The British Journal of Psychiatry最新文献

{"title":"Biomarkers of reproductive psychiatric disorders","authors":"Semra Etyemez, Kruti Mehta, Sonali Iyer, İpek Özdemir, Lauren M. Osborne","doi":"10.1192/bjp.2025.134","DOIUrl":"https://doi.org/10.1192/bjp.2025.134","url":null,"abstract":"<span>Background</span><p>While biomarkers are widely used in other medical fields, psychiatry has yet to introduce reliable biological diagnostic tools. Female reproductive transitions provide a unique window of opportunity for investigating psychiatric biomarkers. Hormonal changes across menstruation, pregnancy, parturition and perimenopause can have dramatic effects on mental health in vulnerable individuals, enabling the identification of unique biomarkers associated with these fluctuations.</p><span>Aims</span><p>This review integrates current evidence concerning potential biomarkers, with focus on recent human studies in perinatal depression, anxiety and obsessive–compulsive disorder, postpartum psychosis, premenstrual dysphoric disorder and perimenopausal depression.</p><span>Method</span><p>We identified potential articles to be included in this narrative review by using PubMed to obtain articles in English since 2010 on the six conditions listed above, with the additional keywords of ‘biomarker’, ‘epigenetics’, ‘neuroactive steroid’, ‘immune’, ‘inflammatory’ and ‘neuroimaging’.</p><span>Results</span><p>There is substantial published evidence regarding potential biomarkers of reproductive psychiatric disorders in the areas of epigenetics, neuroactive steroids, immune function and neuroimaging. This body of research holds significant potential to advance biomarker development, uncover disease mechanisms and improve diagnostic and therapeutic strategies, but there is as yet no clinically useful biomarker in commercial development for any reproductive psychiatric disorder.</p><span>Conclusion</span><p>There is an urgent need for longitudinal, large-scale and multi-modal studies to examine potential biomarkers and better understand their functions across various stages of reproduction.</p>","PeriodicalId":22495,"journal":{"name":"The British Journal of Psychiatry","volume":"236 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-06-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144328989","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Trajectories and dimensional phenotypes of depressive symptoms throughout pregnancy and postpartum in relation to prior premenstrual symptoms","authors":"Ella Schleimann-Jensen, Inger Sundström-Poromaa, Samantha Meltzer-Brody, Tory A. Eisenlohr-Moul, Fotis C. Papadopoulos, Alkistis Skalkidou, Erika Comasco","doi":"10.1192/bjp.2025.38","DOIUrl":"https://doi.org/10.1192/bjp.2025.38","url":null,"abstract":"<span>Background</span><p>Sensitivity to ovarian hormone fluctuations can lead to mental distress during the luteal phase of the menstrual cycle, such as in premenstrual syndrome (PMS) and premenstrual dysphoric disorder (PMDD), and also during pregnancy and postpartum, as in perinatal depression (PND).</p><span>Aims</span><p>In two cohorts, we investigated the relationship between history of PMS/PMDD and PND symptoms. We also examined how premenstrual symptoms are associated with perinatal symptom trajectories and dimensional phenotypes of PND symptoms, which remains unidentified.</p><span>Method</span><p>From early pregnancy until 6 months postpartum, participants of two large longitudinal cohorts were followed using the Edinburgh Postnatal Depression Scale (EPDS). Premenstrual symptoms were self-reported retrospectively.</p><span>Results</span><p>Both pre-pregnancy PMS and PMDD were associated with higher EPDS scores across pregnancy and postpartum, even after adjustment for confounders. The odds of developing PND were higher among those reporting PMS and PMDD, ranging up to 1.68 (95% CI 1.25–2.29) (6–13 weeks postpartum) and 3.05 (95% CI 2.26–4.10) (late pregnancy) respectively for PMS and PMDD, throughout the perinatal period. Premenstrual symptomatology was associated more with certain PND trajectories based on the time of occurrence and persistence of symptoms. However, PND symptom severity did not differ depending on premenstrual symptomatology in any trajectory. Prior PMS/PMDD was associated with underlying dimensions of symptom constructs of PND, including severe and moderate symptoms of depressed mood, anxiety and anhedonia.