General Psychiatry

Comparative efficacy and tolerability of antidopaminergic and muscarinic antipsychotics for acute schizophrenia: a network meta-analysis of randomised controlled trials indexed in international English and Chinese databases
Johannes Schneider-Thoma, Yikang Zhu, Mengchang Qin, Yu Dong, Shiwei Guan, Jiaxi Wang, Jing Tian, Xiao Lin, Alessandro Rodolico, Spyridon Siafis, Irene Bighelli, Melanie Wehner, Christina Veith, Felix Krayer, Elfriede Scheuring, John M Davis, Josef Priller, Adriani Nikolakopoulou, Georgia Salanti, Chunbo Li, Stefan Leucht

Abstract:

Background: Antipsychotic drugs are the established treatment for acute schizophrenia but differ in receptor-binding profiles. In 2024, a new-in-class muscarinic receptor agonist (xanomeline-trospium) was licenced, acting upstream of antidopaminergic agents, and providing hope to decrease the adverse effects burden of antipsychotics. We aimed to compare the efficacy and tolerability of antipsychotics by performing network meta-analysis of randomised controlled trials (RCTs).

Methods: This systematic review (PROSPERO, CRD42022380708) included blinded and open RCTs investigating antipsychotic drugs in participants of any age with acute psychotic symptoms of schizophrenia over 3 weeks to 3 months. Included antipsychotics comprised 23 primarily dopamine-receptor blocking medications and the muscarinic receptor agonist xanomeline-trospium in different applications. We searched Cochrane Schizophrenia group's register, previous reviews, and five Chinese databases for trials published from database inception until July 26, 2024 and contacted authors to assess trials' methodological quality; only trials with appropriate randomisation indicated were included. The primary outcome was rating scale-measured overall symptoms of schizophrenia (efficacy) analysed with random-effects frequentist network meta-analysis. Secondary outcomes comprised 32 further efficacy and tolerability outcomes. The confidence in the estimates was assessed using the Confidence in Network Meta-Analysis approach.

Findings: After screening 18 859 references and contacting authors of 5428 trials, we included 438 RCTs. Of those, 388 RCTs with 78 193 participants (28 448 women and 49 745 men) provided usable data for at least one outcome. 5117 Chinese trials were identified but most were excluded because authors did not reply or reported serious methodological concerns. 256 double-blind studies with 58 948 participants provided usable data for the primary outcome. All antipsychotics reduced symptoms more than placebo with standardised mean differences ranging from -0·90 (95% CI -1·03 to -0·77) to -0·23 (-0·39 to -0·06). Particularly clozapine, as well as amisulpride, olanzapine, and risperidone were more efficacious than at least three other antipsychotics (confidence in estimates were low-to-moderate). Adverse effects varied across medications.

Interpretation: This network meta-analysis provides evidence for small-to-medium clinically relevant differences between antipsychotics in efficacy; this finding warrants stronger and more specific emphasis in clinical guidelines. Nonetheless, important differences in tolerability need to be considered for individualised drug choice, with partial dopamine agonists having overall better tolerability and xanomeline-trospium lacking adverse effects of dopamine-blocking agents but resulting in cholinergic and anticholinergic adverse events. Future research should directly compare xanomeline-trospium with other antipsychotics to confirm its efficacy; modern trials using clozapine early in schizophrenia are needed to establish whether it improves outcomes and prevents chronification.

Annotation

The finding: This is an updated network meta-analysis pooling hundreds of RCTs of antipsychotics to provide a comprehensive assessment of the comparative efficacy and adverse effects of dozens of medications for treatment of schizophrenia. Compared to the last equivalent analysis published by these authors (Huhn et al, Lancet 2019), this one has more medications (notably now including lumateperone and xanomeline-trospium), more outcome measures (including sexual and cholinergic side effects),  more RCTs (including previously excluded Chinese trials), and more than 800 pages of supplementary appendix. Notable new findings include that lumateperone’s efficacy for reducing overall symptoms appears numerically lower than most other antipsychotics, and xanomeline-trospium carries high risks of both cholinergic and anticholinergic adverse effects.

Strength and weaknesses: The hook justifying this updated analysis (the inclusion of xanomeline-trospium and evaluation of cholinergic and anticholinergic adverse effects) isn’t really the main reason to appreciate this paper – especially as xanomeline-trospium has never been randomized against anything besides placebo, it’s actually hard to draw robust conclusions about it in a network meta-analysis. Instead, its main strength is that it’s an even more thorough version of what was already the most comprehensive comparison of antipsychotics available – each of the dozens of tables and figures contains a wealth of clinically relevant data for anyone who prescribes antipsychotics.

