;19:362–366.
36.
Chen EY, Hui CL, Dunn EL, Miao MY, Yeung WS, Wong CK, Chan WF, Tang WN. A prospective 3-year longitudinal study of cognitive predictors of relapse in first-episode schizophrenic patients. Schizophr Res. 2005;77:99–104.
37.
Cha DS, Kudlow PA, Baskaran A, Mansur RB, McIntyre RS. Implications of epigenetic modulation for novel treatment approaches in patients with schizophrenia. Neuropharmacology. 2014;77:481–486.
38.
Hui CL, Wong GH, Tang JY, Chang WC, Chan SK, Lee EH, Lam MM, Chiu CP, Law CW, Chung DW, Tso S, Pang EP, Chan KT, Wong YC, Mo FY, Chan KP, Hung SF, Honer WG, Chen EY. Predicting 1-year risk for relapse in patients who have discontinued or continued quetiapine after remission from first-episode psychosis. Schizophr Res. 2013;150:297–302.
39.
Montreuil T, Bodnar M, Bertrand MC, Malla AK, Joober R, Lepage M. Social cognitive markers of short-term clinical outcome in first-episode psychosis. Clin Schizophr Relat Psychoses. 2010;4:105–114.
40.
Saha S, Chant D, McGrath J. A systematic review of mortality in schizophrenia: is the differential mortality gap worsening over time? Arch Gen Psychiatry. 2007;64:1123–1131.
41.
Thomas P. Relapse: causes and consequences. Encephale. 2013 Sep;39( Suppl 2):S79–82.
42.
Misdrahi D, Llorca PM, Lançon C, Bayle FJ. Compliance in schizophrenia: predictive factors, therapeutical considerations and research implications. Encephale. 2002;28:266–272.
43.
Kreyenbuhl J, Dixon LB, McCarthy JF, Soliman S, Ignacio RV, Valenstein M. Does adherence to medications for type 2 diabetes differ between individuals with vs without schizophrenia? Schizophr Bull. 2010;36:428–435.
44.
Ebisch SJ, Mantini D, Northoff G, Salone A, De Berardis D, Ferri F, Ferro FM, Di Giannantonio M, Romani GL, Gallese V. Altered brain long-range functional interactions underlying the link between aberrant self-experience and self-other relationship in first-episode schizophrenia. Schizophr Bull. 2014;40:1072–1082.
45.
Kane JM. Improving patient outcomes in schizophrenia: achieving remission, preventing relapse, and measuring success. J Clin Psychiatry. 2013;74:e18.
46.
Ascher-Svanum H, Novick D, Haro JM, Bertsch J, McDonnell D, Detke H. Predictors of psychiatric hospitalization during 6 months of maintenance treatment with olanzapine long-acting injection: post hoc analysis of a randomized, double-blind study. BMC Psychiatry. 2013;13:224.
47.
Taylor M, Ng KY. Should long-acting (depot) antipsychotics be used in early schizophrenia? A systematic review. Aust N Z J Psychiatry. 2013;47:624–630.
48.
Stahl SM. Long-acting injectable antipsychotics: shall the last be first? CNS Spectr. 2014;19:3–5.
49.
Kane JM, Aguglia E, Altamura AC, Ayuso Gutierrez JL, Brunello N, Fleischhacker WW, Gaebel W, Gerlach J, Guelfi JD, Kissling W, Lapierre YD, Lindström E, Mendlewicz J, Racagni G, Carulla LS, Schooler NR. Guidelines for depot antipsychotic treatment in schizophrenia. European Neuropsychopharmacology Consensus Conference in Siena, Italy. Eur Neuropsychopharmacol. 1998;8:55–66.
50.
American Psychiatric Association Work Group on Schizophrenia. Practice guideline for the treatment of patients with schizophrenia, second edition. Am J Psychiatry. 2004;161:1–56.
51.