</p><span>Conclusions</span><p>Women with a history of PMS/PMDD require coordinated care by psychiatrists, other mental health clinicians, midwives and gynaecologists during pregnancy as well as postpartum.</p>","PeriodicalId":22495,"journal":{"name":"The British Journal of Psychiatry","volume":"15 1","pages":"1-9"},"PeriodicalIF":0.0,"publicationDate":"2025-06-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144329053","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Reproducible sex differences in personalised functional network topography in youth","authors":"Arielle S. Keller, Kevin Y. Sun, Ashley Francisco, Heather Robinson, Emily Beydler, Dani S. Bassett, Matthew Cieslak, Zaixu Cui, Christos Davatzikos, Yong Fan, Margaret Gardner, Rachel Kishton, Sara L. Kornfield, Bart Larsen, Hongming Li, Isabella Linder, Adam Pines, Laura Pritschet, Armin Raznahan, David R. Roalf, Jakob Seidlitz, Golia Shafiei, Russell T. Shinohara, Lauren K. White, Daniel H. Wolf, Aaron Alexander-Bloch, Theodore D. Satterthwaite, Sheila Shanmugan","doi":"10.1192/bjp.2025.135","DOIUrl":"https://doi.org/10.1192/bjp.2025.135","url":null,"abstract":"<span>Background</span><p>A key step toward understanding psychiatric disorders that disproportionately impact female mental health is delineating the emergence of sex-specific patterns of brain organisation at the critical transition from childhood to adolescence. Prior work suggests that individual differences in the spatial organisation of functional brain networks across the cortex are associated with psychopathology and differ systematically by sex.</p><span>Aims</span><p>We aimed to evaluate the impact of sex on the spatial organisation of person-specific functional brain networks.</p><span>Method</span><p>We leveraged person-specific atlases of functional brain networks, defined using non-negative matrix factorisation, in a sample of <span>n</span> = 6437 youths from the Adolescent Brain Cognitive Development Study. Across independent discovery and replication samples, we used generalised additive models to uncover associations between sex and the spatial layout (topography) of personalised functional networks (PFNs). We also trained support vector machines to classify participants’ sex from multivariate patterns of PFN topography.</p><span>Results</span><p>Sex differences in PFN topography were greatest in association networks including the frontoparietal, ventral attention and default mode networks. Machine learning models trained on participants’ PFNs were able to classify participant sex with high accuracy.</p><span>Conclusions</span><p>Sex differences in PFN topography are robust, and replicate across large-scale samples of youth. These results suggest a potential contributor to the female-biased risk in depressive and anxiety disorders that emerge at the transition from childhood to adolescence.</p>","PeriodicalId":22495,"journal":{"name":"The British Journal of Psychiatry","volume":"8 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-06-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144319871","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Moderators of antidepressant augmentation versus switch in the OPTIMUM randomised controlled trial","authors":"Helena K. Kim, Jordan F. Karp, Helen Lavretsky, Daniel M. Blumberger, Patrick J. Brown, Alastair J. Flint, Emily Lenard, J. Philip Miller, Charles F. Reynolds, Steven P. Roose, Eric J. Lenze, Benoit H. Mulsant","doi":"10.1192/bjp.2025.125","DOIUrl":"https://doi.org/10.1192/bjp.2025.125","url":null,"abstract":"<span>Background</span><p>Older adults with treatment-resistant depression (TRD) benefit more from treatment augmentation than switching. It is useful to identify moderators that influence these treatment strategies for personalised medicine.