June/July 2026

Immunologic, metabolic and increasingly 'immuno-metabolic' approaches, are prominent in contemporary psychiatric discourse, yet translation into clinical practice remains variable. In this Feature, we pragmatically ask where signal ends and speculation begins, and what this means for the clinical psychiatrist. Autoimmune encephalitis provides a rare but instructive yardstick in which antibody-based mechanisms map onto distinct neuropsychiatric syndromes and respond to targeted immunotherapy. More broadly applicable concepts, including an immuno-metabolic subtype of depression, are increasingly supported by mechanistic work, with attendant treatment implications, although differentiation from routine holistic care remains less clear. In psychosis and severe mental illness, immune and cardiometabolic dysfunction may contribute to both psychiatric and physical disease burden beyond lifestyle or treatment effects alone. Emerging therapies, including GLP-1-based (glucagon-like peptide-1-based) approaches, may bind these threads together with gains for body and mind, but specific evaluation within psychiatry continues. Overall, our view is that the opportunities are not lost, but for robust translation, there is an ongoing need for precise, incremental research, interdisciplinary collaboration and rigorous communication of nuance.

The recent study by Aron et al about lithium deficiency and the onset of Alzheimer's disease provides a valuable explanatory framework for understanding how very small doses of lithium, delivered via environmental exposure, can exert neuroprotective effects. It also contains results which will need to be reconciled with foundational chemistry and existing evidence and which could be potentially misleading.

BACKGROUND: AND HYPOTHESIS: Clozapine treatment carries a risk of blood dyscrasias (BD) and requires indefinite monitoring in many jurisdictions, a major factor in its under-utilization. Although previous studies suggest BD risk is highest early in treatment, BD events have also been reported after many years. This study compares early vs late (>6 months) suspected blood dyscrasias (SBD) and examines rechallenge outcomes as a marker for clozapine-related causation. STUDY DESIGN: A retrospective analysis of electronic health records from a large UK mental health service gathered demographic data, characteristics of SBD events, and outcomes of clozapine rechallenge, defined as reinitiation after SBD-related discontinuation. These variables were compared between early- and late-onset SBD groups using a 6-month treatment duration cutoff. STUDY RESULTS: Of 130 patients with SBD leading to clozapine cessation, 59 had early-onset SBD. The incidence rate before 6 months was 5.54% per year vs 0.53% after 6 months, reflecting an incidence rate ratio of 10.4. Early-onset patients were younger, received lower clozapine doses, and had fewer concurrent antipsychotics. Of 81 rechallenge attempts, 71 (87.7%) were successful, with a mean follow-up of 2.5 years. No significant differences in characteristics or rechallenge outcomes were found between the early- and late-onset groups. CONCLUSIONS: Though less frequent, late-onset SBD shares similar characteristics with early-onset SBD and has a comparable risk of recurrence on clozapine rechallenge. The vast majority of clozapine rechallenges are successful, including early-onset BD, suggesting they are not clozapine-induced. However, clozapine-induced BD, defined by recurrence upon rechallenge, may rarely occur even after years of treatment.

Objective: Ketamine rapidly reduces suicidal ideation in major depressive disorder (MDD), but its effects are transient. Preclinical and clinical studies suggest that ketamine's antidepressant and antisuicidal effects may be partly mediated by mu-opioid receptor (MOR) modulation. The authors investigated the efficacy and safety of low-dose sublingual buprenorphine, a partial MOR agonist, as a follow-on treatment to prolong the effects of intravenous ketamine. Methods: This was a randomized, double-blind, placebo-controlled trial conducted at a single outpatient center in the United States. Adults with MDD and a total score ≥6 on the Scale for Suicide Ideation (SSI) were randomly assigned in a 1:1 ratio to receive either sublingual buprenorphine (0.2 to 0.8 mg/day) or a matched placebo for 4 weeks, beginning 48 hours after a single open-label intravenous ketamine infusion (0.5 mg/kg over 40 minutes). The primary outcome was the change in SSI total score, assessed weekly from day 1 through day 31. Results: From November 2020 to March 2025, 50 participants (68% female) received ketamine, of whom 45 completed at least 1 week of follow-on treatment. Both groups showed significant reductions in SSI total scores, with greater improvement in the buprenorphine group (mean change, -11.6, SD=5.8; N=23) than the placebo group (mean change, -6.3, SD=7; N=22) (Glass delta=0.76, 95% CI=0.11, 1.39). Mixed-effects modeling showed a significant time-by-treatment interaction (p<0.001). Depression scores did not differ significantly between groups. No serious treatment-related adverse events occurred. Conclusions: This randomized controlled trial provides the first evidence that a pharmacological intervention, buprenorphine, significantly sustains and enhances the antisuicidal effects of ketamine in MDD. These findings offer a potentially scalable and safe therapeutic option for a population at risk of suicide.

