Depression is associated with premature mortality, but evidence is mainly derived from Western countries. Very limited research has evaluated shortened lifespan in depression using life-years-lost (LYLs), a recently developed mortality metric taking into account the illness onset for life expectancy estimation. Temporal trends of differential mortality gap are understudied. This population-based cohort study, which utilized a territory-wide medical-record database of public inpatient and outpatient healthcare services in Hong Kong, evaluated the extent of premature mortality in 126,573 individuals with depression (persons-years=1,139,073) between January 2002 and December 2021 regarding the standardized mortality ratio (SMR) and excess LYLs. Trends in annual SMRs over 20 years were assessed by joinpoint analyses. The results showed that individuals with depression exhibited significantly higher all-cause (SMR=1.84 [95% CI=1.82-1.88]), natural-cause (1.69 [1.66-1.72]), and unnatural-cause (5.24 [4.97-5.51]) mortality rates than the general population. Suicide-specific SMR was markedly elevated (7.92 [7.47-8.38]), particularly in the 15-34 year-olds (12.75 [10.87-14.79]). Respiratory diseases, cardiovascular diseases and cancers accounted for the majority of deaths. Excess LYLs extended to men (5.67 years, 95% CI = 5.45-5.90) and women (4.06 years, 95% CI = 3.89-4.23). Overall and natural-cause mortality rates improved over time, but unnatural-cause and suicide-related mortality gaps persisted. Taken together, this study indicates that depression is associated with increased premature mortality and reduced lifespan in a predominantly Chinese population, mainly attributed to natural causes. Relative suicide-specific mortality is substantially elevated, especially among young people. The pronounced mortality gap underscores an urgent need for effective interventions targeting improved physical health and suicide risk reduction in individuals with depression.

Despite the multifaceted negative influences of psychotropic medications on the environment, an overview of such effects and of actions to curtail them is currently lacking. We therefore summarized the most relevant literature on what we refer to as Environmentally Conscious Psychopharmacotherapy (ECP), i.e., prescribing the most appropriate psychotropic medications for patients while at the same time considering the wellbeing of the planet. In our literature appraisal we identified viable actions at the levels of industry, physicians, pharmacists, patients, and policymakers that can reduce the environmental hazards associated with psychotropics. We divided these actions into the following categories: careful treatment selection, curtailing overprescribing, adequate disposal of medication by users, and transparent reporting of environmental risk. For each of these categories, we give examples of practices are in line with ECP, which in turn has the potential to reduce the impact of psychotropic medication prescribing practices on the environment. We note that many such practices result in co-benefits for patients, prescribers and the environment. On the other hand, evidence on environmental impact is lacking for several factors related to these medications, e.g., geographical region of manufacturing, duration of use, pharmacological vs. non-pharmaceutical treatment options, and ecotoxicological data. We conclude that general as well as disorder-specific considerations for clinicians prescribing psychotropics already carry the potential to limit the environmental burden associated with these agents. Future research aimed at filling the knowledge gaps we identified is likely to substantially advance ECP in the near future.

Interest in cannabinoids' therapeutic potential in mental health is growing, supported by evidence of the involvement of the endocannabinoid system in psychiatric disorders such as anxiety, depression, and addiction. While the major cannabinoids cannabidiol (CBD) and Δ9-tetrahydrocannabinol (Δ9-THC) have been more extensively researched, approximately 120 minor cannabinoids from the cannabis plant have been identified. Although some displayed promising pharmacological profiles, research on their application for psychiatric disorders is fragmented. This systematic review evaluates, for the first time, both preclinical and clinical studies exploring minor cannabinoids' therapeutic potential in psychiatric disorders. 22 preclinical studies and one clinical study were included, investigating various minor cannabinoids in substance use disorders, anxiety disorders, depressive disorders, trauma and stressor-related disorders, psychotic disorders, neurodevelopmental disorders, and eating disorders. Despite the heterogeneous results and the moderate to high risk of bias in several articles, certain compounds demonstrate promise for further investigation. Δ8-tetrahydrocannabidivarin (Δ8-THCV) exhibited potential for nicotine addiction; Δ9-tetrahydrocannabidivarin (Δ9-THCV) for psychotic-like symptoms; cannabidiolic acid methyl ester (CBDA-ME) alleviated anxiety and depression-like symptoms, and cannabidivarin (CBDV) autism spectrum disorder-like symptoms.