</p><span>Aims</span><p>Our objective was to test whether age, executive dysfunction, comorbid medical burden, comorbid anxiety or the number of previous adequate antidepressant trials could moderate the superiority of augmentation over switching. A significant moderator would influence the differential effect of augmentation versus switching on treatment outcomes.</p><span>Method</span><p>We performed a preplanned moderation analysis of data from the Optimizing Outcomes of Treatment-Resistant Depression in Older Adults (OPTIMUM) randomised controlled trial (<span>N</span> = 742). Participants were 60 years old or older with TRD. Participants were either (a) randomised to antidepressant augmentation with aripiprazole (2.5–15 mg), bupropion (150–450 mg) or lithium (target serum drug level 0.6 mmol/L) or (b) switched to bupropion (150–450 mg) or nortriptyline (target serum drug level 80–120 ng/mL). Treatment duration was 10 weeks. The two main outcomes of this analysis were (a) symptom improvement, defined as change in Montgomery–Asberg Depression Rating Scale (MADRS) scores from baseline to week 10 and (b) remission, defined as MADRS score of 10 or less at week 10.</p><span>Results</span><p>Of the 742 participants, 480 were randomised to augmentation and 262 to switching. The number of adequate previous antidepressant trials was a significant moderator of depression symptom improvement (<span>b</span> = −1.6, <span>t</span> = −2.1, <span>P</span> = 0.033, 95% CI [−3.0, −0.1], where <span>b</span> is the coefficient of the relationship (i.e. effect size), and <span>t</span> is the <span>t</span>-statistic for that coefficient associated with the <span>P</span>-value). The effect was similar across all augmentation strategies. No other putative moderators were significant.</p><span>Conclusions</span><p>Augmenting was superior to switching antidepressants only in older patients with fewer than three previous antidepressant trials. This suggests that other intervention strategies should be considered following three or more trials.</p>","PeriodicalId":22495,"journal":{"name":"The British Journal of Psychiatry","volume":"30 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-06-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144319869","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The Music for Subanesthetic Infusions of Ketamine randomised clinical trial: ketamine as a psychedelic treatment for highly refractory depression.","authors":"Kyle T Greenway,Nicolas Garel,Lê-Anh L Dinh-Williams,Julien Thibault Lévesque,Mendel Kaelen,Vincent Dagenais-Beaulé,Sara de la Salle,David Erritzoe,Karl Looper,Gustavo Turecki,Soham Rej,Séphane Richard-Devantoy","doi":"10.1192/bjp.2025.102","DOIUrl":"https://doi.org/10.1192/bjp.2025.102","url":null,"abstract":"BACKGROUNDKetamine exerts potent but transient antidepressant effects in treatment-resistant depression (TRD). Combinations of ketamine and psychotherapy have attracted interest, but no trial has investigated a psychedelic model of ketamine-psychotherapy for TRD to our knowledge.AIMSThis secondary analysis of a randomised clinical trial (RCT) explores the therapeutic effects and experiential mechanisms of the Montreal Model of ketamine-psychotherapy for TRD, with or without music.METHODA two-centre, single-blinded, RCT conducted in Montreal, Canada, between January 2021 and August 2022 (NCT04701866). Participants received ketamine-psychotherapy for TRD - six subanaesthetic infusions over 4 weeks and psychological support - with either music or matched non-music support during ketamine doses, as per random group assignments. The primary therapeutic outcome was the Montgomery-Åsberg Depression Rating Scale, assessed by blinded raters. Psychedelic-like experiences, evaluated by the Mystical Experience Questionnaire and Emotional Breakthrough Inventory, and