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This study utilized network pharmacology and docking analyses to explore a groundbreaking therapeutic approach for managing the neuropathic pain and depressive disorder (NP/DD) comorbidity. Schisandra chinensis (SC), a common Chinese medicine, has demonstrated numerous beneficial effects in treating neuropsychological disorders. The main objective of this study was to identify potential bioactive components of SC and investigate their interactions with relevant target genes associated with NP/DD. To gain insights into the underlying molecular mechanisms, GO and KEGG analyses were conducted. Furthermore, molecular docking analysis was employed to validate the therapeutic relevance of SC's active ingredients. Seven bioactive components of SC, namely Longikaurin A, Deoxyharringtonine, Angeloylgomisin O, Schisandrin B, Gomisin A, Gomisin G, and Gomisin R, exhibited effectiveness in the treatment of NP/DD. From this list, the first five components were selected for further analysis. The analyses revealed a complex network of interactions between the targets of SC and NP/DD, providing valuable information about the molecular mechanisms involved in the treatment of NP/DD with SC. SC components demonstrated the ability to regulate pathways involving tumor necrosis factor (TNF), vascular endothelial growth factor (VEGF), and other growth hormones (GH). Overall, this study contributes to our understanding of the molecular mechanisms underlying the effects of SC in treating NP/DD. Further investigation is necessary to explore the therapeutic potential of SC as a viable strategy for NP/DD comorbidity. These findings lay a solid foundation for future research endeavors in this field, holding potential implications for the development of novel therapeutic interventions targeting NP/DD., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 IBRO. Published by Elsevier Inc. All rights reserved.)

Background: Pharmacotherapy is one of the primary treatment modalities for depression. However, there is considerable variability in the individual response to antidepressant medications. Personalized medicine guided by pharmacogenomic testing may hold promise in addressing this issue., Methods: In this study, 665 depressive patients were randomly enrolled into two groups: the pharmacogenomic testing group (n = 333) and the control group (n = 332). In the testing group, participants underwent pharmacogenomic testing, and clinicians customized the treatment plan with the result, while the control group relied solely on clinicians' experience. The primary outcomes were the proportion of remission and response, assessed with Hamilton Depression Rating Scale (HDRS). The secondary outcomes included changes in HDRS scores over time and frequency of adverse drug reactions by the participants., Results: At week 8, the pharmacogenomic testing group showed significantly higher remission rates (24.0 % v.s. 15.1 %; RR = 1.117; P = 0.007) and response rates (39.3 % v.s. 25.7 %; RR = 1.225; P < 0.001) compared to the control group. By week 12, the pharmacogenomic testing group continued to demonstrate significant advantages in remission (31.0 % v.s. 20.0 %; RR = 1.159; P = 0.003) and response (48.7 % v.s. 37.3 %; RR = 1.224; P = 0.006). Additionally, adverse drug reactions were less frequent in the pharmacogenomic testing group., Limitations: This study is not blind to clinicians and it's a single-center study., Conclusions: Pharmacogenomic testing-guided drug therapy can provide greater assistance in the treatment of depression., Competing Interests: Declaration of competing interest The authors report no financial interests or potential conflicts of interest., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Omega-3 polyunsaturated fatty acids have received considerable attention in the field of mental health, in particular regarding the treatment of depression. This review presents an overview of current research on the role of omega-3 fatty acids in the prevention and treatment of depressive disorders. The existing body of evidence demonstrates that omega-3 fatty acids, in particular eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), have antidepressant effects that can be attributed to their modulation of neuroinflammation, neurotransmitter function, and neuroplasticity. Nevertheless, clinical trials of omega-3 supplementation have yielded inconsistent results. Some studies have demonstrated significant reductions in depressive symptoms following omega-3 treatment, whereas others have shown minimal to no beneficial impact. A range of factors, encompassing dosage, the ratio of EPA to DHA, and baseline nutritional status, have been identified as having a potential impact on the noted results. Furthermore, it has been suggested that omega-3 fatty acids may act as an adjunctive treatment for those undergoing antidepressant treatment. Notwithstanding these encouraging findings, discrepancies in study designs and variability in individual responses underscore the necessity of further research in order to establish uniform, standardized guidelines for the use of omega-3 fatty acids in the management of depressive disorders.