The delineation of cognitive subgroups of bipolar disorder (BD) might be helpful for identifying biologically valid subtypes of this disorder. This meta-analysis identified peer-reviewed literature on studies investigating cognitive subgroups of BD with data-driven clustering methods. Relevant studies were searched in PubMed, Scopus, and Web of Science. Random-effects meta-analysis was performed using R software. A total of 14 cross-sectional studies including euthymic or mildly symptomatic patients with BD were included in the current meta-analysis. The available studies have consistently supported a 3-cluster solution. The pooled prevalence of the severe-impairment, moderate-impairment, and major good-functioning groups were 23.1 % (95%CI, 18.5 %-27.7 %), 42.5 % (95%CI, 36.3 %-48.8 %), and 33.5 % (95%CI, 25.9 %-41.1 %) respectively. Compared to healthy controls, both the severe-impairment (g=-1.40 to -1.73) and moderate-impairment groups (g=-0.59 to -0.96) had significant deficits in all six cognitive domains (verbal memory, visual memory, executive functions, working memory, attention and processing speed). The good-performance subgroup had a small increase in the performance of executive functions (g=0.23) and normal functioning in all other domains. Compared to the good-performance subgroup, the severe-impairment subgroup was characterized by more severe functional impairment, more hospital admissions, a higher percentage of type I BD and antipsychotic use. The characteristics of the moderate-impairment subgroup were lying between the other two subgroups for most of the measures. The current findings support the existence of 3 cognitive subgroups in BD including severe-impairment and moderate-impairment groups which are associated with a more severe course of illness.

Mitochondrial dysfunctions have been reported in bipolar disorder (BD), but their role in the etiopathogenesis of BD as well as their implications in modulating response to pharmacological treatments with psychotropic medications have been scarcely explored. Mitochondrial DNA copy number (mtDNA-cn) has been linked to mitochondria functioning, and, despite some degree of inconsistence, previous findings showed that BD patients present significant differences in mtDNA-cn compared to healthy controls. Here we measured mtDNA-cn in a sample of 89 patients with BD and 78 healthy controls (HC). Patients in the BD sample were treated either with lithium (n = 47) and characterized as responders (n = 22) or non-responders (n = 25), or with other mood stabilizers (n = 42). BD patients had larger mtDNA-cn compared to HC (adjusted model: F=9.832; p = 0.000095; contribution of diagnosis F= 10.798; p = 0.001). When the BD sample was stratified for treatment exposure, mtDNA-cn was lower in patients treated with lithium compared to those treated with other mood stabilizers (adjusted model: F=23.770, p = 7.0929E-13; contribution of treatment: F=54.300, p = 1.55E-10). Moreover mtDNA-cn was higher in patients treated with other mood stabilizers compared to controls and Li-treated BD patients (F=28.125, p = 1.36E-14; contribution of groups F=36.156, p = 1.25E-13). Finally, there was no difference in mtDNA-cn levels in lithium responders compared to non-responders and neither between the two diagnostic groups (BD type 1 and 2). Our findings suggest that BD may be associated with mitochondrial dysfunctions, and that exposure to lithium but not to other mood stabilizers may restore these abnormalities, though this does not appear correlated with the clinical efficacy of lithium.