Canadian Psychiatric Association. Clinical practice guidelines: treatment of schizophrenia. Can J Psychiatry. 2005;50:7–56.
52.
National Institute for Health and Clinical Excellence. Schizophrenia: Full National Clinical Guideline on Core Interventions in Primary and Secondary Care. Gaskell/British Psychological Society; 2003.
53.
Hasan A, Falkai P, Wobrock T, Lieberman J, Glenthoj B, Gattaz WF, Thibaut F, Möller HJ. WFSBP Task force on Treatment Guidelines for Schizophrenia. World Federation of Societies of Biological Psychiatry (WFSBP) guidelines for biological treatment of schizophrenia, part 2: update 2012 on the long-term treatment of schizophrenia and management of antipsychotic-induced side effects. World J Biol Psychiatry. 2013;14:2–44.
54.
Lehman AF, Steinwachs DM. Survey Co-Investigators of the PORT Project. Patterns of usual care for schizophrenia. Initial results from the Schizophrenia Patient Outcomes Research Team (PORT) Client Survey. Schizophr Bull. 1998;24:11–20.
55.
Moore TA. Schizophrenia treatment guidelines in the United States. Clin Schizophr Relat Psychoses. 2011;5:40–49.
56.
Heres S, Hamann J, Kissling W, Leucht S. Attitudes of psychiatrists toward antipsychotic depot medication. J Clin Psychiatry. 2006;67:1948–1953.
57.
Mond J, Morice R, Owen C, Korten A. Use of antipsychotic medications in Australia between July 1995 and December 2001. Aust N Z J Psychiatry. 2003;37:55–61.
58.
Heres S, Hamann J, Mendel R, Wickelmaier F, Pajonk FG, Leucht S, Kissling W. Identifying the profile of optimal candidates for antipsychotic depot therapy A cluster analysis. Prog Neuropsychopharmacol Biol Psychiatry. 2008;32:1987–1993.
59.
Jeong HG, Lee MS. Long-acting Injectable Antipsychotics in First-episode Schizophrenia. Clin Psychopharmacol Neurosci. 2013;11:1–6.
60.
Kirschner M, Theodoridou A, Fusar-Poli P, Kaiser S, Jäger M. Patients’ and clinicians’ attitude towards long-acting depot antipsychotics in subjects with a first episode of psychosis. Ther Adv Psychopharmacol. 2013;3:89–99.
61.
Heres S, Lambert M, Vauth R. Treatment of early episode in patients with schizophrenia: the role of long acting antipsychotics. Eur Psychiatry. 2014;29S2:1409–1413.
62.
Das AK, Malik A, Haddad PM. A qualitative study of the attitudes of patients in an early intervention service towards antipsychotic long-acting injections. Ther Adv Psychopharmacol. 2014;4:179–185.
63.
Iyer S, Banks N, Roy MA, Tibbo P, Williams R, Manchanda R, Chue P, Malla A. A qualitative study of experiences with and perceptions regarding long-acting injectable antipsychotics: Part I-patient perspectives. Can J Psychiatry. 2013;58(5 Suppl 1):14S–22S.
64.
Llorca PM, Abbar M, Courtet P, Guillaume S, Lancrenon S, Samalin L. Guidelines for the use and management of long-acting injectable antipsychotics in serious mental illness. BMC Psychiatry. 2013;13:340.
65.
Kane JM, Garcia- Ribera C. Clinical guideline recommendations for antipsychotic long- acting injections. Br J Psychiatry Suppl. 2009;52:S63–7.
66.
Marchesi C, Affaticati A, Monici A, De Panfilis C, Ossola P, Tonna M. Severity of core symptoms in first episode schizophrenia and long-term remission. Psychiatry Res. 2015;225:129–132.
67.
Emsley R, Chiliza B, Asmal L, Mashile M, Fusar-Poli P. Long-acting injectable antipsychotics in early psychosis: a literature review. Early Interv Psychiatry. 2013;7:247–254.
68.