Background: Polypharmacy for treatment of depression has been increasing in Taiwan., Methods: Individuals having depressive disorders were identified in a national database for healthcare services and followed up for 5 years. The mean dosage of antidepressants, antipsychotics, mood stabilizers, and sedative-hypnotics was calculated; the associations between the exposure dosage to different psychotropic medications and patients' overall death and death due to cardiovascular diseases (CVD) and suicide were examined., Results: A total of 400,042 individuals with depressive disorders (63.8% women) were identified. Compared with those with no exposure to antidepressants, patients prescribed antidepressants had decreased mortality. Use of antipsychotics had a dose-related increase in overall mortality risk compared to no exposure group. Contrarily, depressed patients taking sedative-hypnotics had decreased overall and CVD mortality compared to no exposure group, with the most prominent decrease in CVD mortality of up to 54.9% for those in the moderate exposure group (hazard ratio: 0.451, 95% confidence interval: 0.405-0.503). A moderate or high dose of antidepressants or sedative-hypnotics was shown to be associated with a significantly increased mortality for suicide compared to those with no exposure., Conclusions: Antidepressant and sedative-hypnotic use was associated with decreased all-cause and CVD-related mortality and use of antipsychotics was associated with a dose-related increase in mortality risk. Future studies are needed to further clarify the involved mechanisms and benefits and risks should be carefully weighed when prescribing psychotropic medications in patients with depressive disorders., Competing Interests: Declaration of Competing Interest None., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Psilocybin-assisted psychotherapy (PAP) is a promising treatment option for depression, with randomized controlled trials (RCTs) providing preliminary support for its safety and efficacy. However, there is a lack of consistency across existing treatment protocols and psychotherapeutic approaches. The objective of this review is to summarize and compare current psychotherapy methods of PAP in treating depression and distress in life-threatening illnesses. We sought to comprehensively summarize published psychotherapy protocols from clinical trials to provide insights for future practices., Methods: A systematic search of four databases (Embase, MEDLINE, PsycINFO, CINAHL) for data relating to psychotherapy protocols was conducted by two independent reviewers., Results: In total, our search identified 1869 articles; after removing duplicates, we screened 1107 articles. We included 70 articles in the full-text review and determined that 28 were eligible for the final review. All protocols include sessions before (preparatory) and after (integration) the psychedelic dosing session with supportive monitoring. However, there was substantial variability and inconsistencies in all other aspects of therapy protocols (e.g., duration and number of sessions, model of therapy). Additionally, significant limitations were identified in the frequent need for more clarity in the description of therapeutic approaches., Conclusion: In published clinical trials, PAP has consisted of preparation, supportive dosing, and integration sessions. Beyond this basic framework, significant heterogeneity and lack of clarity were identified in reported psychotherapy protocols, meaning a validated and universally agreed upon protocol for PAP currently does not exist. Future studies should more clearly define and report psychotherapeutic components to identify the safest and most efficacious approaches to PAP., Competing Interests: Declaration of competing interest Dr. Joshua D Rosenblat has received research grant support from the Canadian Institute of Health Research (CIHR), Physician Services Inc (PSI) Foundation, Labatt Brain Health Network, Brain and Cognition DiscoveryFoundation (BCDF), Canadian Cancer Society, Canadian Psychiatric Association, Academic Scholars Award, American Psychiatric Association, American Society of Psychopharmacology, University of Toronto, University Health Network Centre for Mental Health, Joseph M. West Family Memorial Fund and Timeposters Fellowship and industry funding for speaker/consultation/research fees from iGan, Boehringer Ingelheim, Janssen, Allergan, Lundbeck, Sunovion and COMPASS. He was formerly the Chief Medical and Scientific Officer of Braxia Scientific and the medical director of the Canadian Rapid Treatment Centre of Excellence (Braxia Health). Dr. Roger McIntyre has received research grant support from Global Alliance for Chronic Diseases/Canadian Institutes of Health Research (CIHR)/National Natural Science Foundation of China's Mental Health Team Grant; speaker/consultation fees from Lundbeck, Janssen, Purdue, Pfizer, Otsuka, Takeda, Neurocrine, Sunovion, Bausch Health, Novo Nordisk, Kris, Sanofi, Eisai, Intra-Cellular, NewBridge Pharmaceuticals, Abbvie. Dr. Roger McIntyre is a CEO of Braxia Scientific Corp. Zoe Doyle is a Clinical Project Lead at Braxia Scientific and a Project Lead at Braxia Health (Canadian Rapid Treatment Centre of Excellence). None of the remaining authors have any potential competing interests to disclose., (Copyright © 2024. Published by Elsevier Ltd.)