People with severe-mental-illness (SMI), often defined as "schizophrenia-spectrum disorders and bipolar disorder", have increased premature mortality and elevated prevalence of diabetes compared with general population. Evidence indicated that one-third of their premature death was from cardiovascular diseases (CVD), with risk conferred by diabetes. Although earlier studies have examined SMI-associated diabetes-related outcomes, findings were inconsistent and not systematically evaluated. We systematically reviewed and quantitatively synthesized diabetes-related outcomes in patients with SMI (schizophrenia-spectrum disorders and bipolar disorder) by searching Embase, MEDLINE, PsycInfo, and Web-of-Science from inception to 31-March-2024, and included studies examining mortality and complication outcomes in SMI patients with co-occurring diabetes relative to patients with diabetes-only. Results were synthesized by random-effects models, with stratified-analyses by study-level characteristics. The study was registered with PROSPERO (CRD42023448490). Twenty-one studies involving 161,156 SMI patients with co-occurring diabetes were identified from ten regions. Regarding mortality risk, SMI-diabetes group exhibited increased risks of all-cause mortality (RR=1.77[95 % CI: 1.46-2.14]) and CVD-specific mortality (1.88[1.73-2.04]) relative to diabetes-only group. All-cause mortality risk was present in distinct regions and has persisted over time. Regarding complication risk, SMI-diabetes group showed higher risk of any complications (1.23[1.06-1.43]) than comparison, with stratified-analyses showing higher risk of metabolic-complications (1.84[1.58-2.15]), and lower likelihood of peripheral-vascular complications (0.91[0.84-0.99]), neuropathy (0.85[0.78-0.93]), and retinopathy (0.70[0.60-0.82]), albeit comparable cardiovascular-complications (1.04[0.89-1.22]), cerebrovascular-complications (1.07[0.86-1.33]), and nephropathy (0.92[0.72-1.17]). High heterogeneity was noted and could not be fully-explained by subgroup-analyses. Implementation of targeted interventions is needed to rectify their diabetes-related outcomes and mortality gap.

MicroRNAs (miRNAs) have the potential to affect drug metabolism, and some drugs affect cellular miRNA expression. miRNAs are found inside extracellular vesicles (EVs), and the profile of these EV-miRNAs can change across different diseases and disease states. Consequently, in recent years EV-miRNAs have attracted increasing attention as possible non-invasive biomarkers. For example, analyzing the miRNA expression profile of brain-derived EVs in blood may allow us to non-invasively assess miRNA dysregulation and thus to gain knowledge about the pathophysiology of psychiatric disorders and identify potential new predictive targets. We searched PubMed for all studies related to the effects of psychiatric medications on EV-miRNAs and identified 14 relevant articles. Taken together, findings indicate that certain EV-miRNAs may be targets for psychiatric medications and that antipsychotics such as olanzapine and antidepressants such as fluoxetine may alter the expression levels of particular EV-miRNAs. If confirmed and replicated, these findings may lead to the suggested miRNA profiles being used as pharmacodynamic biomarkers. However, heterogeneities and uncertainties remain regarding the role of EV-miRNAs in psychiatric disorders and their interaction with neuronal gene expression and drugs. This minireview summarizes some of the findings on the effects of psychiatric medications on EV-miRNAs and describes the potential role of EV-miRNAs as pharmacodynamic biomarkers for psychiatric disorders.

Accurate diagnosis in psychiatry remains a significant challenge, often delaying appropriate treatment and resulting in poorer clinical outcomes. Identifying precise biomarkers for differential diagnosis is therefore crucial. This study aimed to identify distinct behavioral and psychophysiological markers of emotional reactivity in virtual reality (VR) settings among individuals with bipolar disorder (BD), borderline personality disorder (BPD), schizophrenia spectrum disorders (SSD), and healthy controls (HC). Participants (BD: n = 32, BPD: n = 21, SSD: n = 17, HC: n = 30) aged 19-60 were exposed to six immersive 360-degree social VR scenarios, ranging from neutral to highly emotional contexts (e.g., an elevator ride, a crying baby). Emotional responses were self-rated on a 1-5 scale, while galvanic skin response (GSR) was continuously recorded. Scenarios assessed feelings of unpleasantness, pleasantness, being observed, and the urge to comfort. Across diagnoses, individuals with mental health conditions reported more negative emotional responses (greater unpleasantness) across both neutral and negative scenarios (ps ≤ 0.02) despite similar GSR levels to HC. Specifically, in the elevator scenario, BPD and SSD experienced greater unpleasantness and feelings of being observed, coupled with stronger GSRs compared to BD (ps ≤ 0.03). SSD reported higher unpleasantness in the canteen scenario, less pleasantness in the happy baby scenario, and overall higher GSR than BD (ps ≤ 0.049). Negative emotional reactivity was consistent across BD, BPD, and SSD, with heightened emotional and physiological responses distinguishing SSD and BPD from BD in specific VR contexts. VR-based assessments of emotional and physiological markers show promise for improving differential diagnosis and identifying transdiagnostic treatment targets.