their session-by-session relationships with depression were explored with multilevel, time-lagged covariate models with autoregressive residuals.RESULTSThirty-two participants with severe and highly comorbid TRD, including high rates of personality disorder and suicidality, received 181 ketamine infusions. Therapeutic outcomes and psychedelic experiences did not differ between music (n = 15) and non-music (n = 17) interventions. Both groups experienced significant reductions in clinician-rated and self-reported depression (d = 1.2 and d = 0.87, respectively; p < 0.001), anxiety (d = 0.8, p < 0.001) and suicidality (d = 0.4, p < 0.05) at 4 weeks, fully maintained at 8-week follow-up. Ketamine experiences were highly emotional and mystical. Converging analyses supported mystical-like ketamine experiences as mechanisms of its antidepressant effects.CONCLUSIONSThis trial found large and notably sustained benefits of ketamine-psychotherapy for severe TRD, with or without music, and psychedelic experiences of comparable intensity to those observed with psilocybin. Mystical-like experiences may particularly contribute to ketamine's immediate and persistent psychiatric benefits.","PeriodicalId":22495,"journal":{"name":"The British Journal of Psychiatry","volume":"232 1","pages":"1-9"},"PeriodicalIF":0.0,"publicationDate":"2025-06-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144311585","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The DEPRE’5 study: pragmatic, multicentre, five-arm, parallel-group randomised controlled trial with blinded assessment to compare treatment strategies in major depression after a failed selective serotonin reuptake inhibitor treatment","authors":"Víctor Pérez, Dolors Puigdemont, Javier de Diego-Adeliño, Matilde Elices, Itziar Leal, Maria Cabello, Roberto Rodriguez-Jimenez, Miguel Ángel Álvarez-Mon, Lorena García-Fernández, Eduardo José Aguilar García-Iturrospe, Maria José Escartí, Angel Luis Montejo, José Manuel Montes, Judith Usall, Ascensión Gallego-Nogueras, Elena Lujan, Raquel López-Carrilero, Ana González-Pinto, Agurtzane Ortiz-Jauregui, Jordi Blanch, Mikel Urretavizcaya, Francesc Colom, Javier García-Campayo, José Luis Ayuso-Mateos","doi":"10.1192/bjp.2025.13","DOIUrl":"https://doi.org/10.1192/bjp.2025.13","url":null,"abstract":"<span>Background</span><p>Selective serotonin reuptake inhibitors (SSRIs) are the first-line treatment for major depressive disorder (MDD), but initial outcomes can be modest.</p><span>Aims</span><p>To compare SSRI dose optimisation with four alternative second-line strategies in MDD patients unresponsive to an SSRI.</p><span>Method</span><p>Of 257 participants, 51 were randomised to SSRI dose optimisation (SSRI-Opt), 46 to lithium augmentation (SSRI+Li), 48 to nortriptyline combination (SSRI+NTP), 55 to switch to venlafaxine (VEN) and 57 to problem-solving therapy (SSRI+PST). Primary outcomes were week-6 response/remission rates, assessed by blinded evaluators using the 17-item Hamilton Depression Rating Scale (HDRS-17). Changes in HDRS-17 scores, global improvement and safety outcomes were also explored. EudraCT No. 2007-002130-11.</p><span>Results</span><p>Alternative second-line strategies led to higher response (28.2% <span>v.</span> 14.3%, odds ratio = 2.36 [95% CI 1.0–5.6], <span>p</span> = 0.05) and remission (16.9% <span>v.</span> 12.2%, odds ratio = 1.46, [95% CI 0.57–3.71], <span>p</span> = 0.27) rates, with greater HDRS-17 score reductions (−2.6 [95% CI −4.9 to −0.4], <span>p</span> = 0.021]) than SSRI-Opt. Significant/marginally significant effects were only observed in both response rates and HDRS-17 decreases for VEN (odds ratio = 2.53 [95% CI 0.94–6.80], <span>p</span> = 0.067; HDRS-17 difference: −2.7 [95% CI −5.5 to 0.0], <span>p</span> = 0.054) and for SSRI+PST (odds ratio = 2.46 [95% CI 0.92 to 6.62], <span>p</span> = 0.074; HDRS-17 difference: −3.1 [95% CI −5.8 to −0.3], <span>p</span> = 0.032). The SSRI+PST group reported the fewest adverse effects, while SSRI+NTP experienced the most (28.1% <span>v.