Background: Combinations of Chinese patent medicines (CPM) with antidepressants (including selective serotonin reuptake inhibitors (SSRI), selective serotonin-norepinephrine reuptake inhibitors (SNRI), tricyclic antidepressants (TCA), and noradrenergic and specific serotonergic antidepressants (NaSSA)) are frequently utilized for treating depression in adults. However, the efficacy and safety of these combination treatments remain to be established., Methods: Systematic search was conducted in seven electronic databases, regulatory websites and international registers of trials from 1994 to 2023 that included adult patients with depressive disorders who received CPM combined with antidepressants. The Multiple-Treatment Meta-Analysis (MTMA) was conducted using a random effects model with Stata/MP17 and R4.3.5 software. Primary outcomes were total efficacy rate, Hamilton Depression Scale (HAMD) score, and Treatment Emergency Symptom Scale (TESS) score. Secondary outcomes included brain-derived neurotrophic factor (BDNF) levels., Results: A total of 146 randomized controlled trials (13,754 participants: 6929 in intervention and 6825 in control groups) were included. For total effective rate, Multiple-Treatment Meta-Analysis results showed that the overall effect of combined intervention was better compared with antidepressants alone, where Jieyuanshenkeli (JYASKL) presented the optimal option for improving total efficacy (OR = 5.39, 95% CI [2.60, 11.18], SUCRA = 84.50%). In reduding the HAMD, Shuganjieyujiaonang (SGJYJN) was most likely to reduce the HAMD score (SMD = -2.20, 95% CI [-3.06, -1.33], SUCRA = 86.10%), Jieyuanshenkeli (JYASKL),Tianewangbuxindan (TWBXD), Shuyukeli (SYKL), Anshenbuxinwan (ASBXW) combination intervention did not appear to be statistically superior to antidepressants alone. In theTreatment Emergency Symptom Scale (TESS), Wulinjiaonang induced the most significant reduction in TESS score (SMD = -1.98, 95% CI [-3.59, -0.36], SUCRA = 90.40%). Tianmengjiaonang (TMJN) + Antidepressants(AD) (SUCRA = 88.30%) displayed the highest scores in increasing the levels of BDNF, although not statistically significant compared to Antidepressants(AD) alone (SMD = 1.23, 95% CI [0.90, 1.55])., Conclusion: Combinations of CPM and antidepressants showed superior efficacy over antidepressants alone. The optimal combinations were determined as Shuganjieyu Jiaonang (SGJYJN)/SSRIs and Jieyuanshenkeli (JYASKL)/SSRIs. In terms of safety, results showed that combination therapy did not show better TESS efficacy than antidepressants alone.Although some of the combination interventions were not superior than antidepressants alone in reducing HAMD scores,our findings provide a potentially significant alternative option for clinical complementary therapy. However, these results require further validation through larger sample sizes, multicenter randomized controlled trials, and real-world data., Competing Interests: Declaration of competing interest All the authors declare no support from any organization for the submitted work; no fnancial relationships with any organizations that might have an interest in the submitted work in the previous; no other relationships or activities that could appear to have infuenced the submitted work., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Interleukin (IL) 6 plays an important role in the pathogenesis of depression comorbid with rheumatoid arthritis (RA), and IL-6 inhibitors used to treat patients with RA may have an antidepressant effect. The objective of the study was to evaluate the effectiveness of Russian iIL-6 olokizumab (OKZ) in reducing symptoms of depression in patients with moderate/high RA activity. To date, 49 RA patients have been included, of which 43 (87.7%) are women, with an average age of 47.8 ± 12.8 years; with a predominant high activity of RA according to DAS28 (CRP) indices (89.8%), SDAI (79.6%) and CDAI (75.5%) and inefficacy of stable 12-week therapy with сDMARDs. In all patients, a psychiatrist, in accordance with ICD-10, diagnosed depression (chronic or recurrent) of varying severity during a semi-structured interview. At week 0, all patients were randomized by the method of sequential numbers in a ratio of 1 : 1 : 1 to one of the three study groups: group 1-cDMARDs + OKZ 64 mg subcutaneously once every 4 weeks (n = 18); group 2-cDMARDs + OKZ 64 mg subcutaneously once every 4 weeks + psychopharmacotherapy (PPT) (n = 26); group 3-cDMARDs + PPT (n = 5). The duration of the study is 24 weeks. The dynamics of depression severity was assessed on the PHQ-9, MADRS scales; anxiety, on HAM-A; experimental psychological projective techniques were also used. After 12 and 24 weeks of therapy, there was a significant decrease in the severity of depression and anxiety in all groups of patients. However, the difference between the final and initial values of all scales was statistically significantly greater (p <0.05) in the groups of patients receiving PPT: cDMARDs + OKZ + PPT (Δ PHQ-9 24-0 = -6.75 ± 3.91; Δ MADRS 24-0 = -22.5 ± 4.83; Δ HAM-A 24-0 = -14.6 ± 5.37) and cDMARDs + PPT (Δ PHQ-9 24-0 = -15.5 ± 3.53; Δ MADRS 24-0 = -25.0 ± 1.41; Δ HAM-A 24-0 = -18.5 ± 3.53), compared with the cDMARDs + OKZ group (Δ PHQ-9 24-0 = -4.00 ± 3.89; Δ MADRS 24-0 = -5.75 ± 8.29; Δ HAM-A 24-0 = -8.50 ± 8.21). According to a semi-structured interview with a psychiatrist and design experimental psychological techniques, the proportion of patients without depression after 24 weeks of therapy was significantly higher in the groups of patients receiving PPT: 90% in the group of cDMARDs + OKZ + PPT and 100%-cDMARDs + PPT, as opposed to 25% in the group of cDMARDs + OKZ. OKZ therapy contributed to the normalization of night sleep but did not lead to a decrease in the frequency and severity of cognitive disorders (CDs). OKZ has an antidepressant effect, leads to a decrease in the frequency of sleep disorders. However, a complete regression of depression symptoms when OKZ is prescribed without PPT is possible only in 25% of RA patients, mainly in the patients with mild depression. A combination of OKZ and PPT is optimal for the complete regression of depression and anxiety and a decrease in the frequency and severity of CDs., (© 2024. Pleiades Publishing, Ltd.)

There are currently no reliable biomarkers to predict clinical response to pharmacological treatments of depressive disorders. Peripheral blood 5-hydroxytryptamine (5-HT; serotonin) has been suggested as a biomarker of antidepressant treatment response, but there has not been an attempt to systematically summarize and evaluate the scientific evidence of this hypothesis. In this systematic review we searched MEDLINE, Embase, PsycINFO, and the Cochrane Central Register of Controlled Trials. Twenty-six relevant studies investigating peripheral 5-HT as an antidepressant biomarker were identified. In all, we did not find robust support for an association between baseline 5-HT and treatment response. Several larger studies with lower risk of bias, however, showed that higher baseline 5-HT was associated with a greater antidepressant response to SSRIs, prompting future studies to investigate this hypothesis. Our results also confirm previous reports that SSRI treatment is associated with a decrease in peripheral 5-HT levels; however, we were not able to confirm that larger decreases of 5-HT are associated with better treatment outcome as results were inconclusive., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Amanda Holck reports financial support was provided by Southern Health Care Region, Sweden. Asa Westrin reports financial support was provided by Swedish governmental funding of clinical research (ALF). Daniel Lindqvist reports financial support was provided by Swedish governmental funding of clinical research (ALF). Daniel Lindqvist reports financial support was provided by Swedish Research Council. Owen M. Wolkowitz reports financial support was provided by Tinberg Fanily (gift). Pouya Movahed reports a relationship with H Lundbeck AB that includes: speaking and lecture fees. Marie Asp reports a relationship with H Lundbeck AB that includes: speaking and lecture fees. Daniel Lindqvist reports a relationship with H Lundbeck AB that includes: speaking and lecture fees. Daniel Lindqvist reports a relationship with Janssen Cilag AB that includes: speaking and lecture fees. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier Inc.)

Chronic neuropathic pain and comorbid depression syndrome (CDS) is a major worldwide health problem that affects the quality of life of patients and imposes a tremendous socioeconomic burden. More than half of patients with chronic neuropathic pain also suffer from moderate or severe depression. Due to the complex pathogenesis of CDS, there are no effective therapeutic drugs available. The lack of research on the neural circuit mechanisms of CDS limits the development of treatments. The purpose of this article is to provide an overview of the various circuits involved in CDS. Notably, activating some neural circuits can alleviate pain and/or depression, while activating other circuits can exacerbate these conditions. Moreover, we discuss current and emerging pharmacotherapies for CDS, such as ketamine. Understanding the circuit mechanisms of CDS may provide clues for the development of novel drug treatments for improved CDS management.

