REVIEWLong-acting injectable antipsychotics (LAIs) for maintenance treatment of bipolar and schizoaffective disorders: A systematic review
Introduction
Bipolar Disorder (BD) is a severe, recurrent and disabling mood disorder characterised by manic, hypomanic or mixed episodes, and alternating episodes of depression that affects approximately 2% of worldwide population (Grande et al., 2016). Affective episodes are recurrent and commonly associated with unfavorable outcomes, including poorer cognitive performance and greater number of hospitalizations (Vieta et al., 2018). BD is typically associated with high mortality due mostly to cardiovascular diseases and an increased risk of suicide (Kendall et al., 2014, Kishi et al., 2016, Vieta et al., 2018). Moreover, BD is often associated with persistent symptoms leading to social and functional impairment (Martinez-Aran et al., 2009, Bortolato et al., 2015, Solé et al., 2018). Due to the chronic nature of the disorder and the negative consequences of unremitted or recurrent symptoms, BD requires long-term maintenance therapy to prevent future mood episodes as the primary goal of treatment after treating an acute affective episode. Despite lithium remains the gold standard prophylactic treatment for BD (Nivoli et al., 2010), patients may not accept lithium due to various reasons including monitoring requirement, side effects or poor adherence to treatment (Murru et al., 2012, Murru et al., 2013). Thus, many patients require alternative prophylactic treatment for BD. Multiple studies and most BD treatment guidelines (Derry and Moore, 2007, Goodwin and Consensus Group of the British Association for Psychopharmacology, 2009, Grunze et al., 2013, National Collaborating Centre for Mental Health (UK) 2018, Yatham et al., 2018) recommend the use of oral second-generation antipsychotics (SGAs) as a long-term option for BD and many SGAs have official European Medical Agency (EMA) approval for this indication.
Similarly, schizoaffective disorder (SAD) is a chronic and severe illness consisting on the concurrent presentation of symptoms of schizophrenia and affective disorders (depression and/or mania) (Murru et al., 2016). Actually, there is a still unresolved debate on nosological distinctions among schizoaffective disorder (SAD), BD-I with psychotic features and schizophrenia (SZ) (Tondo et al., 2016).
Adherence to medication is essential for BD and SAD patients to respond satisfactorily to treatment. Nonetheless, the frequency of nonadherence in BD and SAD patients bipolar type is estimated to range between 10% and 60% (9,10,18) even during euthymic periods (Colom et al., 2000). Nonadherence increases the risk of relapse and suicide (Samalin et al., 2014) as well as the risk of rehospitalization (Gigante et al., 2012). It should be stressed that despite patients’ will to receive LAI treatment, this type of treatment is still less used in patients discharged after hospitalization for a psychotic episode (Hamann et al., 2014), even if their long-term safety has been demonstrated (Lindenmayer et al., 2007).
Long-acting injectable (LAIs) antipsychotics, including first-generation depot antipsychotics (FGDAs) and second-generation depot antipsychotics (SGDAs) may improve treatment adherence in patients with psychiatric illness requiring long-term maintenance treatment (Gigante et al., 2012, Llorca et al., 2013). LAIs have been shown to decrease the rate of relapse and hospitalization in patients with schizophrenia (Correll et al., 2016). The use of LAIs in the maintenance treatment of BD and SAD has raised interest for improving adherence and reducing the risk of relapse (Gigante et al., 2012, Samalin et al., 2014, Kishi et al., 2016). In a recent, large population-based observational cohort effectiveness study (N = 18,018) based on the Finish registry of the whole population of Finland (Lähteenvuo et al., 2018), the most effective treatments to prevent re-hospitalization in BD patients were lithium and LAIs, with 30% of rehospitalization risk reduction with LAIs compared to the same medications in oral formulations. To date, FDA has approved the use of risperidone-LAI (RIS-LAI) as both monotherapy and as adjunct therapy to lithium and valproate for the maintenance treatment of BD-I. Recently, FDA has approved aripiprazole monohydrate extended-release injectable suspension (Ari-M) for the maintenance monotherapy treatment of BD-I. RIS-LAI and recently paliperidone palmitate (Pal-P) have received EMA indication for SAD disorder. On the contrary, no LAI has current EMA indication for BD. Although FGDAs have been studied in BD, they have not been approved for use in this disorder (Gigante et al., 2012).
