Abstract Background Major depressive disorder (MDD) is clinically heterogeneous, hindering identification of reproducible biomarkers. Using a semi-supervised machine learning approach, HYDRA, we previously identified two neuroanatomical dimensions from structural MRI in medication-free MDD from COORDINATE-MDD consortium. These dimensions (D1, D2) showed differential responses to selective serotonin reuptake inhibitor (SSRI) antidepressants and placebo. External replication in UK Biobank linked D2, characterized by widespread subtle neuroanatomical reductions, to an immuno-metabolic profile. Here, we examined whether these dimensions are detectable early in the course of illness. Methods We applied the pre-trained model to structural MRI data from the multisite PRONIA cohort, comprising individuals with recent-onset depression (ROD; n = 377; mean age 25.8 years, SD 6.0; 51.3% female) and healthy controls (n = 267; mean age 25.5 years, SD 6.4; 61.0% female). Participants were assigned to clusters (C1, C2) corresponding to the previously identified dimensions (D1, D2). Clusters were compared on clinical symptom profiles, peripheral inflammatory markers, and in a subset (n = 107), proteomic ageing indices. Results Two neuroanatomical clusters were identified in PRONIA. C1 (n = 265) showed higher negative symptom severity and elevated interleukin-2 levels. C2 (n = 140) was associated with higher residual proteomic age. Overall depressive symptom severity did not differ significantly between clusters. Conclusions Neuroanatomical dimensions of MDD are reproducible and detectable at illness onset. Associations with negative symptom severity, inflammatory signalling, and proteomic ageing suggest these dimensions capture biologically meaningful heterogeneity early in depression. These findings support a biologically informed framework for stratified treatment approaches in MDD.

Background:Major depressive disorder (MDD) is associated with altered brain structure and evidence of accelerated brain aging. However, previous studies have been limited by clinical samples with mixed medication status and multiple mood states, modest sample sizes, small percentage of MDD individuals older than 65 years of age, and/or reliance on summary-level data. Methods:Harmonized T1-weighted MRI from MDD (n = 645), all medication-free and in a current depressive episode, and matched healthy controls (n = 645), segmented into 145 regional volumes, from 11 sites in COORDINATE-MDD consortium. Brain age gap (BAG) was estimated using gradient boosting regression with nested cross-validation. Group differences in BAG (and age-corrected BAG [cBAG]) were examined across age strata. Regional contributions were evaluated using Shapley Additive exPlanations. Results:MDD was associated with significantly elevated cBAG compared with healthy controls (mean difference + 2.01 years). Age-stratified analyses showed no differences before mid-30s, with progressively larger gaps thereafter, reaching +6.85 years in MDD aged 55 and older. cBAG differed across neuroanatomical phenotypes associated with differential antidepressant response, cognitive impairment, increased adverse life events, increased self-harm and suicide attempts, and a pro-atherogenic metabolic profile. Key contributing regions included lateral and medial prefrontal regions, middle temporal gyrus, putamen, supplementary motor cortex, central operculum, and cerebellum. Conclusions:Accelerated structural brain aging in MDD is age-dependent and is most pronounced in a neuroanatomical phenotype associated with worse key clinical outcomes. The findings support neuroprogression models of MDD while demonstrating that cBAG is not a uniform feature of MDD and seem to be more strongly expressed in a specifically clinically vulnerable disease phenotype.