Positive leadership behaviours at work are associated with worker well-being and performance. However there is less knowledge about whether exposure to low levels of positive leadership behaviours increase workers' risk of clinical mental disorders. We investigated whether low levels of positive leadership behaviours are prospectively associated with risk of treatment for depressive and anxiety disorders. In a cohort study, we linked survey data from 59,743 respondents from the Work Environment and Health in Denmark survey with national health register data. Leadership behaviours were measured with an eight-item scale. Treatment was defined as redeemed prescription for antidepressants or anxiolytics or hospital treatment for depression or anxiety. Using Cox proportional hazard regression, adjusting for demographic variables, job type and sector, adverse life events and childhood adversities, we estimated the association between leadership behaviours at baseline and risk of treatment during follow-up. We identified 999 cases of depression and anxiety treatment during follow-up. Compared to high levels of leadership behaviours, exposure to medium low and low levels were associated with an increased risk of treatment after adjustment for covariates. The results suggest that low levels of positive leadership behaviours are associated with an increased risk of treatment for depressive or anxiety disorders., Competing Interests: Declaration of competing interest None., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Psychoactive substances obtained from botanicals have been applied for a wide variety of purposes in the rituals of different cultures for thousands of years. Classical psychedelics from N,N'-dimethyltryptamine, psilocybin, mescaline and various lysergamides cause specific alterations in perception, emotion and cognition by acting through serotonin 5-HT 2A receptor activation. Lysergic acid diethylamide, the first famous breakthrough in the field, was discovered by chance by Albert Hoffman in the Zurich Sandoz laboratory in 1943, and studies on its psychoactive effects began to take place in the literature. Studies in this area were blocked after the legislation controlling the use and research of psychedelic drugs came into force in 1967, but since the 1990s, it has started to be a matter of scientific curiosity again by various research groups. In particular, with the crucial reports of psychotherapy-assisted psilocybin applications for life-threatening cancer-related anxiety and depression, a new avenues have been opened in the treatment of psychiatric diseases such as treatment-resistant depression and substance addictions. An increasing number of studies show that psychedelics have a very promising potential in the treatment of neuropsychiatric diseases where the desired efficiency cannot be achieved with conventional treatment methods. In this context, we discuss psychedelic therapy, encompassing its historical development, therapeutic applications and potential treatment effects-especially in depression, trauma disorders and substance use disorders-within the framework of ethical considerations., (© 2024 The Authors. European Journal of Neuroscience published by Federation of European Neuroscience Societies and John Wiley & Sons Ltd.)

Objective: In this review, the authors update the 2018 position statement of the American Psychiatric Association Council of Research Workgroup on Biomarkers and Novel Treatments on pharmacogenomic (PGx) tools for treatment selection in depression., Methods: The literature was reviewed for new clinical trials and meta-analyses, published from 2017 to 2022, of studies using PGx tools for treatment selection in depression. The blinding and control conditions, as well as primary and secondary outcomes and post hoc analyses, were summarized., Results: Eleven new clinical trials and five meta-analyses were identified; all studies had primary outcome measures related to speed or efficacy of treatment response. Three trials (27%) demonstrated efficacy on the primary outcome measure with statistical significance; the three studies used different PGx tools; one study was open-label and the other two were small single-blind trials. Five trials (45%) did not detect efficacy with statistical significance on either primary or secondary outcome measures. Only one trial (9%) used adverse events as a primary outcome measure. All studies had significant limitations; for example, none adopted a fully blinded study design, only two studies attempted to blind the treating clinician, and none incorporated measures to estimate the effectiveness of the blinds or the influence of lack of blinding on the study results., Conclusions: The addition of these new data do not alter the recommendations of the 2018 report, or the advice of the U.S. Food and Drug Administration, that the evidence does not support the use of currently available combinatorial PGx tools for treatment selection in major depressive disorder. Priority efforts for future studies and the development and testing of effective tools include fully blinded study designs, inclusion of promising genetic variants not currently included in any commercially available tests, and investigation of other uses of pharmacogenomics, such as estimating the likelihood of rare adverse drug effects, rather than increasing the speed or magnitude of drug response., Competing Interests: Dr. Baum receives royalties from Oxford University Press. Dr. Widge has received donations of deep brain stimulation devices from Medtronic and consulting fees from Abbott, and he holds multiple granted and pending patents related to deep brain stimulation. Dr. Carpenter has received research support from Affect Neuro, Janssen Pharmaceuticals, Neuronetics, Neurolief, Nexstim, and SynapseBio, and she has served as a scientific adviser or consultant for Affect Neuro, Janssen Pharmaceuticals, Neuronetics, Neurolief, Nexstim, Otsuka, Sage Therapeutics, and Sunovion. Dr. McDonald is a Deputy Editor of the American Journal of Psychiatry; disclosures of Editors’ financial relationships appear in the April 2024 issue of the Journal. Dr. Nemeroff has served as a consultant for AbbVie, ANeuroTech, Autobahn Therapeutics, BioXcel Therapeutics, Clexio, EMA Wellness, EmbarkNeuro, Engrail Therapeutics, GoodCap Pharmaceuticals, Guidepoint, Intra-Cellular Therapies, Magstim, Ninnion Therapeutics, Pasithea Therapeutics Corp., Relmada Therapeutics, Sage, Senseye, Signant Health, Silo Pharma, and SynapseBio; he is a stockholder in Antares, Corcept Therapeutics, EMA Wellness, Naki Health, PreciseMent Health, Relmada Therapeutics, and Seattle Genetics; he has served on scientific advisory boards for ANeuroTech, the Anxiety and Depression Association of America (ADAA), the Brain and Behavior Research Foundation, Galen Health, Heading Health, the Laureate Institute for Brain Research, Pasithea Therapeutics Corp., Sage, Signant Health, and Skyland Trail and on the boards of directors for ADAA, Gratitude America, and Lucy Scientific Discovery; and he is named on patents on a method and devices for transdermal delivery of lithium and a method of assessing antidepressant drug therapy via transport inhibition of monoamine neurotransmitters by ex vivo assay. Dr. Cohen reports no financial relationships with commercial interests.