To summarize the available evidence, we conducted a systematic review of studies comparing the efficacy and safety of first- and second-generation depot antipsychotics (FGDAs and SGDAs, respectively) to placebo (PBO) or oral medications for BD and SAD. We decided to include in this review also SAD due to the similarities in acute and long-term need for treatments aimed at manic, mixed, depressive polarities, both psychotic and nonpsychotic, that justify a conceptual framework of continuity across these two conditions (Murru et al., 2016, Argolo et al., 2018).
Section snippets
Procedures
This review has been conducted according to the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) statement (Moher et al., 2009). Search Methods and Results are highlighted in Fig. 1.
Systematic search results
The pooled records amounted to 640 Records (Fig. 1). Excluded were: 114 Reviews, 113 NBSA, 77 No LAI, 65 Open (open design-no mirror), 130 Case (reports/series), 0 Inadeq (inadequate design or outcomes), 33 E/O (editorials/opinion papers), 13 PhEc (Pharmacoeconomic studies), 14 Surveys, 1 Biotech (biotechnologies, laboratory), 15 PhK (pharmacokinetics), 12 BM/Gen (biomarkers, brain imaging, or genetics), 3 Technical, 3 Animal/Cell (studies on nonhumans or on isolated cell tissues), 1 was a
Discussion
We here performed a systematic review of the efficacy of LAI treatments in BD and SA; we rated our review according to the AMSTAR system and we found it to be of moderate quality (Shea et al., 2017). The present systematic review examined the efficacy of LAIs for maintenance treatment of BD and SAD compared with PBO and oral medications. Regarding FGDAs, although there are not head-to-head comparisons between FGDAs and SGDAs, the trials reviewed indicate that there are some differences between
Role of funding source
This work was supported with funding from the Spanish Ministry of Science, Innovation and Universities, the Centro de Investigación en Red de Salud Mental, CIBERSAM, the Instituto de Salud Carlos III through a “Río Hortega” contract (CM17/00258) to NV, Recerca del DIUE de la Generalitat de Catalunya to the Bipolar Disorders Group (2017-SGR-01365).
Contributors
Drs. Pacchiarotti and Vieta conceived the review and provided indications for the design; Drs. Pacchiarotti and Kotzalidis designed the searches and conducted them, identified relevant literature and wrote the first drafts of the paper; Drs. Tiihonen, Verdolini, Murru, Goikolea, Valentí, and Aedo contributed in writing substantial portions of the manuscript; Prof. Vieta reviewed the final draft; all authors participated in Delphi rounds to reach consensus about study inclusion and approved the
Conflict of interest
Dr. Pacchiarotti has received CME-related honoraria, or consulting fees from ADAMED, Janssen-Cilag, and Lundbeck
Dr. Tiihonen reported serving as a consultant to AstraZeneca, Bristol- Myers Squibb, Eli Lilly, F. Hoffman-La Roche, Janssen-Cilag, Lundbeck, Organon, and Finnish Medicines Agency; receiving fees for giving expert testimony to AstraZeneca, Bristol-Myers Squibb, Eli Lilly, GlaxoSmithKline, Janssen-Cilag, Lundbeck, Otsuka, and Pfizer; receiving lecture fees from AstraZeneca,
Acknowledgments
The authors thank the support of the Spanish Ministry of Science, Innovation and Universities integrated into the Plan Nacional de I+D+I and co-financed by the ISCIII-Subdirección General de Evaluación and the Fondo Europeo de Desarrollo Regional (FEDER); the Instituto de Salud Carlos III that supported this work through a “Río Hortega” contract (CM17/00258 to NV); the CIBERSAM (Centro de Investigación Biomédica en Red de Salud Mental); the Secretaria d'Universitats i Recerca del Departament
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