Importance: Consistent results from preclinical and clinical studies indicate that activation of glucagon-like peptide-1 receptors (GLP-1Rs) affects reward processes; however, to our knowledge, no study has previously evaluated whether a GLP-1R agonist (GLP-1RA) affects motivated behavior in individuals with major depressive disorder (MDD) in a randomized clinical trial. Objective: To assess the effects of a GLP-1RA, semaglutide, on reward-related dysfunction in a population with MDD. Design, Setting, and Participants: This study was a 16-week, double-blind, placebo-controlled, parallel-group randomized clinical trial. A total of 72 participants with a diagnosis of MDD and a body mass index (calculated as weight in kilograms divided by height in meters squared) of 25 or higher were randomized to oral semaglutide (n = 35) or placebo (n = 37). Participants were recruited from the Mood Disorders Psychopharmacology Unit, University Health Network, Toronto, a university-based mood disorders program. Participants were enrolled between March 14, 2022, and July 26, 2024. Data analysis was performed from January 7, 2025, through February 3, 2025. Intervention: Patients were randomized 1:1 to receive placebo or oral semaglutide, 14 mg (initiated at 4 mg and titrated using a 4-week dose-escalation regimen), adjunctive to their existing treatment. Main Outcomes and Measures: The preregistered outcome of this secondary analysis was performance on the Effort-Expenditure for Rewards Task (EEfRT). Results: A total of 72 participants were randomized to oral semaglutide (n = 35 [49.7%]; mean [SD] age, 38.17 [11.79] years; 18 female participants [51.4%]) or placebo (n = 37 [51.3%]; mean [SD] age, 40.27 [9.32] years; 19 female participants [51.3%]). Semaglutide-treated participants exhibited a pattern of increased willingness to exert physical efforts with higher expected values of reward (treatment × visit × expected value interaction: χ² = 12.024; P = .02). Computational modeling indicated that semaglutide's effects on choice behavior were a result of reduced effort discounting. Sensitivity to effort was significantly reduced by treatment with semaglutide (β = −1.737; P = .03), whereas there was no treatment effect on sensitivity to probability (β = −0.776; P = .51). Conclusions: and Relevance: In this secondary analysis of a double-blind randomized clinical trial, treatment with semaglutide significantly improved measures of motivation in patients with MDD. Semaglutide reduced the perceived cost of effort, relative to the monetary reward; the results of this trial have implications for the treatment of multiple neuropsychiatric disorders, which are characterized by varied reward dysfunctions. Trial Registration: ClinicalTrials.gov Identifier: NCT04466345

Cannabis use often begins in adolescence and young adulthood, when anxiety, depression, psychosis, and bipolar disorder typically first develop. Young people aged in their mid-teens to mid-twenties who engage in daily cannabis use and develop a cannabis use disorder have a higher prevalence of these mental disorders. We assessed the coherence of evidence from epidemiological, genetic, experimental, and preclinical studies to assess relationships between daily cannabis use and the increased incidence, prevalence, and persistence of psychosis, bipolar disorder, anxiety, depression, and suicidal behaviours.