Cognitive difficulties are known to persist after remission of symptoms and to affect psychosocial functioning and quality of life. Cognitive function, measured with the Cambridge Neuro-psychological Test Automated Battery (CANTAB), is a reliable approach to measure cognitive function in major depression. This systematic review and meta-analysis appraise cross-sectional and longitudinal studies that used specific CANTAB tests to measure cognitive function in major depression and the effect of treatment (PROSPERO ID: CRD42022355903). 1212 studies were identified and 41 were included, 1793 patients and 1445 healthy controls. Deficits in executive functions were detected with the Stocking Of Cambridge (SOC) ‘number of problems solved with minimal number of moves’ and ‘subsequent thinking time’, Intra-Extra Dimensional Set Shift ‘number of trials to complete the test’, Spatial Working Memory ‘strategy score’ and ‘between errors score’, Spatial Span. Memory deficits were detected with Paired Associates Learning ‘number of total errors’, Pattern Recognition Memory (PRM) ‘% of correct answers’ and ‘response latency’, Spatial Recognition Memory ‘% of correct answers’, Delayed Matching To Sample (DMS) ‘% of total responses’. Impaired attention was detected by Rapid Visual Information Processing ‘response latency’ and probability to detect target’. Mental and motor responses increased when Reaction Time was measured. SOC ‘number of problems solved with minimal number of moves', PRM ‘response latency’ and DMS ‘% of total responses' improved after a course of treatment. A range of variables including year of publication, age, IQ, severity and duration of illness influenced cognitive changes. The presence of significant cognitive deficits requires novel targeted interventions.

There is paucity of mental health epidemiological data from the Middle East. Therein we present detailed clinical characterization of mood disorders patients from a university tertiary clinic established in the United Arab Emirates. The majority of patient experienced depressive and anxiety symptoms largely in the moderate range according to both self-rated and clinician rated scales, accompanied by significant co-morbidities, functional impairment, mild reduction in cognitive function, and a significant ruminative thinking style. These preliminary findings support the need for larger-scale research in the Middle East to address the burden of poor mental health affecting communities.

Background/Objectives: Lamotrigine has been widely investigated in the treatment and prevention of the emergence of symptoms of depression in unipolar and bipolar depression. This work systematically appraises published and unpublished double-blind randomised controlled trials of lamotrigine to provide up-to-date guidance on the use of lamotrigine in the presence of depressive symptoms. Methods: Systematic searches identified 32 randomised controlled trials, of which 24 were included in the meta-analysis, involving 2257 patients and 2320 controls. Results: Evidence supports the use of lamotrigine in the acute phase of bipolar depression in monotherapy vs. placebo (SMD: 0.155; CI: 0.005–0.305) in the absence of significant heterogeneity and small study effects. In the prophylaxis of bipolar depression, lamotrigine reduced the risk of the emergence of depressive symptoms (RR: 0.78; CI: 0.63, 0.98) and prolonged the duration of symptoms survival (RR: 1.59; CI: 1.19, 2.11) compared to placebo, with no evidence of publication and small study bias. Lamotrigine was not found to be superior to lithium in the acute treatment and prophylaxis of bipolar depression. In the treatment of unipolar depressive episodes, with the inclusion in the analyses of three unpublished studies, lamotrigine was not superior to placebo in monotherapy and as adjunct treatment. There were no maintenance studies in unipolar depression. Conclusions: There is evidence supporting the use of lamotrigine in monotherapy as acute and prophylactic treatment of bipolar depression. Evidence of the use of lamotrigine in unipolar disorders is lacking. PROSPERO registration ID: CRD42025633709.