Antidepressive pharmacotherapy has undergone various phases in its history. The euphoria of the early years on the relief of depressive symptoms was followed by a long period of clinical experience and intensive scientific work resulting in a more balanced perspective. Current debates circle around the actual effectiveness, especially with respect to long-term treatment, the prevention of suicide and the sequelae of discontinuation of an antidepressant. The evaluation of antidepressants as a group and often also the risk-benefit ratio of an individual treatment change over time. Antidepressants are typical for many forms of psychiatric treatment which, in a term from Hanfried Helmchen, are just as Janus-faced as psychiatry in a general sense is as a science and as a clinical discipline., (© 2024. The Author(s).)

Depression is a complicated neuropsychiatric condition with an incompletely understoodetiology, making the discovery of effective therapies challenging. Animal models have been crucial in improving our understanding of depression and enabling antidepressant medication development. The CUMS model has significant face validity since it induces fundamental depression symptoms in humans, such as anhedonia, behavioral despair, anxiety, cognitive impairments, and changes in sleep, food, and social behavior. Its construct validity is demonstrated by the dysregulation of neurobiological systems involved in depression, including monoaminergic neurotransmission, the hypothalamic-pituitary-adrenal axis, neuroinflammatory processes, and structural brain alterations. Critically, the model's predictive validity is demonstrated by the reversal of CUMS-induced deficits following treatment with clinically effective antidepressants such as selective serotonin reuptake inhibitors, serotonin-norepinephrine reuptake inhibitors, tricyclic antidepressants, and monoamine oxidase inhibitors. This review comprehensivelyassesses the multifarious depressive-like phenotypes in the CUMS model using behavioral paradigms like sucrose preference, forced swim, tail suspension, elevated plus maze, and novel object recognition tests. It investigates the neurobiological mechanisms that underlie CUMS-induced behaviors, including signaling pathways involving tumor necrosis factor-alpha, brain-derived neurotrophic factor and its receptor TrkB, cyclooxygenase-2, glycogen synthase kinase-3 beta, and the kynurenine pathway. This review emphasizes the CUMS model's importance as a translationally relevant tool for unraveling the complex mechanisms underlying depression and facilitating the development of improved and targeted interventions for this debilitating neuropsychiatric disorder by providing a comprehensive overview of its validity, behavioral assessments, and neurobiological underpinnings., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Women with menopausal transition (MT) have an elevated risk of experiencing common mental health diagnoses (CMHD: depression or anxiety). There is no recent data comparing the rate, and treatment, of CMHD between men and women., Methods: In this population-based study, incidence rates (IR) per 100 person-years-at-risk (PYAR) for men and women ≥45 years registered with an UK primary care practice between 2010 and 2021 were estimated. Incidence rate ratios (IRR) with 95 % confidence intervals (CIs) of CMHD were estimated using men as a reference. We measured first prescriptions for psychotropic medications received within 12 months after CMHD. For selective serotonin reuptake inhibitors (SSRIs) /selective norepinephrine reuptake inhibitors (SNRIs), we measured the IR of prescribing per 100 PYAR, by 10-year bands. Proportion of SSRIs/SNRIs prescribing was estimated per 100 persons., Results: Rates of anxiety and depressive disorders were 1.68 and 1.69 per 100 PYAR in women aged 45-54 years-old compared to 0.91 and 1.20 per 100 PYAR in men, with IRR of 1.84 (95 % CI 1.72-1.97) and 1.44 (1.35-1.53) respectively. SSRIs/SNRIs were the most prescribed medication; in 2021, IRs for SSRIs/SNRIs were 13.4 per 100 PYAR in both sexes. In 2021, the proportion of SSRIs/SNRIs prescribing was 50.67 per 100 women and 41.91 per 100 men., Limitations: MT is assumed based on women's age as menopause onset is rarely recorded in primary care databases., Conclusions: Women ≥45 years experienced more CMHD compared to men, especially 45-54 years-olds, which coincides with MT. The proportion of SSRIs/SNRIs prescribing was higher in women., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Dana Alsugeir reports financial support was provided by Saudi Arabian Cultural Bureau. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: The comparative effectiveness of selective serotonin reuptake inhibitors (SSRIs) has been subjected to relatively little research. However, a recent study based on target trial emulation suggested that sertraline may be more effective than escitalopram., Aims: To investigate whether sertraline, citalopram, and escitalopram differ in their effectiveness-assessed via the risk of psychiatric hospital admission and suicide following treatment initiation. The choice to focus on sertraline, citalopram, and escitalopram was made to limit confounding by indication, as the Danish depression treatment guideline from 2007 specifically listed these three SSRIs as first choice., Method: We conducted a target trial emulation based on data from Danish registers. We identified all individuals that initiated treatment for depression with sertraline, citalopram, or escitalopram in the period from January 1, 2007, to March 1, 2019. These individuals were followed until psychiatric hospital admission or suicide (separate analyses), death, 1 year after treatment initiation or end of data. Cox proportional hazards regression adjusted for relevant baseline covariates was performed to emulate randomized treatment allocation, comparing the rate of psychiatric hospital admission and suicide for individuals treated with sertraline (used as reference), citalopram or escitalopram, respectively. For escitalopram, we conducted a sensitivity analysis excluding data from the period during which the drug was sold under patent, as the price of the drug during that time likely entailed a different prescription pattern, increasing the risk of ("patent-related") confounding by indication., Results: We identified 56,865, 118,145, and 31,083 individuals initiating treatment with sertraline, citalopram, and escitalopram, respectively. Using sertraline as reference, the adjusted hazard rate ratio (aHRR) for psychiatric admission was 0.98 (95% CI = 0.91-1.05) for citalopram and 1.21 (95% CI = 1.10-1.32) for escitalopram. Notably, in the sensitivity analysis only including patients initiating treatment after the escitalopram patent had expired, the increased risk of psychiatric hospital admission associated with escitalopram treatment was no longer present (aHRR = 0.98, 95% CI = 0.82-1.18). The results of the analyses of suicide were inconclusive, due to few outcome events., Conclusions: Sertraline, citalopram, and escitalopram do not seem to have differential effectiveness in the treatment of depression. Taking potential patent-related, time varying, confounding by indication (via severity) into account is critical for pharmacoepidemiological studies, including those employing target trial emulation., (© 2024 The Author(s). Acta Psychiatrica Scandinavica published by John Wiley & Sons Ltd.)