</span> 75%; <span>p</span> &lt; 0.01), largely mild.</p><span>Conclusions</span><p>Patients with MDD and insufficient response to SSRIs would benefit from any other second-line strategy aside from dose optimisation. With limited statistical power, switching to venlafaxine and adding psychotherapy yielded the most consistent results in the DEPRE'5 study.</p>","PeriodicalId":22495,"journal":{"name":"The British Journal of Psychiatry","volume":"14 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-06-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144311919","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Differential sensitivity: not more or less.","authors":"David R Rubinow,Peter J Schmidt","doi":"10.1192/bjp.2025.40","DOIUrl":"https://doi.org/10.1192/bjp.2025.40","url":null,"abstract":"Although posited as an explanation for reproductive endocrine-related mood disorders, differential hormone sensitivity is an elusive concept. In this editorial, we define differential sensitivity, embed it in current understanding of the generation of brain states and discuss its practical utility.","PeriodicalId":22495,"journal":{"name":"The British Journal of Psychiatry","volume":"37 1","pages":"1-3"},"PeriodicalIF":0.0,"publicationDate":"2025-06-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144311581","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Increased risk of provisional premenstrual dysphoric disorder (PMDD) among females with attention-deficit hyperactivity disorder (ADHD): cross-sectional survey study.","authors":"Thomas Broughton,Ellen Lambert,Jasmin Wertz,Jessica Agnew-Blais","doi":"10.1192/bjp.2025.104","DOIUrl":"https://doi.org/10.1192/bjp.2025.104","url":null,"abstract":"BACKGROUNDDue to historical under-recognition of attention-deficit hyperactivity disorder (ADHD) among girls and women, little is known about female-specific factors that may affect individuals with ADHD, including those related to changes in ovarian hormones (e.g. across the menstrual cycle).AIMSWe investigated whether females with a self-reported clinical diagnosis of ADHD are more likely to experience premenstrual dysphoric disorder (PMDD). We also examined associations between PMDD and ADHD defined by a symptom and impairment threshold.METHODParticipants were aged between 18 and 34 years, were assigned female at birth and were recruited via Prolific.com (n = 715). Participants self-reported clinician diagnosis of ADHD, depression and anxiety. ADHD symptoms were assessed via the Adult ADHD Self-Report Scale (ASRS), to which we applied a DSM-5-based symptom and impairment cut-off ('ASRS-based ADHD'). PMDD symptoms were assessed via the Premenstrual Symptoms Screening Tool (PSST), which identifies provisional PMDD. Using Poisson regression models, we compared risk for provisional PMDD among females with ADHD (self-reported clinical diagnosis [n = 102] or ASRS-based [n = 229]) with a non-ADHD reference group (n = 305). We additionally compared risk for provisional PMDD among individuals with ADHD and depression/anxiety diagnoses, ADHD only and a non-ADHD reference group.RESULTSThe prevalence of provisional PMDD was elevated among individuals with a self-reported clinical ADHD diagnosis (31.4%), and among participants with ASRS-based ADHD (41.1%), compared with the non-ADHD reference group (9.8%). Individuals with ASRS-based ADHD and depression and/or anxiety diagnoses were at highest risk for provisional PMDD (relative risk 4.53 [3.10, 6.61]) compared with the non-ADHD reference group.CONCLUSIONSClinicians should be aware that individuals with a diagnosis of ADHD, or with high ADHD symptom levels, and who have a menstrual cycle may be more likely to experience PMDD. Future research should investigate the underlying mechanisms that link ADHD and disorders associated with hormonal sensitivity, such as PMDD.","PeriodicalId":22495,"journal":{"name":"The British Journal of Psychiatry","volume":"43 