Longer-term outcome and safety data of repeated subcutaneous racemic ketamine for treatment-resistant depression (TRD) is lacking, as is knowledge of the impact of prior ketamine treatment on subsequent response.

To evaluate the effectiveness and safety of a 4-week course of subcutaneous racemic ketamine over 6 months and investigate whether prior ketamine treatment influences treatment response.

An open label extension (OLE) of a randomised controlled trial (RCT) was conducted at seven mood disorder centres in Australasia, enrolling consenting trial participants who had a Montgomery-Åsberg Depression Rating Scale (MADRS) score of ≥20 at post-trial assessment. Participants initially received twice-weekly 0.5 mg/kg subcutaneous racemic ketamine (fixed regimen) for 4 weeks. Dosing was revised after a Data Safety Monitoring Board recommendation, to a ‘flexible regimen’ (0.5–0.9 mg/kg with response-guided increments). Depression and safety outcomes were assessed throughout treatment, and 4 weeks and 6 months later.

130 RCT participants entered the OLE phase of whom 32 underwent the fixed OLE regimen and 98 the flexible regimen. At treatment end, 30% (36/116) had responded (MADRS reduction ≥50%), and 4 weeks later 17% (19/110) were ‘responders’. Over 50% experienced <25% MADRS reduction. There was no difference in depression response at any time point between regimens. Those treated with ketamine during the RCT showed a transient reduced response after first OLE treatment but at no other assessment point. There were no reports of suicide or suicidal behaviour requiring admission and only expected side-effects observed.

In a highly treatment-resistant sample, a 4-week course of subcutaneous racemic ketamine produced short-term clinical benefit in a minority of participants, with response rates declining substantially after treatment cessation, and no unexpected safety concerns. Exploratory subgroup analyses showed no association between prior RCT ketamine exposure and OLE outcomes.

ACTRN12616001096448 at www.anzctr.org.au.

In preparing for our Clinical and Translational Science Award (CTSA) UM1 application, we recognized the need to develop a shared understanding of the distinctions between translational science (TS) and translational research (TR). We describe our efforts to develop and evaluate the reliability of a concise instrument that investigators and reviewers could use to distinguish between TS and TR.

Groups of faculty and staff individually reviewed published translational studies to determine whether the project involved TS and, separately, TR. One group (n = 10) first reviewed 14 publications with limited guidance; the same group and a second group (n = 9) then reviewed another set of 14 publications guided by a detailed algorithm. We used kappa statistics to measure agreement in the determinations of TS and TR for each publication.

The overall kappa coefficients in the three sets of TS determinations (two by the first group and one by the second group) were 0.61, 0.33, and 0.18, respectively. The overall kappa coefficients in the three sets of TR determinations were 0.26, 0.11, and 0.40, respectively. The median kappa coefficients for all 42 determinations were 0.39 for TS and 0.22 for TR, both indicating only fair agreement. We found no evidence that the algorithm helped to improve agreement rates.

Our results show gaps in understanding the distinction between TS and TR among CTSA hub faculty and staff. We discuss some reasons for this gap and propose ways that could improve the recognition of TS and TR.

Although lithium has been used effectively as a medication to treat bipolar and major depressive disorders, there are limited data defining lithium use patterns during pregnancy.

To investigate trends and patterns of lithium prescribing in the perinatal period (before, during and after pregnancy) among pregnancies in the UK.

We conducted a population-based study using primary healthcare records from the Clinical Practice Research Datalink GOLD, analysing 752 112 pregnancies during the period 1995–2018. We assessed the prevalence and patterns of lithium prescriptions, including discontinuation, continuation and dosage. Maternal characteristics were defined for lithium non-users and users, and between those who continued and discontinued use.

From 1995 to 2018, the prevalence of lithium prescribing per 10 000 pregnancies was 3.02 (95% CI: 2.64, 3.44) before pregnancy, 1.89 (95% CI: 1.59, 2.23) during pregnancy and 2.81 (95% CI: 2.44, 3.21) postpartum. Prescribing during pregnancy was low across the study period, with the most recent prevalence in 2018 of 1.03 (95% CI: 0.26, 4.11) per 10 000 pregnancies. Among 337 pregnancies with perinatal lithium prescribing, 48.4% involved a diagnosis of bipolar disorder. Of 227 pregnancies where lithium was prescribed preconception, 15.4% continued treatment throughout pregnancy; discontinuation occurred before pregnancy in 20.7%, and during second or third trimester in 30.8%; 33.0% followed other prescribing patterns. Women who discontinued lithium were more likely to be younger, have a body mass index ≥30 kg/m2, a diagnosis of bipolar disorder, a history of smoking and >10 primary care consultations in the 12 months preconception, compared with those who continued treatment.

Lithium prescribing during pregnancy in the UK is uncommon and discontinuation is frequent, particularly in the later stages of pregnancy. These findings highlight the need for proactive perinatal mental healthcare strategies and close clinical monitoring, to reduce unintentional first-trimester exposure while ensuring continuity of care for maternal mental health.

The results of a previous randomized trial showed that mentalization-based treatment for psychotic disorder (MBTp) was associated with greater improvement than treatment as usual (TAU) in social functioning up to 6 months after treatment. The purpose of the present study is to examine the effect after 5 years.

The researchers tried to find all patients who had participated in the trial (n = 84) and to assess, blind to previous treatment status, their social functioning and mentalizing capacity. Social functioning was measured using the Social Functioning Scale, mentalizing using the Social Cognition and Object Relations Scale and the Hinting Task.