Relevance: This is a terrific paper to refer to when selecting antipsychotics, especially in patients with medical comorbidities that make specific adverse effects critically important. If you need to absolutely minimize the contribution of your medication to constipation, QTc prolongation, hyperprolactinemia, etc., the dozens of tables and figures in this study will show you exactly how to do it.

Long-Term Safety and Efficacy of Xanomeline and Trospium Chloride in Schizophrenia: A 52-Week Open-Label Extension Trial
Inder Kaul, Amy Claxton, Colin Sauder, Tejendra Patel, Soumya Chaturvedi, David Brown, Haiyuan Zhu, Ronald Marcus, Sharon Sawchak, Stephen K Brannan

Abstract:

Objective: Xanomeline and trospium chloride (X/T) reduced symptoms and was generally well tolerated in two phase 3, 5-week, randomized, double-blind, placebo-controlled trials in adults with schizophrenia. The authors evaluated the long-term safety, tolerability, and efficacy of X/T in an open-label extension of the two phase 3 trials.

Methods: EMERGENT-4 was a 52-week open-label extension trial of participants who completed the EMERGENT-2 and EMERGENT-3 acute trials. Between February 2021 and October 2023, 152 participants initiated twice-daily oral doses of xanomeline 50 mg/trospium 20 mg and titrated to a maximum dosage of twice-daily oral xanomeline 125 mg/trospium 30 mg. The primary endpoint was the proportion of participants reporting a treatment-emergent adverse event (TEAE). Efficacy measures included Positive and Negative Syndrome Scale (PANSS) and Clinical Global Impressions severity scale (CGI-S).

Results: A total of 156 (42.6%) of the 366 participants who completed EMERGENT-2 or EMERGENT-3 enrolled in EMERGENT-4; of these 34 (21.8%) enrolled participants completed the 52-week treatment period. Overall, 81 (53.3%) of 152 treated participants experienced at least one TEAE. Consistent with the acute trials, the most common treatment-related adverse events were gastrointestinal disorders (e.g., nausea, vomiting, dyspepsia, dry mouth) that were mild or moderate in intensity and resolved with continued treatment. No new safety or tolerability issues were observed. X/T was not associated with clinically meaningful motor symptoms, hyperprolactinemia, weight gain, or adverse effects on metabolic parameters. X/T was associated with continued symptom improvement over the trial duration. Mean changes in PANSS total score from acute trial baseline to week 52 were -33.8 and -31.3 in the treatment groups receiving X/T and placebo, respectively, in the acute trials. Similar patterns of continued improvement were observed for scores on the CGI-S, PANSS positive subscale, and PANSS negative subscale.

Conclusions: Long-term treatment with X/T over 52 weeks was safe, generally well tolerated, and associated with durable symptom improvement in people with schizophrenia.

Annotation

The finding: This was an open-label extension of two large industry-sponsored RCTs of xanomeline-trospium for treatment of schizophrenia. About 40% of participants from the acute treatment trials agreed to participate in the open-label extension, and only about 20% of these completed a year of treatment. About half of patients experienced some sort of adverse event, with ~30% experiencing GI side effects – and surprisingly, this did not differ between patients previously exposed to xanomeline-trospium and those who’d gotten placebo in the blinded trial. Among patients who continued taking the medication, improvements in PANSS from the initial acute trials were sustained over a year.

Strength and weaknesses: Given the low rates of enrollment and continuation in this trial, it’s challenging to draw any meaningful conclusions from it about long-term efficacy. However, the adverse effect data is meaningful, and quite informative.

Relevance: It’s been a rough year for xanomeline-trospium – first its trial augmenting other antipsychotics failed, and now its industry-sponsored long-term tolerability data is less than reassuring. Most concerning are its persistent GI side effects – while its initial trial reports had asserted that GI side effects were reliably transient, this long-term data undermines that notion, and suggests clinicians need to be cautious about ongoing GI side effects even in patients who’ve been on a stable dose of xanomeline-trospium for months.

Emergency Department-Initiated Buprenorphine for Opioid Use Disorder: A Randomized Clinical Trial
Gail D'Onofrio, Andrew A Herring, Kathryn F Hawk, Jeanmarie Perrone, Ethan Cowan, Ryan P McCormack, James Dziura, Abigail G Matthews, Michael V Pantalon, Patricia Owens, Shara Martel, Edouard Coupet Jr, Michele R Lofwall, Sharon L Walsh, E Jennifer Edelman, Joseph E Carpenter, Tania D Strout, Michael R Baumann, Erik Anderson, Tyler W Barrett, Alyrene Dorey, Peter Taillac, Gerald Cochran, Cameron S Crandall, Jason Wilson, Jacob Manteuffel, Jon B Cole, Lauren K Whiteside, Christopher Jones, Elizabeth Samuels, Kristen Huntley, David A Fiellin; ED INNOVATION Investigators