Background: People with psychosis have high rates of post-traumatic stress disorder (PTSD), which is associated with a poor prognosis. We aimed to investigate the effectiveness of a trauma-focused therapy integrated with cognitive behavioural therapy for psychosis (CBTp) in people with psychosis. Methods: STAR was a rater-blind, parallel-group, pragmatic randomised controlled trial conducted across five UK sites. We randomly assigned (1:1) adults with co-occurring PTSD and psychosis in secondary care to trauma-focused CBTp plus treatment as usual or treatment as usual only, using randomly varying block size, stratified by site. Trauma-focused CBTp is a flexible, individualised, formulation-based therapy integrating trauma-focused therapeutic components with CBTp, lasting 9 months. The comparator was treatment as usual only, delivered by mental health services. Treatment as usual consisted of multidisciplinary care, including medication and outpatient psychiatric appointments, psychologically informed case management, and potential access to various psychotherapies, including CBTp. Therapists were doctoral-level clinical psychologists or CBT therapists with a minimum of 2 years' experience of working with patients with severe mental health problems. The primary outcome was PTSD symptom severity, assessed using the clinician-administered PTSD scale for DSM-5 (CAPS-5), at 4 months (mid-therapy) and 9 months (primary endpoint). Secondary outcomes were (1) percentage of participants showing PTSD remission from diagnosis and clinically significant change, individual symptom clusters, post-traumatic cognitions, and dissociation; (2) psychosis symptoms; (3) mood disorders; (4) psychological recovery; and (5) social functioning, assessed at the same timepoints. Findings: Between Oct 1, 2020, and March 20, 2023, we randomly assigned 305 participants (151 [49·5%] to treatment as usual and 154 [50·5%] to trauma-focused CBTp plus treatment as usual). The mean age of participants was 38·9 years (SD 12·4). 127 (42%) participants were men, 171 (56%) were women and seven (2%) were non-binary or preferred not to say; 232 (76%) were White. All reported repeated and multiple traumas. Of 154 in the trauma-focused CBTp plus treatment-as-usual group, 144 (94%) engaged with therapy and 146 (95%) received a minimal therapeutic dose. 267 (88%) of 305 participants attended a follow-up assessment (4 months, 9 months, or both); at 9 months, 241 (79%) participants provided primary outcome data and 169–248 (55–81%) provided secondary outcome data. There were significant effects on CAPS-5 scores (adjusted mean difference in PTSD symptom severity –8·67 [95% CI –13·41 to –3·94]; p=0·0003; Cohen's d –0·73) and on 22 (81%) of 27 secondary outcomes, unadjusted for multiple testing (Cohen's d ranging from –0·26 to –0·82), including all PTSD outcomes (except derealisation and depersonalisation); delusions, paranoia, and hallucinations in other modalities; suicidal ideation, depression, anxiety, and stress; and psychological recovery. There were no effects on voices, referential beliefs, substance use, or social functioning (Cohen's d ranging from –0·05 to –0·28). 62 (50%) of 125 participants in the therapy group showed PTSD remission compared with 25 (22%) of 116 in the treatment-as-usual group (odds ratio [OR; PTSD present] 0·11, 95% CI 0·03–0·32; p=0·0001) and 56 (45%) participants in the therapy group compared with 31 (27%) in the treatment-as-usual group had clinically significant change in CAPS-5 score (OR 4·45, 95% CI 1·59–12·44; p=0·0044; number needed to treat for PTSD remission was 4). No serious adverse event was unexpected and related to trial procedures (78 reported in each group), with the most common being physical illness or injury. Interpretation: Trauma-focused CBTp is safe, highly acceptable, and effective in people with co-occurring psychosis and PTSD. This underserved population should no longer be denied access to psychological interventions to treat their trauma sequelae. Funding: National Institute for Health and Care Research (NIHR).

Pharmacogenetic (PGx) testing to guide antidepressant prescribing is becoming increasingly available. However, its uptake into routine psychiatric practice for young people remains limited due to insufficient youth-specific evidence and uncertainty regarding optimal trial design and outcome selection. This pilot study aimed to evaluate the feasibility of implementing a rigorous triple-blind randomized controlled trial to examine PGx-guided antidepressant treatment compared with treatment-as-usual (TAU) in young Australians with depression. The pharmacoGENEtics in Youth Depression (GENE-YD) study recruited young people aged 16–24 years old with major depressive disorder over 13 months, allocating 1:1 to PGx-Guided treatment or TAU. Treatment Guides written by an unblinded psychiatrist on the research team, informed by participants' demographic, clinical, and PGx information, were provided to participants' prescribing clinicians who were encouraged to follow the recommendations provided on the Treatment Guide, whilst using their clinical judgement on what was appropriate for their patient. Participants were required to initiate or modify antidepressant treatment to complete Baseline assessment and be included in the analytic sample. Clinically meaningful improvements were observed, with the PGx-Guided group showing greater reductions in depressive symptom severity, higher rates of treatment response and remission, and improved quality-of-life outcomes compared with TAU. The GENE-YD Study demonstrated that a triple-blind PGx-guided antidepressant trial is feasible and acceptable in young people with depression, with preliminary indications of clinical benefit.

Informing caregivers of the plan to make a referral to child protective services (CPS) for concerns of child abuse or neglect is a challenging conversation. Some fears that healthcare professionals have include risk of caregiver agitation, damage to the therapeutic relationship, and litigation. Although the body of literature exploring the decision to place the referral itself is more robust, publications on how to inform the caregiver that a referral is being placed are scant. We draw on the literature and expert opinion to provide practical trauma-informed guidance in informing a caregiver of the decision to make a referral to CPS. There is a need for additional education and training to apply these principles into practice to improve confidence and competence of healthcare professionals with these ethically challenging and uncomfortable conversations.

