Trace amine-associated receptor 1 (TAAR1) agonists offer a new approach, but there is uncertainty regarding their effects, exact mechanism of action and potential role in treating psychosis.

To evaluate the available evidence on TAAR1 agonists in psychosis, using triangulation of the output of living systematic reviews (LSRs) of animal and human studies, and provide recommendations for future research prioritisation.

This study is part of GALENOS (Global Alliance for Living Evidence on aNxiety, depressiOn and pSychosis). In the triangulation process, a multidisciplinary group of experts, including those with lived experience, met and appraised the first co-produced living systematic reviews from GALENOS, on TAAR1 agonists.

The animal data suggested a potential antipsychotic effect, as TAAR1 agonists reduced locomotor activity induced by pro-psychotic drug treatment. Human studies showed few differences for ulotaront and ralmitaront compared with placebo in improving overall symptoms in adults with acute schizophrenia (four studies, n = 1291 participants, standardised mean difference (SMD) 0.15, 95% CI −0.05 to 0.34). Large placebo responses were seen in ulotaront phase three trials. Ralmitaront was less efficacious than risperidone (one study, n = 156 participants, SMD = −0.53, 95% CI −0.86 to −0.20). The side-effect profile of TAAR1 agonists was favourable compared with existing antipsychotics. Priorities for future studies included (a) using different animal models of psychosis with greater translational validity; (b) animal and human studies with wider outcomes including cognitive and affective symptoms and (c) mechanistic studies and investigations of other potential applications, such as adjunctive treatments and long-term outcomes. Recommendations for future iterations of the LSRs included (a) meta-analysis of individual human participant data, (b) including studies that used different methodologies and (c) assessing other disorders and symptoms.

This co-produced, international triangulation examined the available evidence and developed recommendations for future research and clinical applications for TAAR1 agonists in psychosis. Broader challenges included difficulties in assessing the risk of bias, reproducibility, translation and interpretability of animal models to clinical outcomes, and a lack of individual and clinical characteristics in the human data. The research will inform a separate, independent prioritisation process, led by lived experience experts, to prioritise directions for future research.

The Royal Australian and New Zealand College of Psychiatrists clinical practice guidelines for mood disorders (MDcpg2015 and MDcpg2020) provide evidence-based and consensus-based recommendations for managing mood disorders.

We examined Australian real-world prescribing habits to determine whether management in clinical practice aligned with MDcpg2015 recommendations.

A retrospective analysis of a cohort of patients ≥16 years old who had been dispensed a Pharmaceutical Benefits Scheme (PBS)-listed antidepressant between July 2013 and June 2019 was conducted using Australian Commonwealth Department of Human Services PBS 10% sample data.

Between July 2013 and June 2019, 239 944 patients in Australia commenced antidepressant treatment. Of these, 22% (52 694 patients) received a second treatment (a new class of treatment after a period of discontinuation or additional antipsychotic therapy) and 6% (15 741 patients) received a third treatment. Patients were initially prescribed primarily selective serotonin reuptake inhibitors (SSRIs; 52% of prescriptions) or tricyclic antidepressants (TCAs; 25%), even though TCAs are not recommended for first-line treatment. Fewer than one-quarter of patients were prescribed serotonin–noradrenaline reuptake inhibitors (13%) or other agents (10%). General practitioners (GPs) were more likely to initiate TCAs than psychiatrists (22% v. 7%).

Once initiated, the overall median time patients remained on treatment was 4.5 months; this was highest with SSRIs (5.8 months) and lowest with TCAs (0.9 months).

First-line prescribing broadly follows guidelines. GP and psychiatrist prescribing patterns differ, perhaps reflecting different patient groups and the need to tailor treatment to individuals. Future guidelines should aim to capture the different presentations and complexity of depression.