The development of appropriate and valid multicultural and multilingual instruments research is necessary due to a growing multicultural and multilingual society in the 21st century. We explored the use of a cognitive scale related to subjective complaints, focusing on the first step: a cross-cultural and semantic validation. This study presents the translation and cross-validation process of the “Subjective Scale to Investigate Cognition in Schizophrenia” (SSTICS) for the United Arab Emirates (UAE) region via different languages used in Dubaï/Abu Dhabi. This scale measures cognitive complaints and has been validated with psychosis and used in 20 clinical trials worldwide. It evaluates areas of the illness related to self-awareness focusing on memory dysfunction and deficits of attention, language, and praxis. We described the method of cross-cultural validation, with back-translation, semantic steps, and societal contexts. The use of the Subjective Scale to Investigate Cognition in Emirates (SSTIC-E) was explored with different samples of UAE Arabic-speaking subjects. First, a pilot sample mean SSTICS total score was 16.5 (SD:16.9); (p < 0.001). The SSTIC-E was then administered to 126 patients and 84 healthy control participants. The healthy group has a lower mean score of 22.55 (SD = 12.04) vs. 34.06 (SD = 15.19). The method was extended to nine other languages, namely, Pakistani/Urdu, Hindi, Marathi, Lithuanian, Serbian, German, Romanian, Sinhala, and Russian. The scales are provided in the article. The overall aim of the translation process should be to stay close to the original version of the instrument so that it is meaningful and easily understood by the target language population. However, for construct validity, some items must be adapted at the time of translation to ensure that the questioned cognitive domain is respected. For example, cooking, an executive function, does not have the same occurrence for an Emirati male, or remembering a prime minister’s name, semantic memory, requires an electoral system to appoint the leader of a country. Translation methods and processes present many challenges but applying relevant and creative strategies to reduce errors is essential to achieve semantic validation. This study aims to measure personally experienced knowledge or attitudes; such language effects can be a thorny problem.

Major depressive disorder (MDD) is a heterogeneous clinical syndrome with widespread subtle neuroanatomical correlates. Our objective was to identify the neuroanatomical dimensions that characterize MDD and predict treatment response to selective serotonin reuptake inhibitor (SSRI) antidepressants or placebo. In the COORDINATE-MDD consortium, raw MRI data were shared from international samples ( N = 1,384) of medication-free individuals with first-episode and recurrent MDD ( N = 685) in a current depressive episode of at least moderate severity, but not treatment-resistant depression, as well as healthy controls ( N = 699). Prospective longitudinal data on treatment response were available for a subset of MDD individuals ( N = 359). Treatments were either SSRI antidepressant medication (escitalopram, citalopram, sertraline) or placebo. Multi-center MRI data were harmonized, and HYDRA, a semi-supervised machine-learning clustering algorithm, was utilized to identify patterns in regional brain volumes that are associated with disease. MDD was optimally characterized by two neuroanatomical dimensions that exhibited distinct treatment responses to placebo and SSRI antidepressant medications. Dimension 1 was characterized by preserved gray and white matter ( N = 290 MDD), whereas Dimension 2 was characterized by widespread subtle reductions in gray and white matter ( N = 395 MDD) relative to healthy controls. Although there were no significant differences in age of onset, years of illness, number of episodes, or duration of current episode between dimensions, there was a significant interaction effect between dimensions and treatment response. Dimension 1 showed a significant improvement in depressive symptoms following treatment with SSRI medication (51.1%) but limited changes following placebo (28.6%). By contrast, Dimension 2 showed comparable improvements to either SSRI (46.9%) or placebo (42.2%) ( β = –18.3, 95% CI (–34.3 to –2.3), P = 0.03). Findings from this case-control study indicate that neuroimaging-based markers can help identify the disease-based dimensions that constitute MDD and predict treatment response.

Major depressive disorder (MDD) is manifested by mood, behavioural, cognitive, and somatic symptoms. This is reflected in the diagnostic criteria of both DSM-5 and ICD-10. Differential diagnosis typically includes the consideration of other mood and psychiatric disorders, neurological, medical and genetic conditions, as well as bereavement. Diagnostic investigations are commonly combined with the evaluation of functioning since the vast majority of MDD patients experience functional impairment. Suicidality is a major challenge in the management of MDD. Rigorous risk assessment, minimisation of risk factors, and promotion of protective factors are essential in suicide prevention. Treatment strategies can be split into acute, continuation, and maintentance phases. Depending on depression severity and other specifiers (e.g., psychosis, risk) both pharmacotherapy and psychotherapy can be efficacious first-line treatment options. Switching or augmenting initial treatment can be considered for non-responders. For continuation and maintenance phases, the primary aim of treatement is prolonging remission, preventing episode recurrence, and restoring psychosocial functioning.