Post-COVID-19 syndrome (PCS) is an escalating global health concern, marked by persistent cognitive, neurological, and psychiatric symptoms following acute SARS-CoV-2 infection. Although its underlying mechanisms remain incompletely understood, mounting evidence implicates chronic neuroinflammation as a key driver. Sustained microglial and astrocyte activation, blood-brain barrier disruption, and aberrant cytokine signaling contribute to prolonged immune dysregulation within the central nervous system, promoting long-term brain dysfunction. In this expert review, we synthesize emerging insights into how neuroimmune processes impair brain function in PCS. We explore novel mechanistic pathways - including local sleep intrusions, impaired memory reconsolidation, and astrocyte-mediated destabilization of functional networks - that may underlie the syndrome's fluctuating and heterogeneous presentation.

OBJECTIVE: Psychosis in Alzheimer's disease (AD), including hallucinations and delusions, affects up to 50% of patients and is linked to faster cognitive decline. Delusions can occur across AD, with persecutory delusions early and misidentification delusions late, while hallucinations emerge in advanced stages and predict greater cognitive and functional decline. The APOE4 allele is the strongest genetic risk factor for late-onset AD, although its influence on neuropsychiatric symptoms, including psychosis, remains unclear. This study examined the interaction between APOE4 status, sex, estrogen hormone therapy (EHT) use, and psychosis symptoms in AD using data from participants in the National Alzheimer's Coordinating Center Uniform Data Set. METHODS: Generalized Additive Models assessed nonlinear associations between predictors and psychosis outcomes, including the presence of delusions, hallucinations, and their visual and auditory subtypes. Analyses were stratified by sex (males: n = 13,841, females: n = 15,354). Predictor variables included APOE4 status and current use of estrogen hormone therapy (EHT) in females. RESULTS: APOE4 homozygosity increases the risk of psychosis in Alzheimer's disease in a symptom- and sex-specific manner, being positively associated with hallucinations and delusions in females and with delusions only in males. In sex-stratified analyses, APOE4 homozygosity in women was associated with greater odds for delusions (OR 1.26; P<.01) and hallucinations (OR 1.29; P<.05). Additionally, estrogen hormone therapy was associated with reduced odds of experiencing hallucinations in females, pointing to hormonal regulation as a key modifier of certain psychosis features. CONCLUSIONS: These findings underscore sex-specific genetic and biological contributors to psychosis in AD and support sex-stratified approaches to understanding and addressing psychosis symptoms in clinical settings. The findings underscore the importance of considering sex- and symptom-specific mechanisms in AD psychosis, highlighting the need for targeted, sex- and hormone-informed approaches to clinical evaluation and intervention. Clinical Reviews & Meta-Analyses

Question: Which pharmacological interventions are associated with reducing body weight in individuals with schizophrenia spectrum disorders (SSDs) treated with antipsychotics? Findings: In this systematic review and network meta-analysis of 95 randomized clinical trials published between 1965 and 2025 involving approximately 5,900 adults with SSDs, 39 independent pharmacological interventions were evaluated. Semaglutide was associated with the greatest weight reduction (approximately 11 kg [~24 lb] compared with placebo), the largest effect among all interventions studied. Liraglutide, topiramate, metformin, and exenatide were also associated with meaningful weight reductions (ranging from approximately 3 kg to just over 5 kg), supported by moderate-certainty evidence. Meaning: These results help clarify the relative positioning of commonly used and emerging pharmacological strategies for antipsychotic-associated weight gain in patients with schizophrenia spectrum disorders.

Objective: To quantify the prevalence of cannabis use (CU) and cannabis use disorders (CUD) in Early-Onset Psychosis (EOP; <18 years) and examine their correlates, clinical and functional impact. Method: This PRISMA-compliant systematic review and meta-analysis (CRD420251070701) searched six databases until 1/7/2025, for studies evaluating CU/CUD in EOP. Data were extracted by independent researchers, and quality assessment was conducted using the Newcastle-Ottawa Scale. Heterogeneity, publication bias, subgroup and meta-regression analyses were performed. A narrative synthesis was conducted. Results: Forty studies (N=3,473; age=16.2±1.6 years; male=59%) were included. In EOP, pooled prevalence was for current CU 32.8% (95%CI=18.5-51.2), for lifetime CU 40.2% (95%CI=31.3-49.7), and for lifetime CUD 36.6% (95%CI=18.2-59.9). In meta-regression analyses, current CU was associated with male sex (β=0.012, p=0.021) and hospitalization rates (β=0.006, p=0.021), but with less severe negative symptoms (β=-0.191, p=0.001) and lower proportion of schizophrenia diagnosis (β=-0.026, p=0.049). Lifetime CU was associated with cocaine use (β=0.101, p=0.003) and again less severe negative symptoms (β=-0.173, p=0.030). Our narrative synthesis indicated that CU commonly preceded psychosis onset, and was linked to negative outcomes (e.g. longer duration of untreated psychosis and higher hospitalization rates) in EOP. Study quality was mostly fair (67.5%); GRADE certainty ranged from low to moderate. Conclusion: CU and CUD are common in EOP and relate to clinical presentation. Screening and integrated substance use care should be embedded in primary care and clinical settings. Further longitudinal studies and randomized clinical trials to evaluate the efficacy of interventions to reduce CU and CUD are needed.