Tiihonen J, Haukka J, Taylor M, Haddad PM, Patel MX, Korhonen P. A nationwide cohort study of oral and depot antipsychotics after first hospitalization for schizophrenia. Am J Psychiatry. 2011;168:603–609.
69.
Jeong HG, Lee MS. Long-acting Injectable Antipsychotics in First-episode Schizophrenia. Clin Psychopharmacol Neurosci. 2013;11:1–6.
70.
Parellada E, Velligan D, Emsley R, Kissling W. Long-acting injectable antipsychotics in first-episode schizophrenia. Schizophr Res Treatment. 2012:318535.
71.
Chue P. Long-acting risperidone injection: efficacy, safety, and cost-effectiveness of the first long-acting atypical antipsychotic. Neuropsychiatr Dis Treat. 2007;3:13–39.
72.
Fleischhacker WW, Eerdekens M, Karcher K, Remington G, Llorca PM, Chrzanowski W, Martin S, Gefvert O. Treatment of schizophrenia with long-acting injectable risperidone: a 12-month open-label trial of the first long-acting second-generation antipsychotic. J Clin Psychiatry. 2003;64:1250–1257.
73.
Kane JM, Eerdekens M, Lindenmayer JP, Keith SJ, Lesem M, Karcher K. Long-acting injectable risperidone: efficacy and safety of the first long-acting atypical antipsychotics. Am J Psychiatry. 2003;160:1125–1132.
74.
Lindenmayer JP, Eerdekens E, Berry SA, Eerdekens M. Safety and efficacy of long-acting risperidone in schizophrenia: a 12-week, multicenter, open-label study in stable patients switched from typical and atypical oral antipsychotics. J Clin Psychiatry. 2004;65:1084–1089.
75.
Turner M, Eerdekens E, Jacko M, Eerdekens M. Long-acting injectable risperidone: safety and efficacy in stable patients switched from conventional depot antipsychotics. Int Clin Psychopharmacol. 2004;19:241–249.
76.
Chue P, Eerdekens M, Augustyns I, Lachaux B, Molcan P, Eriksson L, Pretorius H, David AS. Comparative efficacy and safety of long-acting risperidone and risperidone oral tablets. Eur Neuropsychopharmacol. 2005;15:111–117.
77.
Möller HJ, Llorca PM, Sacchetti E, Martin SD, Medori R, Parellada E. StoRMi Study Group. Efficacy and safety of direct transition to risperidone long-acting injectable in patients treated with various antipsychotic therapies. Int Clin Psychopharmacol. 2005;20:121–130.
78.
Singh D, O’ Connor DW. Efficacy and safety of risperidone long-acting injection in elderly people with schizophrenia. Clin Interv Aging. 2009;4:351–355.
79.
Chue PS, Heeg B, Buskens E, van Hout BA. Modelling the impact of compliance on the costs and effects of long-acting risperidone in Canada. Pharmacoeconomics. 2005;23:62–74.
80.
De Graeve D, Smet A, Mehnert A, Caleo S, Miadi-Fargier H, Mosqueda GJ, Lecompte D, Peuskens J. Long-acting risperidone compared with oral olanzapine and haloperidol depot in schizophrenia: a Belgian cost-effectiveness analysis. Pharmacoeconomics. 2005;23:35–47.
81.
Edwards NC, Locklear JC, Rupnow MF, Diamond RJ. Cost effectiveness of long-acting risperidone injection versus alternative antipsychotic agents in patients with schizophrenia in the USA. Pharmacoeconomics. 2005;23:75–89.
82.
Laux G, Heeg B, van Hout BA, Mehnert A. Costs and effects of long-acting risperidone compared with oral atypical and conventional depot formulations in Germany. Pharmacoeconomics. 2005;23:49–61.
83.
Taylor DM, Young CL, Mace S, Patel MX. Early clinical experience with risperidone long-acting injection: a prospective, 6- month follow-up of 100 patients. J Clin Psychiatry. 2004;65:1076–1083.