Background Regional gray matter volume (GMV) differences between individuals with mental disorders and comparison subjects may be confounded by co-occurring disorders. To disentangle the disorder-specific GMV correlates, we conducted a large-scale multi-disorder meta-analysis using a novel approach that explicitly models co-occurring disorders. Methods We systematically reviewed voxel-based morphometry studies indexed in PubMed and Scopus up to January 2023 comparing adults with major mental disorders (anorexia nervosa, schizophrenia-spectrum, anxiety, bipolar, major depressive, obsessive-compulsive, and post-traumatic stress disorders, plus attention-deficit/hyperactivity, autism spectrum, and borderline personality disorders) to comparison subjects. Two authors independently extracted data and assessed quality using the Newcastle-Ottawa Scale. We derived GMV correlates for each disorder using: a) a multi-disorder meta-analysis accounting for all co-occurring mental disorders simultaneously; b) separate standard meta-analyses for each disorder ignoring co-occurring disorders. We assessed the alterations’ extent, intensity (effect size), and specificity (inter-disorder correlations and transdiagnostic alterations) for both approaches. Results We included 433 studies (499 datasets) involving 19,718 patients and 16,441 comparison subjects (51% females, aged 20-67 years). We provide GMV correlate maps for each disorder using both approaches. The novel approach, which accounted for co-occurring disorders, produced GMV correlates that were more focal and disorder-specific (less correlated across disorders and fewer transdiagnostic abnormalities). Conclusions This work offers the most comprehensive atlas of GMV correlates across major mental disorders. Modeling co-occurring disorders yielded more specific correlates, supporting this approach’s validity. The atlas NIfTI maps are available online.

Suicide is a health priority and one of the most common causes of death in mood disorders. One of the limitations of this type of research is that studies often establish rates of suicide behaviors in mood disorders by using diverse comparison groups or simply monitoring cohort of patients over a time period.In this registry-based systematic review, national registers were identified through searches in six academic databases, and information about the occurrence of suicide behaviors in mood disorders was systematically extracted. Odds ratios were subsequently calculated comparing rates of death by suicide in mood disorders in comparison with age and period matched rates of death by suicide in the general population obtained from country-wide national registers. The aim was to provide the most recent summary of epidemiological and clinical factors associated to suicide in mood disorders whilst calculating the likelihood of death by suicide in mood disorders in comparison with non-affected individuals according to national databases. The study follows the Preferred Reporting Guidelines for Systematic Reviews and Meta-analyses and was prespecify registered on Prospero (CRD42020186857).Results suggest that patients with mood disorders are at substantially increased risk of attempting and dying by suicide. Several epidemiological, clinical and social factors are reported to be associated with clinical populations at risk of suicide. Meta-analyses of completed deaths by suicide suggest that the likelihood for dying by suicide in mood disorders is 8.62 times higher in major depression and 8.66 times higher in bipolar disorder with higher number of untoward events in women compared to men in both conditions. The likelihood of dying by suicide in major depressive disorders is higher in the first year following discharge. Clinical guidelines might consider longer periods of monitoring following discharge from hospital.Overall, due to the higher risk of suicide in mood disorders, efforts should be made to increase detection and prevention whilst focusing on reducing risk in the most severe forms of illness with appropriate treatment to promote response and remission at the earliest convenience.

Major depression is a frequent condition which variably responds to treatment. In view of its high prevalence, the presence of treatment resistance in major depression significantly impacts on quality of life. Tailoring pharmacological treatment based on genetic polymorphisms is a current trend to personalizing pharmacological treatment in patients with major depressive disorders. Current guidelines for the use of genetic tests in major depression issued by the Clinical Pharmacogenomics Implementation Consortium (CPIC) are based on CYP2D6 and CYP2C19 polymorphisms which constitute the strongest evidence for pharmacogenomic guided treatment. There is evidence of increased clinical response to pharmacological treatment in major depression although largely in non-treatment resistant patients from Western countries. In this study, well characterised participants (N = 15) with complex, largely treatment resistant unipolar major depression were investigated, and clinical improvement was measured at baseline and at week-8 after the pharmacogenomics-guided treatment with the Montgomery Åsberg Depression Rating Scale (MÅDRS). Results suggested a statistically significant improvement (p = 0.01) of 16% at endpoint in the whole group and a larger effect in case of changes in medication regime (28%, p = 0.004). This small but appreciable effect can be understood in the context of the level of treatment resistance in the group. To our knowledge, this is the first study from the Middle East demonstrating the feasibility of this approach in the treatment of complex major depressive disorders.