What is the primary question addressed by this study? This meta-analysis evaluates the efficacy of intranasal insulin in reducing the incidence of postoperative delirium and postoperative cognitive dysfunction in adult surgical patients. Background: Postoperative delirium (POD) is a serious problem affecting 15%–53% of older adults after surgery and 70%–87% of patients in intensive care units. POD is characterized by restlessness, irritability, difficulty focusing, hallucination, and slurred speech. Intranasal insulin (INI) is a new therapy that may have a protective effect against perioperative neurocognitive disorders by regulating key physiological processes. We conducted a systematic review and meta-analysis to determine the efficacy of perioperative administration of INI in reducing the incidence of POD and postoperative cognitive dysfunction (POCD) and its effects on inflammatory biomarkers. Methods: A comprehensive search on 4 databases was conducted to retrieve the relevant articles. This systematic review and meta-analysis follow the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines and adhere to the Cochrane Handbook for Systematic Reviews of Interventions. The study was prospectively registered on PROSPERO (ID: CRD42025635178). Using a random-effects model, data were pooled as risk ratios (RR) or mean differences (MD) with 95% confidence intervals (CI). The comparator was intranasal saline administration. Results: (What is the main finding of this study?): Intranasal insulin significantly reduced the incidence of postoperative delirium (RR = 0.39) and cognitive dysfunction (RR = 0.51) while decreasing inflammatory markers like IL-6 and TNF-α. Our results revealed that INI significantly lowered the probability of developing POD and POCD compared to the control group, with significant improvements with both 20 IU and 40 IU doses. As demonstrated in our subgroup analysis, the results remain consistent with a reduction in all assessment times. Conclusions: (What is the meaning of the finding?): Intranasal insulin represents a promising brain-targeted, anti-inflammatory intervention for preventing perioperative neurocognitive disorders. Perioperative INI is an ideal therapy for decreasing the risk of POD and POCD in adult surgical patients. Most importantly, since INI has been shown to attenuate neuroinflammation in several trials, clinicians may be willing to consider prophylactic therapy with INI, especially at doses between 20 and 40 IU. Interesting Viewpoints

No abstract available. This is an editorial commentary on the Rovers et al. Delphi-based expert consensus study on relapse prevention strategies following successful ECT for major depressive disorder. The editorial discusses the evidence supporting pharmacotherapy with lithium and an antidepressant as an essential relapse prevention strategy for all patients after successful ECT, and the role of continuation/maintenance ECT (with tapering rather than abrupt cessation) for patients at high risk of relapse and those with severe or psychotic depression. The authors highlight that lithium, because of its proven track record of preventing relapses, should be prescribed for more patients than it currently is.

In this article, I focus on three new views of lithium’s clinical and biological properties, indicating the much greater need for its use in bipolar disorder. Lithium’s extensive but underappreciated positive properties in the treatment of bipolar disorder beyond the treatment of mania are briefly summarized. First, I make the case that lithium differs from conventional treatment agents for bipolar disorder because of its extensive breadth of positive effects (1–3). Second, I argue that lithium should be considered a disease-modifying drug. Like other agents in this category in the treatment of medical diseases such as multiple sclerosis and rheumatoid arthritis, they should be considered for use early in the course of these illnesses to prevent illness progression and disability (4). Third, I discuss a revolutionary view of lithium that emerged recently in an article in Nature (5) that presented cogent clinical and preclinical data indicating that deficits in brain lithium are found in mild cognitive impairment (MCI) and Alzheimer’s disease. Moreover, when lithium is replaced in cognitively impaired animals given lithium-deficient diets, the abnormalities are reversed (5). Lithium orotate is a more effective remediator than regular lithium, as it is not sequestered in Alzheimer’s plaques the way natural lithium is.

This Viewpoint discusses considerations in training mental health clinicians and implementing institutional workflows to use large language models (LLMs) as clinical instruments for improving care.