Twenty-three MBTp patients and 23 TAU patients collaborated. There was no evidence of selective drop-out. A complete case, repeated measure analysis of variance on the basis of intention-to-treat showed that, 5 years post-treatment, MBTp patients still scored better on social functioning compared to baseline [ηp2 = .25, p = .01], whereas TAU patients did not [ηp2 = .01, p = .67], with a significant difference between the conditions [ηp2 = .10, p = .03]. A sensitivity analysis with linear mixed models, however, showed weaker evidence for an additive effect of MBTp over TAU on social functioning 5 years post-treatment, F = 3.731, p = .06. MBT patients also showed a greater improvement in one aspect of mentalizing, understanding of social causality [ηp2 = 0.17, p = .04], but not other aspects of mentalizing.

The results suggest a durable effect of MBTp.

Negative symptoms in schizophrenia, particularly motivational deficits, pose significant challenges to treatment and recovery. Despite their profound impact on functional outcomes, these symptoms remain poorly understood and inadequately addressed by current interventions.

The CHANSS (Characterising Negative Symptoms in Schizophrenia) study aims to dissect the cognitive mechanisms underlying motivational impairments by focusing on three interconnected domains: executive cognition, motivational cognition and meta-cognition.

This large, international, cross-sectional study recruits a heterogeneous sample of patients across illness stages – from first-episode psychosis to treatment-resistant schizophrenia – and uses a comprehensive cognitive battery, clinical scales, self-report measures and computerised cognitive tasks. Four novel tasks assess key processes in motivated behaviour: option generation, reward-based decision-making, risk sensitivity and performance self-evaluation. By incorporating control for secondary influences like depression, psychosis, sedation and illness chronicity, the study seeks to identify distinct cognitive and behavioural subtypes within motivational dysfunction.

CHANSS tests the hypothesis that specific patient profiles exhibit predominant impairments in one or more cognitive domains, which may differentially affect goal-directed behaviour. The study’s design allows exploration of hierarchical relationships between cognitive processes, such as how neurocognitive deficits may cascade to impair motivation and self-evaluation.

Ultimately, CHANSS aims to advance mechanistic understanding of motivational deficits in schizophrenia and pave the way for personalised, targeted interventions. Its findings may inform future clinical trials and contribute to a shift away from one-size-fits-all approaches towards more effective, stratified treatment strategies in schizophrenia.

Observational studies indicate that higher educational attainment (EA) is associated with a lower risk of many mental health conditions (MHC). We assessed to what extent this association is influenced by genetic nurture and demographic factors (i.e., assortative mating and population structure).

We conducted a within-sibship Mendelian randomization (MR) study. The sample consisted of 61 880 siblings (27 507 sibships) from the Trøndelag Health Study-HUNT (Norway) and UK Biobank (United Kingdom). MHC outcomes included symptom scores for anxiety, depression, and neuroticism, measured using the Hospital Anxiety and Depression Scale, the 7-item Generalized Anxiety Disorder Scale, the 9-item Patient Health Questionnaire, and the Eysenck Personality Questionnaire, along with self-reported psychotropic medication use.

One standard deviation (SD) increase in liability to EA was associated with lower anxiety (−0.20 SD [95% CI: −0.26, −0.14]), depression (−0.11 SD [−0.43, −0.22]), and neuroticism scores (−0.30 SD [−0.53, −0.06]), as well as lower odds of psychotropic medication use (OR: 0.60 [0.52, 0.69]). Within-sibship MR estimates remained consistent with population-based estimates: anxiety (−0.17 SD [−0.33, −0.00]); depression (−0.18 SD [−1.26, 0.89]); neuroticism (−0.29 SD [−0.43, −0.15]); psychotropic medication use (OR, 0.52 [0.34, 0.82]).

Higher EA or genetic liability to education reduces symptoms of anxiety, neuroticism, and psychotropic medication use. These mental health benefits do not seem to be explained by EA-linked genetic nurture or demographic factors. Regarding depression, results were less conclusive due to imprecise estimates, though beneficial effects of genetic liability to higher EA are possible and warrant further investigation.

Genetic research on nicotine dependence has utilized multiple assessments that are in weak agreement.

We conducted a genome-wide association study (GWAS) of nicotine dependence defined using the Diagnostic and Statistical Manual of Mental Disorders (DSM-NicDep) in 61,861 individuals (47,884 of European ancestry [EUR], 10,231 of African ancestry, and 3,746 of East Asian ancestry) and compared the results to other nicotine-related phenotypes.

We replicated the well-known association at the CHRNA5 locus (lead single-nucleotide polymorphism [SNP]: rs147144681, p = 1.27E−11 in EUR; lead SNP = rs2036527, p = 6.49e−13 in cross-ancestry analysis). DSM-NicDep showed strong positive genetic correlations with cannabis use disorder, opioid use disorder, problematic alcohol use, lung cancer, material deprivation, and several psychiatric disorders, and negative correlations with respiratory function and educational attainment. A polygenic score of DSM-NicDep predicted DSM-5 tobacco use disorder criterion count and all 11 individual diagnostic criteria in the independent National Epidemiologic Survey on Alcohol and Related Conditions-III sample. In genomic structural equation models, DSM-NicDep loaded more strongly on a previously identified factor of general addiction liability than a “problematic tobacco use” factor (a combination of cigarettes per day and nicotine dependence defined by the Fagerström Test for Nicotine Dependence). Finally, DSM-NicDep showed a strong genetic correlation with a GWAS of tobacco use disorder as defined in electronic health records (EHRs).

Our results suggest that combining the wide availability of diagnostic EHR data with nuanced criterion-level analyses of DSM tobacco use disorder may produce new insights into the genetics of this disorder.