03. Acute Schizophrenia: Which Antipsychotics Are Most Effective and Tolerable?

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New Network Meta-Analysis of Antipsychotics: Helpful for Clinicians?

For this Quick Take today, let us look together at a network meta-analysis of randomized controlled trials of antipsychotics for acute schizophrenia published in the Lancet by Johannes Schneider-Thoma and Yikang Zhu as co-first authors. One of the senior authors is Stefan Leucht who you may recognize as being one of the leading experts in network meta-analyses to summarize the psychiatric literature for us.

This current meta-analysis is basically an updated and expanded version of Leucht’s important 2019 summary of the literature. The expansion for this analysis includes studies from China in addition to the usual international studies, ultimately resulting in a large dataset of 388 randomized controlled trials with almost 80,000 subjects.

The typical study duration was six weeks and the median age of patients was 37 years, with about 2/3 being male. The main outcome was symptoms of schizophrenia based on rating scales.

I will first briefly review the results of the study before then essentially questioning its value for clinicians in the trenches. Given the expertise of the authors, let us trust the selection of studies to include in the meta-analysis and the statistics used and focus on some key findings.

Antipsychotics Differ in Efficacy and Tolerability

None of the findings should come as a surprise. The main takeaway point is that antipsychotics are more effective than placebo and that antipsychotics differ in their efficacy and in their side effects.

The authors make the correct statement that the small to medium differences in efficacy between antipsychotics are clinically relevant and should not be ignored in clinical guidelines.

The group of antipsychotics that are broadly more effective includes clozapine together with amisulpride, olanzapine and risperidone.

Xanomeline/Trospium Ranks in Top Third

The newer non-dopaminergic antipsychotic xanomeline/trospium looked pretty good, ranking in the top third of antipsychotics with regard to efficacy but also with a high rate of discontinuation.

It is important to note here that the ranking of xanomeline/trospium is purely based on statistical methods and not based on direct head-to-head comparisons in clinical trials.

Side Effect Profiles Confirm Known Patterns

The side effects of currently available antipsychotics are all well described by now and I did not see anything surprising in the publication.

For example, clozapine and olanzapine together with sertindole and zotepine were associated with the most weight gain. Haloperidol caused significant extrapyramidal symptoms. By contrast, lumateperone was noted to have few side effects compared to other antipsychotics but also ranked very low on efficacy, actually last.

The only antipsychotic where I think we will need more clinical experience with regard to side effects is xanomeline/trospium, since it has quite different side effects compared to dopamine-blocking antipsychotics, basically being a mixture of cholinergic and anticholinergic side effects.

Value for Guideline Development

Now before being critical about network meta-analyses, let me acknowledge the incredible amount of work that went into this publication. Let me also state that such an updated review is potentially helpful when talking with decision makers about guidelines, a point the authors emphasize.

However, they also perhaps overstate this point. More recent guidelines are in fact already quite nuanced and they consider and acknowledge differences between antipsychotics.

The international INTEGRATE guidelines for schizophrenia, for example, suggest aripiprazole as a good first choice. While perhaps not the most effective in some efficacy ranking including the one in this meta-analysis, aripiprazole is one with a generally low side effect burden.

Personalization Beats Generalization in Clinical Decision-Making

More importantly, however, I would argue that this review does not help you terribly when selecting an antipsychotic with and for your patient with schizophrenia, where you need personalization and not generalization. Let me repeat this: personalization and not generalization. Something an accompanying editorial that colleagues Barbui and Ostuzzi also noted.

Put differently, a major issue is the fact that efficacy and tolerability based on group findings have little relevance for the patient in front of you.

Even worse, patients do not view efficacy and tolerability as two independent variables, something you need for a meta-analysis. They essentially combine efficacy and tolerability into one variable. You may call it subjective experience with the medication, something like that.

The Best Antipsychotic is the One Your Patient Will Accept

Since we don’t have biomarkers to select a treatment, we still end up having to use sequential trials to identify the best antipsychotic for a given patient.

The best antipsychotic for your patient is not your choice based on some ranking and your value judgment of which side effects should be tolerable and which are not. The best antipsychotic is the one your patient will accept, and it is usually going to be a subjective judgment by the patient who weighs efficacy and side effects as actually experienced and valued by him or her.

The optimal dose is another aspect of finding an acceptable antipsychotic. In my experience, there are also very different considerations for antipsychotic choice depending on stage of illness and degree of treatment resistance, for which we also do not have biomarkers.

First-Episode Patients Need Different Considerations

Let’s take a young first-episode patient for example. I expect a good response to almost any antipsychotic except for those first-episode patients who are already treatment resistant. They represent a biologically different group.

So the issue of relative efficacy differences may not be clinically relevant at all for this subgroup of typical first-episode patients. However, on the other hand, side effects are incredibly important including sexual side effects, for example. They are not captured well in clinical trials and therefore also not really discussed in this analysis.

This meta-analysis is based on a very heterogeneous sample which limits applicability for subgroups of patients like I just described, first-episode patients for example.

Bottom Line: One Size Does Not Fit All

In summary, I think it is good to have an updated network meta-analysis since it shows that most antipsychotics are somewhat unique, as there are clinically meaningful differences between them with regard to both efficacy and tolerability.

That is a point that may be helpful for patients to hear, including if you frame it as one size does not fit all and that more than one antipsychotic may need to be tried.

In the end, network meta-analyses to be precise like this one cannot replace patient-centered shared decision making and the painstaking conduct of sequential antipsychotic trials with your patients.

I hate to say it so bluntly but this meta-analysis is no substitute for the clinical work you need to do in order to find the best antipsychotic and dose for your patient, as only the patient can judge efficacy and tolerability together almost like one variable, if you will, something that no statistical method can accomplish for you.

Abstract

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, M.D.; Yikang Zhu, M.D.; Mengchang Qin; Yu Dong; Shiwei Guan; Jiaxi Wang; & et al.

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.

Funding

German Research Foundation, German Ministry of Research, Technology and Space, and National Natural Science Foundation of China.

Reference

Schneider-Thoma, J. M.D.; Zhu, Y. M.D.; Qin, M; Dong, Y; Guan, S; Wang, J. & et al. (2026). 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. The Lancet, 407, 876-891.