Abstract:

Importance: Extended-release injectable buprenorphine may expand the reach of initiating medications for opioid use disorder in high-risk and hard-to-reach individuals who visit the emergency department (ED) and can be administered in low levels of withdrawal.
Objective: To compare the effect of ED-initiated 7-day extended-release injectable buprenorphine vs sublingual buprenorphine on treatment engagement at 7 days.
Design, setting, and participants: Multicenter randomized clinical trial enrolling adult patients presenting to the ED with untreated opioid use disorder and a Clinical Opiate Withdrawal Scale (COWS) score of 4 or higher across 29 EDs in the US from July 12, 2020, to August 21, 2024. Final follow-up was completed on October 24, 2024.

Interventions: Patients were randomized to receive a 24-mg injection of extended-release buprenorphine (equivalent to 16 mg/d) or sublingual buprenorphine, which included either self-administration instructions if the COWS score was less than 8 or administration of 8 mg of sublingual buprenorphine in the ED if the COWS score was 8 or higher. All sublingual buprenorphine group patients received a 7-day prescription for 16 mg/d. Both groups were provided referral for ongoing medication with a scheduled appointment within 7 days.

Main outcomes and measures: Engagement in opioid use disorder treatment on day 7 was the primary outcome. Secondary outcomes included engagement at 30 days, precipitated withdrawal and overdose events, craving scores, days of illicit opioid use, and patient satisfaction with treatment.
Results: Among 2000 patients randomized, 6 who were enrolled twice were excluded, resulting in 991 in the extended-release group and 1003 in the sublingual group. The median age was 37 (IQR, 30-47) years, 68% were male, 31% had an initial COWS score of 4 to 7, and 76% tested positive for fentanyl. The adjusted proportion of engagement in opioid use disorder treatment at 7 days was 40.5% with extended-release buprenorphine vs 38.5% with sublingual buprenorphine (adjusted difference, 1.6%; 95% CI, -2.8% to 6.0%). Engagement at 30 days was similar, with adjusted proportions of 43.8% with extended-release buprenorphine vs 44.9% with sublingual buprenorphine (adjusted difference, -1.5%; 95% CI, -6.2% to 3.2%). Precipitated withdrawal was rare: 6 (0.6%) with extended-release buprenorphine and 8 (0.8%) with sublingual buprenorphine. Overdose events within 30 days occurred in 18 participants (2.3%) in each group. Patients receiving extended-release buprenorphine reported lower mean craving scores at 7 days vs those receiving sublingual buprenorphine (scale, 0-100; mean score, 26.5 vs 30.2, respectively; adjusted mean difference, -3.85; 95% CI, -7.08 to -0.63), fewer days of illicit opioid use in the past 7 days (adjusted ratio of means, 0.77; 95% CI, 0.68-0.95), and better treatment satisfaction scores (scale, 1-5; adjusted mean difference, 0.13; 95% CI, 0.01-0.25).

Conclusions and relevance: No difference was detected in opioid use disorder treatment engagement on day 7 between the 7-day extended-release and sublingual buprenorphine groups. Both buprenorphine formulations were well tolerated; precipitated withdrawal was rare despite a high prevalence of fentanyl.

Annotation

The finding: In this ED-based trial, patients with opioid use disorder and COWS score of 4 or higher were randomized to sublingual buprenorphine (~16 mg/day, with timing of dosing depending on COWS score) vs. a new week-long injectable buprenorphine formulation called Brixadi which produces a gradual rise in plasma concentrations that eliminates the need for oral induction. All patients in both arms received referrals for ongoing addiction care with an appointment 7 days later. Engagement in care at that appointment (the primary outcome) was ~40%, and equivalent between the two buprenorphine formulations. Rates of precipitated withdrawal were low (~0.5% of patients), likely due to the pharmacokinetics of Brixadi in the injectable and a test-dose approach in the sublingual buprenorphine arm: all patients with COWS scores of 8-12 received a 4 mg initial dose of buprenorphine and proceeded to higher doses only if this was tolerated without worsening of withdrawal symptoms.

Strength and weaknesses: This is a large, carefully conducted RCT with a population and setting that is difficult to study – patients with opioid use disorder in the emergency department. Despite this, there are still some questions about the generalizability of the enrolled patients – notably 40% had urine positive for buprenorphine at baseline – but it may be hard to do much better than this in the context of an RCT.

Relevance: For those who happen to have Brixadi on formulary, this looks quite promising – a simple, single-injection treatment that can be given safely to patients without needing to wait for significant withdrawal symptoms is quite appealing! For the rest of us, while we wait for this new formulation to become cheaper and more widely available, this trial provides validation for a relatively simple test-dosing approach that can minimize precipitated withdrawal risk even in acute settings.