The Polish standard of treatment with racemic ketamine for patients with depressive disorders was developed by a Working Group appointed by the National Consultant in the field of psychiatry. Despite the wide range of available medications, as many as one-third of depressed patients do not respond to standard antidepressant treatment, raising the need for an ongoing search for new effective and safe therapies. In recent years, the possible role of overactivity of the glutamatergic system in the etiopathogenesis of depression has again attracted the attention of many experts. The possibility of using substances with a modulating effect on the glutamatergic system in the treatment of depressive disorders has been postulated, among others, the long-known anesthetic ketamine, which is a noncompetitive NMDA receptor antagonist. This paper summarizes the results of studies on the efficacy and safety of racemic ketamine (administered intravenously) in the treatment of patients with depressive symptoms in the course of both unipolar and bipolar affective disorder, and, meeting the expectations of many practicing psychiatrists wishing to broaden the range of therapies offered to their patients, presents recommendations on indications, contraindications, precautions and the treatment regimen itself with intravenous ketamine for patients with mood disorders.

Context: The effect of testosterone on depressive symptoms in men with hypogonadism remains incompletely understood., Objective: We assessed the effects of testosterone-replacement therapy (TRT) in improving depressive symptoms in hypogonadal men with and without depressive symptoms enrolled in the TRAVERSE cardiovascular safety trial., Methods: A randomized, placebo-controlled, double-blind study was conducted at 316 trial sites. Participants included men, aged 45 to 80 years, with 2 fasting testosterone levels less than 300 ng/dL, 1 or more hypogonadal symptoms, cardiovascular disease (CVD), or increased risk of CVD. We evaluated 3 subgroups of participants: (1) men with rigorously defined, late-life-onset, low-grade persistent depressive disorder (LG-PDD, previously "dysthymia"); (2) all men with significant depressive symptoms (Patient Health Questionnaire-9 Score >4); and (3) all randomly assigned men. Intervention included 1.62% transdermal testosterone or placebo gel. Outcome measures included the proportions of participants (1) meeting criteria for LG-PDD or (2) with significant depressive symptoms; and changes in depressive symptoms, energy, sleep quality, and cognition in testosterone-treated vs placebo-treated men in the 3 subgroups., Results: Of 5204 randomly assigned participants, 2643 (50.8%) had significant depressive symptoms, but only 49 (1.5%) met rigorous criteria for LG-PDD. Among those with LG-PDD, there was no significant difference in any outcome measure between the TRT and placebo groups, possibly reflecting low statistical power. In men with significant depressive symptoms (n = 2643) and in all randomly assigned participants (n = 5204), TRT was associated with modest but significantly greater improvements in mood and energy but not cognition or sleep quality., Conclusion: Depressive symptoms are common in middle-aged and older men with hypogonadism but LG-PDD is uncommon. TRT is associated with small improvements in mood and energy in hypogonadal men with and without significant depressive symptoms., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

The treatment of suicidal ideation in patients with depression has been a major problem faced by psychiatric and emergency departments, and reasonable drug selection is particularly important. Ketamine has been shown to reduce suicidal ideation rapidly, but the strength of the effect is unclear and there is little evidence-based medical evidence to support this. We systematically searched all articles published on PubMed, Cochrane Library, Web of Science, CNKI and EMBASE. Stata 15 and R 4.1.3 were used for meta-analysis, and odds ratios were calculated in fixed effects or random effects models based on the heterogeneity test results. Our search resulted in 505 articles; we analyzed 14 studies, which included 1,380 participants. The 14 studies included 10 randomized controlled trial (RCT) studies and 4 single-arm studies. Our study suggests that, ketamine has a significant therapeutic effect on suicidal ideation throughout the treatment cycle. We performed network meta-analyses(NMA) and pairwise meta-analyses to compare the efficacy of ketamine in the reduction of suicidal ideation. There was a significant reduction in suicidal ideation within the first day after treatment (NMA ketamine day1 RR = 10.02, 95%CI = 4.24 to 23.68). In repeated treatment, the degree of recovery of suicidal ideation after the last dose was significantly greater than that after the first dose (RR = 0.56, 95%CI = 0.51 to 0.62). Recovery of suicidal ideation was also significantly better in the treatment end point than in the placebo group at the same time point (NMA ketamine day26 RR = 4.29, 95%CI = 1.41 to 13.08). This is the first network meta-analysis to demonstrate the role of ketamine in the alleviation of suicidal ideation. Our network meta-analysis also compared the effects of different drugs at different time points, which was not done in previous studies. This is of great reference significance for future drug research andrational drug use., (© 2024. The Author(s).)

Bradykinin (BK), a well-studied mediator of physiological and pathological processes in the peripheral system, has garnered less attention regarding its function in the central nervous system, particularly in behavioural regulation. This review delves into the historical progression of research focused on the behavioural effects of BK and other drugs that act via similar mechanisms to provide new insights into the pathophysiology and pharmacotherapy of psychiatric disorders. Evidence from experiments with animal models indicates that BK modulates defensive reactions associated with panic symptoms and the response to acute stressors. The mechanisms are not entirely understood but point to complex interactions with other neurotransmitter systems, such as opioids, and intracellular signalling cascades. By addressing the existing research gaps in this field, we present new proposals for future research endeavours to foster a new era of investigation regarding BK's role in emotional regulation. Implications for psychiatry, chiefly for panic and depressive disorders are also discussed.