COPYRIGHT © 2023 Pellicano, Aa es-van Doorn, Anzolin, Arnone and Borghini. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. Editorial: Use of neuroimaging techniques for the prevention, assessment, and treatment of mood disorders

Background: Efforts to develop neuroimaging-based biomarkers in major depressive disorder (MDD), at the individual level, have been limited to date. As diagnostic criteria are currently symptom-based, MDD is conceptualized as a disorder rather than a disease with a known etiology; further, neural measures are often confounded by medication status and heterogeneous symptom states. Methods: We describe a consortium to quantify neuroanatomical and neurofunctional heterogeneity via the dimensions of novel multivariate coordinate system (COORDINATE-MDD). Utilizing imaging harmonization and machine learning methods in a large cohort of medication-free, deeply phenotyped MDD participants, patterns of brain alteration are defined in replicable and neurobiologically-based dimensions and offer the potential to predict treatment response at the individual level.International datasets are being shared from multi-ethnic community populations, first-episode and recurrent MDD, which are medication-free, in a current depressive episode with prospective longitudinal treatment outcomes and in remission. Neuroimaging data consist of de-identified, individual, structural MRI and resting-state functional MRI with additional positron emission tomography (PET) data at specific sites. State-of-the-art analytic methods include automated image processing for extraction of anatomical and functional imaging variables, statistical harmonization of imaging variables to account for site and scanner variations, and semi-supervised machine learning methods that identify dominant patterns associated with MDD from neural structure and function in healthy participants. Results: We are applying an iterative process by defining the neural dimensions that characterise deeply phenotyped samples and then testing the dimensions in novel samples to assess specificity and reliability. Crucially, we aim to use machine learning methods to identify novel predictors of treatment response based on prospective longitudinal treatment outcome data, and we can externally validate the dimensions in fully independent sites. Conclusion: We describe the consortium, imaging protocols and analytics using preliminary results. Our findings thus far demonstrate how datasets across many sites can be harmonized and constructively pooled to enable execution of this large-scale project.

The anniversary of the publication of 'One Flew Over the Cuckoo's Nest' by Ken Kesey offers an opportunity for reflection on the use of neurosurgery in psychiatry. We used a narrative, historical and dialectical method to deliver an account of the controversial subject. A balanced representation of the negative and positive aspects, acknowledging some of the questionable ethical practices while describing well-reasoned applications is provided. It includes neurosurgeons, psychiatrists who have embraced these procedures with unwarranted enthusiasm and those who have opposed. Neurosurgical techniques for the treatment of severe mental disorders have evolved from rudimentary procedures which were used to 'correct' unwanted behaviours associated with a wide range of severe mental disorders to more refined and selective approaches used as a last resort to treat specific mental health conditions. In the absence of specific aetiological models to guide ablative surgical targets, non-ablative, stimulatory techniques have more recently been developed to allow reversibility when surgical treatment fails to obtain a sizeable improvement in quality of life. The subject is concretely illustrated by two eloquent clinical images: one on a series of brain computed tomography scans carried out on a Canadian population of subjects, who underwent leukotomy decades ago, and the other more contemporary on an implantation surgery to epidural stimulation. Alongside technical advances in psychosurgery, a regulatory framework has gradually developed to ensure vigilance in the appropriateness of patients' selection. Nevertheless, harmonisation of protocols around the world is necessary to ensure consistency in obtaining and maintaining the highest possible ethical standards for the benefit of patients. If the neurosciences promise today, in their new, better framed, and reversible applications, to provide answers to unmet therapeutic needs, we still must remain attentive to drifts linked the introduction of intrusive technologies for purposes of domination or behaviour modification that would impede our individual freedom.

