Efficacy of oral versus long-acting antipsychotic treatment in patients with early-phase schizophrenia in Europe and Israel: a large-scale, open-label, randomised trial (EULAST)

Leucht, Stefan; Glenthøj, Birte; Haim, Mor Bar; Leucht, Claudia; Kemmler, Georg; Kahn, René S.; Fleischhacker, W.W.; Davidson, Michael; Rossum, Inge Winter-van; Weiser, Mark; Luykx, Jurjen J.; Hasan, Alkomiet; Mosescu, M.D.; Galderisi, Silvana; Kupchik, Marina; Stefanis, Nikos; Teitelbaum, Alexander; Rocca, Paola; Psota, Georg; Umoh, George; Bitter, István; Hranov, Lucho G; Hofer, Alex; Cordes, Joachim; Nilforooshan, Ramin; Bobes, Julio; Reitan, Solveig Klebo; Morrens, Manuel; Nireştean, Aurel; Geddes, John; Faccorro, Benedicto Crespo; Olajossy, Marcin; Rossi, Alessandro; Johnsen, Erik; László, Csekey; Ciobanu, Adela Magdalena; Haddad, Peter M.; Oife, Igor; Bernardo, Miquel; Stan, Rodicutza; Jarema, Marek; Rujescu, Dan; Ustohal, Libor; Mayfield, Neil; Dazzan, Paola; Valevski, Avi; Libiger, Jan; Köhler, Richard; Mohr, Pavel; Pappa, Sofia; Drosos, Petros; Barnes, Thomas R. E.; DeClercq, Esther; Wagner, Elias; Bucci, Paola; Mucci, Armida; Rabinowitz, Yaacov; Adamopoulous, Adam; Draiman, Benjamin; Montemagni, Cristiana; Greslechner, Manfred; Herlihy, Hannah; Bolyós, Csilla; Kraepelin-Schmidt, Christian; True, Jessica; Garcia, Leticia Alvarez; Walla, Berit; Sabbe, Bernhard; Emese, Lucaks; Mather, Sarah; Skoczeń, Nikodem; Parnanzone, Serena; Bjarke, Jill; Karácsonyi, Krisztina; Lankshear, Steve; Garriga, Marina; Wichniak, Adam; Baumbach, Heidi; Schurr, Timo; Willebrands, Leonie; Nasib, Lyliana; Okhuijsen-Pfeifer, Cynthia; Huijsman, Elianne

doi:10.1016/s2215-0366(23)00005-6

Cited by 22 publications

(10 citation statements)

References 21 publications

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“…After excluding duplicates, 197 records were assessed at the abstract level, and 39 were assessed at the full-text level. Finally, 11 independent RCTs were included in the analyses ( Figure 1 ), of which 10 were patient-level randomized RCTs 36 – 38 , 60 – 67 and one was a cluster-randomized RCT. 37 The number of included participants ranged from 37 to 764 (median = 85).…”

Section: Resultsmentioning

confidence: 99%

“…Only one study 63 used a first-generation LAI (fluphenazine decanoate); all others used a second-generation LAI, such as LAI paliperidone, 38 , 62 , 65 , 66 LAI risperidone, 60 , 61 , 64 , 67 LAI aripiprazole 37 and both LAI aripiprazole and LAI paliperidone. 36 In seven RCTs, LAIs were compared against a mix of different OAPs 37 , 38 , 60 – 62 , 64 , 66 ; in the other four trials, the comparators were oral risperidone 67 oral olanzapine 65 oral fluphenazine 63 and both oral aripiprazole and oral paliperidone. 36 Only three RCTs matched the antipsychotics in the LAI and OAP treatment arm.…”

Section: Resultsmentioning

confidence: 99%

“…No statistically significant differences were observed regarding medication adherence and treatment acceptability. Notably, after the publication of this review (whose search dates back to 2019) three large RCTs comparing LAIs and OAPs in patients with EP-SSDs were completed, 36 – 38 substantially increasing the amount of available evidence on the topic.…”

Section: Introductionmentioning

confidence: 99%

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Efficacy and safety of long-acting injectable versus oral antipsychotics in the treatment of patients with early-phase schizophrenia-spectrum disorders: a systematic review and meta-analysis