Depressive disorders are widely debilitating psychiatric disease. Despite the considerable progress in the field of depression therapy, extensive research spanning many decades has failed to uncover pathogenic pathways that might aid in the creation of long-acting and rapid-acting antidepressants. Consequently, it is imperative to reconsider existing approaches and explore other targets to improve this area of study. In contemporary times, several scholarly investigations have unveiled that persons who have received a diagnosis of depression, as well as animal models employed to study depression, demonstrate a decrease in both the quantity as well as density of astrocytes, accompanied by alterations in gene expression and morphological attributes. Astrocytes rely on a diverse array of channels and receptors to facilitate their neurotransmitter transmission inside tripartite synapses. This study aimed to investigate the potential processes behind the development of depression, specifically focusing on astrocyte-associated neuroinflammation and the involvement of several molecular components such as connexin 43, potassium channel Kir4.1, aquaporin 4, glutamatergic aspartic acid transporter protein, SLC1A2 or GLT-1, glucocorticoid receptors, 5-hydroxytryptamine receptor 2B, and autophagy, that localized on the surface of astrocytes. The study also explores novel approaches in the treatment of depression, with a focus on astrocytes, offering innovative perspectives on potential antidepressant medications., Competing Interests: Declaration of competing interest None., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Background: Understanding the impact of CYP2D6 metabolism on paroxetine, a widely used antidepressant, is essential for precision dosing., Methods: We conducted an 8-week, multi-center, single-drug, 2-week wash period prospective cohort study in 921 Chinese Han patients with depressive or anxiety disorders (ChiCTR2000038462). We performed CYP2D6 genotyping (single nucleotide variant and copy number variant) to derive the CYP2D6 activity score and evaluated paroxetine treatment outcomes including steady-state concentration, treatment efficacy, and adverse reaction. CYP2D6 metabolizer status was categorized into poor metabolizers (PMs), intermediate metabolizers (IMs), extensive metabolizers (EMs), and ultrarapid metabolizers (UMs). The influence of CYP2D6 metabolic phenotype on paroxetine treatment outcomes was examined using multiple regression analysis and cross-ethnic meta-analysis. The therapeutic reference range of paroxetine was estimated by receiver operating characteristic (ROC) analyses., Findings: After adjusting for demographic factors, the steady-state concentrations of paroxetine in PMs, IMs, and UMs were 2.50, 1.12, and 0.39 times that of EMs, with PM and UM effects being statistically significant (multiple linear regression, P = 0.03 and P = 0.04). Sex and ethnicity influenced the comparison between IMs and EMs. Moreover, poor efficacy of paroxetine was associated with UM, and a higher risk of developing adverse reactions was associated with lower CYP2D6 activity score. Lastly, cross-ethnic meta-analysis suggested dose adjustments for PMs, IMs, EMs, and UMs in the East Asian population to be 35%, 40%, 143%, and 241% of the manufacturer's recommended dose, and 62%, 68%, 131%, and 159% in the non-East Asian population., Interpretation: Our findings advocate for precision dosing based on the CYP2D6 metabolic phenotype, with sex and ethnicity being crucial considerations in this approach., Funding: National Natural Science Foundation of China; Academy of Medical Sciences Research Unit., Competing Interests: Declaration of interests The PMEDA consortium is funded by the Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences (2021-I2M-C&T-B-099) and “the Fundamental Research Funds for the Central Universities” (Peking University Medicine Fund for world's leading discipline or discipline cluster development, BMU2022DJXK007). WY, YL, Yu S, JG, ZK, and YZ disclose that there is a planned and pending patent related to a device for predicting the treatment outcome of paroxetine, which is relevant to the content of this manuscript. Other authors declare that they have no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: Tailoring antidepressant drugs (AD) to patients' genetic drug-metabolism profile is promising. However, literature regarding associations of ADs' treatment effect and/or side effects with drug metabolizing genes CYP2D6 and CYP2C19 has yielded inconsistent results. Therefore, our aim was to longitudinally investigate associations between CYP2D6 (poor, intermediate, and normal) and CYP2C19 (poor, intermediate, normal, and ultrarapid) metabolizer-status, and switching/discontinuing of ADs. Next, we investigated whether the number of perceived side effects differed between metabolizer statuses., Methods: Data came from the multi-site naturalistic longitudinal cohort Netherlands Study of Depression and Anxiety (NESDA). We selected depression- and/or anxiety patients, who used AD at some point in the course of the 9 years follow-up period (n = 928). Medication use was followed to assess patterns of AD switching/discontinuation over time. CYP2D6 and CYP2C19 alleles were derived using genome-wide data of the NESDA samples and haplotype data from the PharmGKB database. Logistic regression analyses were conducted to investigate the association of metabolizer status with switching/discontinuing ADs. Mann-Whitney U-tests were conducted to compare the number of patient-perceived side effects between metabolizer statuses., Results: No significant associations were observed of CYP metabolizer status with switching/discontinuing ADs, nor with the number of perceived side effects., Conclusions: We found no evidence for associations between CYP metabolizer statuses and switching/discontinuing AD, nor with side effects of ADs, suggesting that metabolizer status only plays a limited role in switching/discontinuing ADs. Additional studies with larger numbers of PM and UM patients are needed to further determine the potential added value of pharmacogenetics to guide pharmacotherapy., (© 2024. The Author(s).)