Maternal stress during pregnancy can impact offspring health, increasing the risk of neuropsychiatric disorders. The human placenta plays a crucial role in understanding this effect, influencing fetal programming as it connects maternal and fetal circulation. Our hypothesis centers on maternal stress influencing children's outcomes through placental DNA methylation, targeting three cortisol-regulating genes: NR3C1, FKBP5, and HSD11B2. In this pilot study, chorionic villi and maternal decidua placental layers from 45 mother-infant dyads (divided into two groups based on high/low maternal stress exposure) were analyzed for DNA methylation at the genes of interest via targeted bisulfite sequencing. Pregnant women provided four saliva samples throughout a day for cortisol determinations and were assessed for the presence of depressive symptoms at each of the three trimesters of pregnancy. Newborns underwent neurodevelopmental assessments and salivary cortisol evaluations at 7 weeks. Increased maternal diurnal cortisol levels in the first trimester of pregnancy was significantly associated with elevated DNA methylation at exon 1D of the NR3C1 gene and lower DNA methylation at intron 7 of the FKBP5 gene, both in chorionic villi samples. Elevated DNA methylation at introns 1 and 7 of FKBP5 in the maternal decidua were strongly linked to an anticipated delivery. DNA methylation at the HSD11B2 promoter region was uniformly low across all placental samples. No associations with newborn neurodevelopment were found. These results emphasize the importance of exploring layer-specific methylation differences at distinct pregnancy stages, highlighting the complex interplay between maternal stress, placental epigenetic modifications, and fetal development throughout the prenatal period.

People with depression have increased premature mortality and elevated prevalence of diabetes-mellitus compared to general population. However, risk of mortality and diabetes-related complications among patients with depression and co-occurring diabetes is under-studied. This population-based propensity score-matched (1:10) cohort study identified 12,175 patients with pre-existing depression and incident-diabetes (depression-diabetes group) and 117,958 patients with incident-diabetes only (diabetes-only group) between 2002 and 2021 in Hong-Kong, using territory-wide medical-record database of public-healthcare services, to investigate whether depression increased the risk of overall mortality, complications and post-complication mortality in people with diabetes. Associations of depression with all-cause mortality, complication and post-complication all-cause mortality rates were examined by Cox proportional-hazards model. Complications were assessed by Diabetes-Complications-Severity-Index (DCSI). Associations of complications, in terms of DCSI scores (complication burden), specific types and two-way combinations of complications (complication patterns) with all-cause mortality rate in depression were also examined. Our results showed that depression-diabetes group exhibited increased all-cause mortality risk (adjusted hazards-ratio: 1.06 [95 %CI: 1.02-1.10]) relative to diabetes-only group, particularly among men and older age group, with significantly higher rate of experiencing neuropathy (1.44 [1.27-1.62]) and metabolic complications (1.30 [1.09-1.56]) and lower likelihood of peripheral-vascular complications, retinopathy and nephropathy, albeit comparable macrovascular and microvascular complication rates. The mortality-rate-ratio for patients with depression and diabetes was significantly higher than patients with diabetes-only at a low level of complication burden. In conclusion, depression patients with co-occurring diabetes are at increased risk of excess mortality. Further research is warranted to improve diabetes-related outcomes and reduce mortality gap in this vulnerable population.