This week in Psychiatry

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Welcome to This Week in Psychiatry. This week we're covering 10 notable papers spanning new evidence in addiction treatment and service delivery, biological signatures of aging and treatment response across depression, trauma and catatonia, and the developmental and social roots of psychiatric risk. Let's dive in.

We start with substance use, where this week brings a positive pharmacologic trial, a negative service-delivery trial with an intriguing mortality signal, and a national picture of who is turning up in acute care. In the American Journal of Psychiatry, Santos and colleagues ran a phase 2b double-blind trial of kudzu, an herbal extract, in 120 adults with alcohol use disorder who binge drink [1]. Participants took 2 grams only on days they anticipated binge drinking, alongside weekly counselling for 12 weeks. Retention was high, with close to nine in ten participants completing the trial. In the intention-to-treat analysis, kudzu cut binge-drinking days by roughly a quarter compared with placebo, and among participants who took it regularly the reduction was closer to 40 percent, with fewer participants testing positive on phosphatidylethanol, the blood marker of heavy drinking. The reduction in binge days held at three months after treatment ended, and adverse events were similar between groups. This is a single, modest-sized trial, and the primary effect only just reached significance, so it supports targeted kudzu as a promising option for people who binge drink rather than an established one; a larger confirmatory trial would be needed before guidelines move. In JAMA Psychiatry, Shoptaw and colleagues report HPTN 094, which randomized 409 people who inject drugs across five American cities to integrated HIV pre-exposure prophylaxis and opioid use disorder medication delivered on a mobile unit with peer navigation, versus peer navigation to existing community services [2]. The primary outcomes were negative: uptake of both prophylaxis and opioid medication was low and similar in both arms at 26 and 52 weeks, with medication use hovering around one in seven participants. But there were 4 deaths in the mobile arm against 13 in the control arm, roughly a seventy percent lower hazard. That was a secondary outcome with small event numbers, and the authors themselves say it bears replication, so it reopens a question rather than settles one. Rounding out the theme, Steinle and colleagues, also in the American Journal of Psychiatry, analysed more than five million substance-related emergency and inpatient encounters from commercial and Medicaid claims between 2016 and 2023 [3]. Alcohol dominated among older adults, involved in roughly three quarters of encounters for people aged 55 to 64, while cannabis was involved in most adolescent encounters. Alcohol involvement grew fastest among adults aged 25 to 44, and cannabis involvement grew fastest among 19 to 24 year olds, with rising presentations for psychosis and hyperemesis. When restricted to primary diagnoses, though, cannabis trends weakened and actually declined in adolescents, suggesting much of the rise reflects cannabis recorded as a secondary rather than primary problem. These are descriptive claims data, but they sketch a clear age gradient for acute care planning.

Our second theme is biological aging and molecular markers, where several large studies converge on the idea that psychiatric illness leaves measurable traces, though modest ones. In Biological Psychiatry, Sharma and colleagues from the COORDINATE-MDD consortium compared brain MRI from 645 medication-free adults in a current depressive episode with 645 matched controls [4]. On average, brains in depression looked about two years older than expected, but the gap was absent before the mid-thirties and widened with age, reaching several years in people over 55. The excess aging concentrated in one neuroanatomical subtype previously linked to poorer outcomes. The authors are careful to say this is consistent with, but does not prove, neuroprogression, since the data are cross-sectional. Also in Biological Psychiatry, Wolf and colleagues examined DNA methylation clocks in more than 43,000 veterans from the Million Veteran Program, about twenty times larger than any previous study of the question [5]. Both PTSD diagnosis and symptom severity were linked to older epigenetic age, by up to about two years on the GrimAge clock, with stronger associations in younger veterans and fewer significant associations among participants of African ancestry. The authors describe the effects as small for any individual, but meaningful at population scale. Moving from aging to treatment response, Müller and colleagues in Molecular Psychiatry report what they describe as the first longitudinal epigenome-wide study during antidepressant treatment, following 162 patients and 48 controls across eight weeks [6]. They found a handful of methylation regions, in genes tied to neuroplasticity and inflammation, associated with symptom change, though no single baseline position reached significance. This is hypothesis-generating work that needs replication before it informs prescribing. Finally, in the American Journal of Psychiatry, Volkmer and colleagues used normative modelling against tens of thousands of healthy scans to map individual brain deviations in catatonia across two independent cohorts totalling 280 patients with mood or schizophrenia spectrum disorders [7]. Catatonia was consistently linked to enlarged ventricles and thinning in the posterior cingulate and insular cortex across both cohorts, supporting a transdiagnostic motor-salience circuit model. Functional connectivity findings did not survive correction, so the structural signal is the firmer result, and it mainly offers targets for future mechanistic and neuromodulation research.

Our final theme looks at where risk comes from: development, social context, and the state of a whole field. In Molecular Psychiatry, Xu and colleagues used the Adolescent Brain Cognitive Development study of nearly ten thousand children to build an environmental risk score from twelve baseline factors at ages nine to eleven [8]. Parental depression, witnessing domestic violence, sleep duration and dieting were the strongest predictors of depression two years later. The environmental score classified major depression moderately well and outperformed a polygenic score alone, while combining the two gave the best accuracy. Discrimination was still only moderate and the model lacks external validation, so it is a research tool for now, though it flags sleep and dieting as potentially modifiable targets. In the American Journal of Psychiatry, Ayón and Link surveyed 908 Asian, Black and Latinx immigrant-origin adults in the United States and found that interpersonal and internalised stigma, meaning discrimination, social exclusion, shame and feeling devalued, were the most robust predictors of psychological distress and PTSD symptoms [9]. Each additional stigma exposure was associated with higher symptom levels in a dose-response pattern, and racial and ethnic disparities shrank once immigration-related stigma was accounted for. The design is cross-sectional, so causality cannot be established, but it supports the authors' case for trauma-informed, culturally responsive care. And in The Lancet, Schmidt and colleagues offer a seminar on eating disorders [10]. They describe psychological treatments as first line with medication playing an adjunctive role, note that novel biological and digital interventions are emerging only slowly, and highlight persistent underfunding and genuine controversy over care for the most severe and longstanding illness, particularly anorexia nervosa. They argue progress will come from longitudinal multimodal studies, big data, and more flexible, personalised trial designs.

If you only have time for one paper this week, make it the kudzu trial from Santos and colleagues in the American Journal of Psychiatry [1]. It is a rare randomized, placebo-controlled test of an inexpensive, as-needed option for binge drinking, a group often poorly served by existing medications, and it reopens the question of whether targeted dosing deserves a confirmatory trial.

That's your roundup for This Week in Psychiatry. The full transcript and references are available on the episode page. See you next week.

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