1","pages":"1-8"},"PeriodicalIF":0.0,"publicationDate":"2025-06-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144311583","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Psychiatric symptoms on the ovarian hormone roller-coaster.","authors":"Erika Comasco,C Neill Epperson,Jayashri Kulkarni","doi":"10.1192/bjp.2025.10298","DOIUrl":"https://doi.org/10.1192/bjp.2025.10298","url":null,"abstract":"This themed issue examines the impact of ovarian hormone fluctuations on women's mental health across the lifespan, including puberty, the menstrual cycle, pregnancy, postpartum and menopause. It highlights critical gaps and calls for sex-specific approaches in reproductive psychiatry and hormone-informed mental care.","PeriodicalId":22495,"journal":{"name":"The British Journal of Psychiatry","volume":"39 1","pages":"1-2"},"PeriodicalIF":0.0,"publicationDate":"2025-06-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144311580","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Linking prolonged childhood and adolescent loneliness to schizophrenia spectrum disorders: results from EU-GEI study.","authors":"Álvaro Andreu-Bernabeu,Javier González-Peñas,Alberto Mora,Miguel Bernardo,Gisela Mezquida,Silvia Amoretti,Julio Bobes,Pilar A Saiz,Maria Paz García-Portilla,Julio Sanjuan,José Luis Santos,Estela Jiménez-López,Manuel Arrojo,Angel Carracedo,Mara Parellada,Nadja P Maric,Cem Atbaşoğlu,Alp Üçok,Köksal Alptekin,Meram Can Saka,Lotta-Katrin Pries,Michael O'Donovan,Jim van Os,Bart P F Rutten,Philippe Delespaul,Sinan Guloksuz,Celso Arango,Covadonga M Díaz-Caneja","doi":"10.1192/bjp.2025.100","DOIUrl":"https://doi.org/10.1192/bjp.2025.100","url":null,"abstract":"BACKGROUNDProlonged childhood and adolescent loneliness (CAL) is linked to various adverse mental health outcomes, yet its impact on schizophrenia spectrum disorders (SSD) has been understudied. While loneliness is associated with psychosis and worsens symptoms in SSD, few studies have explored the long-term effects of early loneliness on SSD risk. Understanding how CAL interacts with genetic liability to schizophrenia is essential for identification of high-risk individuals.AIMSThis study evaluated whether prolonged CAL is associated with increased SSD risk and examined the interaction between CAL and genetic liability for schizophrenia. Gender differences in these associations were also explored.METHODData from the European Gene-Environment Interactions in Schizophrenia (EU-GEI) study were analysed, including 1261 individuals with SSD, 1282 unaffected siblings and 1525 healthy controls. CAL was retrospectively assessed for periods before age 12 years and age 12-16 years. Genetic risk was measured using polygenic risk scores for schizophrenia. Logistic regression models and the Relative Excess Risk due to Interaction (RERI) method were used to examine gene-environment interactions, with stratification by gender.RESULTSProlonged CAL was associated with higher odds of SSD (odds ratio [95% CI] = 5.20 [3.85-7.01] for loneliness before age 12; odds ratio [95% CI] = 7.26 [5.63-9.38] for loneliness during adolescence). The interaction between CAL and genetic risk was strongest during adolescence (RERI [95% CI] = 23.46 [10.75-53.53]). Females showed a greater effect (odds ratio [95 %CI] = 10.04 [6.80-14.94]) than males (odds ratio [95% CI] = 5.50 [3.95-7.66]). Incorporating CAL and genetic interaction increased predictive values to 17% for SSD risk - rising to 22.5% in females - compared with 2.6 and 2.8%, respectively, for genetic risk alone.CONCLUSIONSProlonged CAL significantly increases SSD risk, particularly in females. The inclusion of CAL alongside genetic risk substantially enhances predictive accuracy. Early identification of CAL could inform preventive strategies, especially in genetically vulnerable populations.","PeriodicalId":22495,"journal":{"name":"The British Journal of Psychiatry","volume":"42 1","pages":"1-9"},"PeriodicalIF":0.0,"publicationDate":"2025-06-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144296011","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}