A recent "umbrella" review examined various biomarkers relating to the serotonin system, and concluded there was no consistent evidence implicating serotonin in the pathophysiology of depression. We present reasons for why this conclusion is overstated, including methodological weaknesses in the review process, selective reporting of data, over-simplification, and errors in the interpretation of neuropsychopharmacological findings. We use the examples of tryptophan depletion and serotonergic molecular imaging, the two research areas most relevant to the investigation of serotonin, to illustrate this.

Abstract Cotard syndrome is a rare condition characterized by delusions ranging from a belief that one has lost organs to insisting that one has lost one's soul or is dead. This is the report a case of a 45-year-old man who was comatose after an attempted suicide. This was initially diagnosed as brain death and use of his organs for transplantation was actively considered. However, he awakened days later with new-onset Cotard syndrome. It remains difficult to know the link, unconscious or conscious, between this patient's delusions and the fleeting intention of doctors who intended to transplant his organs. This is the first description of a coincidence between delusional denial of an organ and the potential medico-surgical act of having an organ removed. This case is an opportunity to revisit the philosophical concepts of negation and nihilism. A multidisciplinary reflection is needed to give meaning to other clinical presentations.

Background To date, only few studies have investigated ghrelin levels in bipolar disorders, and all have exclusively measured acylated ghrelin, with none investigating total ghrelin (acylated and des-acylated). We aimed to investigate peripheral levels of acylated and total ghrelin in subjects experiencing a manic episode of bipolar disorder. Methods Peripheral levels of acylated and total ghrelin were measured in hospitalised medicated individuals recovering from a manic episode. Enzyme-linked immunosorbent assays (ELISA) were used to measure ghrelin levels in patients and compared with healthy controls. The relationship between ghrelin levels in bipolar disorder, self-reported hunger measures, demographic and clinical parameters was investigated with correlational analyses. Results Twenty-four subjects (15 males, 9 females) recovering from mania and 27 matched healthy controls (13 males, 14 females) were recruited for the study. Mean values of both acylated (187 vs.520 pg/mL) and total ghrelin (396 vs. 648 pg/mL) were significantly reduced in bipolar disorder ( p = 0.001). Ghrelin levels correlated positively with markers of illness severity and negatively with prescribed mood stabilizers, second-generation antipsychotics, weight and body mass index. Conclusion Peripheral measurements of acylated and total ghrelin were both reduced in bipolar disorder patients compared to healthy controls. Whilst illness severity promotes higher ghrelin levels, pharmacological treatment and weight gain exercise the opposite effect.

Dufour and colleagues' work investigated the frequency of psychological distress among healthcare workers (HW) in the province of Quebec during and after the fi rst wave of COVID-19 pandemic. 1 Authors reported peak point prevalence of mental health symptoms in HW of 22.2% for post-traumatic stress, 29.9% for depression and 26.9% for anxiety, consistent with similar data collected around the World. 2 These fi ndings are mirrored in a recent cross-sectional survey conducted in Abu Dhabi in the United Arab Emirates (UAE) at the zenith of the fi rst wave of the pandemic, suggesting that an overall 39% of HW were affected by symptoms of depression, anxiety and stress, 13% of them severely. 3 An email with a link to an online questionnaire was sent out to all UAE ’ s largest public health sector employees, a total of 18,371. A total of 2184 responses were collected. The questionnaire consisted of the Depression and Anxiety Screening Scale (DASS-21) and basic demographic questions. The study protocol also included a dedicated psychological support helpline for staff members. However, this study on a self-selected sample of HW was a telephone-based helpline for HW, and it is not fully comparable.