Vita,

Tavella,

Ostuzzi

et al. 2024

Therapeutic Advances in Psychopharmacology

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Background: Long-acting injectable antipsychotics (LAIs) have advantages over oral antipsychotics (OAPs) in preventing relapse and hospitalization in chronically ill patients with schizophrenia-spectrum disorders (SSDs), but evidence in patients with first-episode/recent-onset, that is, early-phase-SSDs is less clear. Objectives: To assess the relative medium- and long-term efficacy and safety of LAIs versus OAPs in the maintenance treatment of patients with early-phase SSDs. Method: We searched major electronic databases for head-to-head randomized controlled trials (RCTs) comparing LAIs and OAPs for the maintenance treatment of patients with early-phase-SSDs. Design: Pairwise, random-effects meta-analysis. Relapse/hospitalization and acceptability (all-cause discontinuation) measured at study-endpoint were co-primary outcomes, calculating risk ratios (RRs) with their 95% confidence intervals (CIs). Subgroup analyses sought to identify factors moderating differences in efficacy or acceptability between LAIs and OAPs. Results: Across 11 head-to-head RCTs ( n = 2374, median age = 25.2 years, males = 68.4%, median illness duration = 45.8 weeks) lasting 13–104 (median = 78) weeks, no significant differences emerged between LAIs and OAPs for relapse/hospitalization prevention (RR = 0.79, 95%CI = 0.58–1.06, p = 0.13) and acceptability (RR = 0.92, 95%CI = 0.80–1.05, p = 0.20). The included trials were highly heterogeneous regarding methodology and patient populations. LAIs outperformed OAPs in preventing relapse/hospitalization in studies with stable patients (RR = 0.65, 95%CI = 0.45–0.92), pragmatic design (RR = 0.67, 95%CI = 0.54–0.82), and strict intent-to-treat approach (RR = 0.64, 95%CI = 0.52–0.80). Furthermore, LAIs were associated with better acceptability in studies with schizophrenia patients only (RR = 0.87, 95%CI = 0.79–0.95), longer illness duration (RR = 0.88, 95%CI = 0.80–0.97), unstable patients (RR = 0.89, 95%CI = 0.81–0.99) and allowed OAP supplementation of LAIs (RR = 0.90, 95%CI = 0.81–0.99). Conclusion: LAIs and OAPs did not differ significantly regarding relapse prevention/hospitalization and acceptability. However, in nine subgroup analyses, LAIs were superior to OAPs in patients with EP-SSDs with indicators of higher quality and/or pragmatic design regarding relapse/hospitalization prevention (four subgroup analyses) and/or reduced all-cause discontinuation (five subgroup analyses), without any instance of OAP superiority versus LAIs. More high-quality pragmatic trials comparing LAIs with OAPs in EP-SSDs are needed. Trial registration: CRD42023407120 (PROSPERO).

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Efficacy and safety of long-acting injectable versus oral antipsychotics in the treatment of patients with early-phase schizophrenia-spectrum disorders: a systematic review and meta-analysis

Vita,

Tavella,

Ostuzzi

et al. 2024

Therapeutic Advances in Psychopharmacology

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“…Of note, the time to discontinuation of antipsychotics may influence the inclusion and sequence of administration of other drugs, thereby influencing the switching strategies [ 64 ]. Contrarily, a recently published RCT (EULAST trial) with 533 patients with early-phase schizophrenia reported that there was no significant difference in time to all-cause discontinuation between the combined oral and combined LAI treatment groups (71% vs 64%) [ 65 ]. The contrary results may be explained by different baseline characteristics.…”

Section: Discussionmentioning

confidence: 99%

Effectiveness and Safety of Switching from Oral Antipsychotics to Once-Monthly Paliperidone Palmitate (PP1M) in the Management of Schizophrenia: A Systematic Review and Meta-Analysis