84.
Parellada E, Andrezina R, Milanova V, Glue P, Masiak M, Turner MS, Medori R, Gaebel W. Patients in the early phases of schizophrenia and schizoaffective disorders effectively treated with risperidone long-acting injectable. J Psychopharmacol. 2005;19:5–14.
85.
Lasser RA, Bossie CA, Zhu Y, Locklear JC, Kane JM. Long-acting risperidone in young adults with early schizophrenia or schizoaffective illness. Ann Clin Psychiatry. 2007;19:65–71.
86.
Napryeyenko O, Burba B, Martinez G, Neznanov NG, Fischel T, Baylé FJ, Corrivetti G, Smeraldi E, Rabinowitz J, Schreiner A. Risperidone long-acting injectable in recent-onset schizophrenia examined with clinician and patient self-report measures. J Clin Psychopharmacol. 2010;30:200–202.
87.
Malla A, Chue P, Jordan G, Stip E, Koczerginski D, Milliken H, Joseph A, Williams R, Adams B, Manchanda R, Oyewumi K, Roy MA. An Exploratory Open-Label Randomized Trial Comparing Risperidone Long Acting Injectable (RLAI) with Oral Antipsychotic Medication in the Treatment of Early Psychosis. Clin Schizophr Relat Psychoses. 2013;17:1–26.
88.
Kim B, Lee SH, Choi TK, Suh S, Kim YW, Lee E, Yook KH. Effectiveness of risperidone long-acting injection in first-episode schizophrenia: in naturalistic setting. Prog Neuropsychopharmacol Biol Psychiatry. 2008;32:1231–1235.
89.
Emsley R, Medori R, Koen L, Oosthuizen PP, Niehaus DJ, Rabinowitz J. Long-acting injectable risperidone in the treatment of subjects with recent-onset psychosis: a preliminary study. J Clin Psychopharmacol. 2008;28:210–213.
90.
Emsley R, Oosthuizen P, Koen L, Niehaus DJ, Medori R, Rabinowitz J. Remission in patients with first-episode schizophrenia receiving assured antipsychotic medication: a study with risperidone long-acting injection. Int Clin Psychopharmacol. 2008;23:325–331.
91.
Weiden PJ, Schooler NR, Weedon JC, Elmouchtari A, Sunakawa A, Goldfinger SM. A randomized controlled trial of long-acting injectable risperidone vs continuation on oral atypical antipsychotics for first-episode schizophrenia patients: initial adherence outcome. J Clin Psychiatry. 2009;70:1397–1406.
92.
Bartzokis G, Lu PH, Amar CP, Raven EP, Detore NR, Altshuler LL, Mintz J, Ventura J, Casaus LR, Luo JS, Subotnik KL, Nuechterlein KH. Long acting injection versus oral risperidone in first-episode schizophrenia: differential impact on white matter myelination trajectory. Schizophr Res. 2011;132:35–41.
93.
Weiden PJ, Schooler NR, Weedon JC, Elmouchtari A, Sunakawa-McMillan A. Maintenance treatment with long-acting injectable risperidone in first-episode schizophrenia: a randomized effectiveness study. J Clin Psychiatry. 2012;73:1224–1233.
94.
Fu DJ, Bossie CA, Sliwa JK, Ma YW, Alphs L. Paliperidone palmitate versus oral risperidone and risperidone long-acting injection in patients with recently diagnosed schizophrenia: a tolerability and efficacy comparison. Int Clin Psychopharmacol. 2014;29:45–55.
95.
De Berardis D, Marini S, Carano A, Lang AP, Cavuto M, Piersanti M, Fornaro M, Perna G, Valchera A, Mazza M, Iasevoli F, Martinotti G, Di Giannantonio M. Efficacy and safety of long acting injectable atypical antipsychotics: a review. Curr Clin Pharmacol. 2013;8:256–264.