Li,

et al. 2023

CNS Drugs

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Background Considering the improvement in adherence and convenience, once-monthly paliperidone palmitate (PP1M) has been increasingly used in the treatment of schizophrenia. However, the outcomes for patients who switch from oral antipsychotics (OAPs) to PP1M have not been reliably assessed. The objective of this systematic review and meta-analysis was to investigate the efficacy and safety of PP1M in the management of patients with schizophrenia with a prior history of OAP use. Methods We conducted a systematic search in PubMed, EMBASE, and the Cochrane Library on 19 July 2022 to identify eligible studies. All studies that examined the effectiveness and safety of switching from OAPs to PP1M in patients with schizophrenia were included. The primary outcomes were relapse rate, hospitalisation rate, and the change from baseline in the Positive and Negative Syndrome Scale (PANSS) total score. The secondary outcomes included the changed number of inpatient visits, changed length of stay hospitalisation, change from baseline in the Clinical Global Impressions-Severity (CGI-S) score and the personal and social performance (PSP) total score, response rate, proportion of treatment discontinuation, and adverse events. We included randomised-controlled trials (RCTs), single-arm studies, and observational studies. Case reports, case series, and reviews were excluded. The quality assessment of included studies was performed using the Revised Cochrane risk-of-bias tool for randomised trials (RoB2), the 9-point Newcastle-Ottawa Scale (NOS) instrument for non-randomised studies and cohort studies, and the 12-item National Institutes of Health (NIH) quality assessment tool for before-after (Pre-Post) study without control group. Follow-up times were reported as short- (≤ 13 weeks), medium- (14–26 weeks), and long term (≥ 27 weeks). Data were pooled using meta-analysis. Results Fifteen studies with a total of 4740 patients were included. The long-term relapse rates and hospitalisation rates were 12% (95% CI 0.07–0.18) and 18% (95% CI 0.15–0.20), respectively. The short-, medium-, and long-term change in PANSS total score was − 21.69 (95% CI − 30.02 to −13.36), − 14.98 (95% CI − 21.45 to − 8.51) and − 17.88 (95% CI − 31.94 to −3.82), respectively. Approximately 50% of patients reported at least a 30% reduction in the PANSS score at the short-term follow-up. Improvements in CGI-S and PSP score were observed during various periods. There was a reduction in the length of stay hospitalisation and the number of inpatient visits at the medium- and long-term follow-ups. Low discontinuation and adverse event rates were reported. Conclusion Based on our findings, this study may support the efficacy and safety of switching from OAPs to PP1M for the treatment of patients with schizophrenia. Future large-scale studies are warranted to confirm our findings. Supplementary Information The online version contains su...

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“… 73 Surprisingly, the specific antipsychotic or the formulation (depot vs oral) does not seem to increase treatment adherence or improve outcomes. 74 On the contrary, it is possible that irregular rather than continuous medication presents some advantages. 75 However, as indicated by the proponents of depot medication, it is also conceivable that treatment-adherent patients are more likely to participate in prospective comparison trials of oral vs depot medication, thus obscuring the advantages of depot medication.…”

Section: The Different Points Of View In Benefit/risk Assessmentmentioning

confidence: 99%

Targeted Treatment of Schizophrenia Symptoms as They Manifest, or Continuous Treatment to Reduce the Risk of Psychosis Recurrence

Davidson,

Carpenter

2023

Schizophrenia Bulletin

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Current pharmacological treatment of schizophrenia employs drugs that interfere with dopamine neurotransmission, aiming to suppress acute exacerbation of psychosis and maintenance treatment to reduce the risk of psychosis recurrence. According to this treatment scheme, available psychotropic drugs intended to treat negative symptoms, cognitive impairment, or anxiety are administered as add-ons to treatment with antipsychotics. However, an alternative treatment scheme proposes a targeted or intermittent treatment approach, by which antipsychotic drugs are administered upon psychosis exacerbation and discontinued upon remission or stabilization, while negative symptoms, cognitive impairment, or anxiety are treated with specific psychotropics as monotherapy. Along these lines, antipsychotics are renewed only in the event of recurrence of psychotic symptoms. This 50-year-old debate between targeted and continuous treatment schemes arises from disagreements about interpreting scientific evidence and discordant views regarding benefit/risk assessment. Among the debate’s questions are: (1) what is the percentage of individuals who can maintain stability without antipsychotic maintenance treatment, and what is the percentage of those who exacerbate despite antipsychotic treatment? (2) how to interpret results of placebo-controlled 9- to 18-month-long maintenance trials in a life-long chronic disorder, and how to interpret results of the targeted trials, some of which are open label or not randomized; (3) how to weigh the decreased risk for psychotic recurrence vs the almost certainty of adverse effects on patient’s quality of life. Patients’ profiles, preferences, and circumstances of the care provision should be considered as the targeted vs continuous treatment options are considered.

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Efficacy of oral versus long-acting antipsychotic treatment in patients with early-phase schizophrenia in Europe and Israel: a large-scale, open-label, randomised trial (EULAST)

Cited by 22 publications

References 21 publications

Efficacy and safety of long-acting injectable versus oral antipsychotics in the treatment of patients with early-phase schizophrenia-spectrum disorders: a systematic review and meta-analysis

Efficacy and safety of long-acting injectable versus oral antipsychotics in the treatment of patients with early-phase schizophrenia-spectrum disorders: a systematic review and meta-analysis

Effectiveness and Safety of Switching from Oral Antipsychotics to Once-Monthly Paliperidone Palmitate (PP1M) in the Management of Schizophrenia: A Systematic Review and Meta-Analysis

Targeted Treatment of Schizophrenia Symptoms as They Manifest, or Continuous Treatment to Reduce the Risk of Psychosis Recurrence

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