Background: New National Institute for Health and Care Excellence (NICE) guidance endorses the prescription of statins in larger population groups for the prevention of cardiovascular and cerebrovascular morbidity and mortality, especially in people with severe mental illness. However, the evidence base for their safety and risk/benefit balance in depression is not established., Objectives: This study aims to assess the real-world mortality and adverse events of statins in depressive disorders., Methods: Population-based, nationwide (England), between-subject, cohort study. We used electronic health records (QResearch database) of people aged 18-100 years with first-episode depression, registered with English primary care practices over January 1998-August 2020 for 12(+) months, divided into statin users versus non-users.Primary safety outcomes included all-cause mortality and any adverse event measured at 2, 6 and 12 months. Multivariable logistic regression was employed to control for several potential confounders and calculate adjusted ORs (aORs) with 99% CIs., Findings: From over 1 050 105 patients with depression (42.64% males, mean age 43.23±18.32 years), 21 384 (2.04%) died, while 707 111 (67.34%) experienced at least one adverse event during the 12-month follow-up. Statin use was associated with lower mortality over 12 months (range aOR 2-12months 0.66-0.67, range 99% CI 0.60 to 0.73) and with lower adverse events over 6 months (range aOR 2-6months 0.90-0.96, range 99% CI 0.91 to 0.99), but not at 1 year (aOR 12months 0.99, 99% CI 0.96 to 1.03). No association with any other individual outcome measure (ie, any other neuropsychiatric symptoms) was identified., Conclusions: We found no evidence that statin use among people with depression increases mortality or other adverse events., Clinical Implications: Our findings support the safety of updated NICE guidelines for prescribing statins in people with depressive disorders., Competing Interests: Competing interests: All authors have completed the ICMJE uniform disclosure form at http://www.icmje.org/disclosure-of-interest/ and declare the following: RDG is supported by the Wellcome Trust (award 102176/Z/13/Z, grant 216452/Z/19/Z, title 'The effects of anti-inflammatory drugs on emotional and reward processing'). FDC is supported by the National Institute for Health Research (NIHR) Research Professorship to AC (grant RP-2017-08-ST2-006) and by the NIHR Oxford Health Biomedical Research Centre (grant BRC-1215-20005). EGO is supported by the NIHR Research Professorship to AC (grant RP-2017-08-ST2-006). PC is supported by the Medical Research Council (MRC) (grant MR/S003037/1, title 'Clinical Psychopharmacology of Depression'). CJH is supported by the NIHR Oxford Health Biomedical Research Centre. SF is supported by the NIHR Oxford Health Biomedical Research Centre. AC is supported by the NIHR Oxford Cognitive Health Clinical Research Facility, by an NIHR Research Professorship (grant RP-2017-08-ST2-006), by the NIHR Oxford and Thames Valley Applied Research Collaboration, by the NIHR Oxford Health Biomedical Research Centre (grant BRC-1215-20005) and by Wellcome Trust (GALENOS Project). CJH has received consultancy fees from P1vital, Lundbeck, Servier, UCB, Zogenix, J&J and Syndesi outside of the current work. AC has received research and consultancy fees from INCiPiT (Italian Network for Paediatric Trials), CARIPLO, Lundbeck and Angelini Pharma outside of the current work. The other authors declare that they have no conflict of interest., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY. Published by BMJ.)

Purpose/background: Depressive disorder or mental cold is the most common mental disorder, and depression exists all over the world and in all countries and cultures. The results of several studies have shown that using compounds with antioxidant properties has been fruitful in patients with depression. Coenzyme Q10 (CoQ10) is a fat-soluble antioxidant and exerts its antioxidant effect by directly neutralizing free radicals or reducing tocopherol and preventing the inhibition of mitochondrial activity because of oxidative stress. This study aimed to investigate the effects of oral CoQ10 in patients with depression as an adjunctive treatment., Methods/procedures: Sixty-nine patients with moderate and severe depression were randomly divided into 2 CoQ10 groups (36) and placebo (33). The first group of patients received CoQ10 supplements at a dose of 200 mg daily for 8 weeks along with standard interventions and treatments for depression, and the second group received standard treatments for depression along with a placebo. The change in the score of Montgomery-Åsberg Depression Rating Scale depression scale was evaluated 4 and 8 weeks after the intervention. Also, at baseline and 8 weeks later at the end of the study, serum levels of total antioxidant capacity, total thiol groups, nitric oxide, malondialdehyde, and interleukin 6 were assessed., Findings/results: The changes in the depression score at the end of the study showed that, in the group receiving the CoQ10 supplement after 8 weeks, there was a reduction in depression symptoms, which was statistically significant compared with before the start of the study Meanwhile, no significant changes were observed in the patients of the placebo group in terms of symptom reduction. Compared with baseline and the placebo condition, serum levels of nitric oxide and total thiol groups significantly decreased and increased, respectively. Also, no statistically significant changes were observed for interleukin 6, malondialdehyde, and total antioxidant capacity., Implications/conclusions: A dose of 200 mg of CoQ10 supplement daily for 8 weeks can reduce depression and fatigue, as well as improve the quality of life of patients with depression. In addition, CoQ10 can significantly improve inflammation and oxidative stress status in patients with depression., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

COVID-19 is associated with increased risks for mood or anxiety disorders, but it remains uncertain how the association evolves over time or which patient groups are most affected. We conducted a retrospective cohort study using a nationwide database of electronic health records to determine the risk of depressive or anxiety disorder diagnoses after SARS-CoV-2 infection by 3-month blocks from January 2020 to April 2022. The study population comprised 822,756 patients (51.8% female; mean age 42.8 years) with COVID-19 and 2,034,353 patients with other respiratory tract infections (RTIs) (53.5% female, mean age 30.6 years). First time diagnoses of depressive or anxiety disorders 14 days to 3 months after infection, as well as new or new plus recurrent prescriptions of antidepressants or anxiolytics, were compared between propensity score matched cohorts using Kaplan-Meier survival analysis, including hazard ratio (HR) and 95% confidence interval (CI). Risk of a new diagnosis or prescription was also stratified by age, sex, and race to better characterize which groups were most affected. In the first three months of the pandemic, patients infected with SARS-CoV-2 had significantly increased risk of depression or anxiety disorder diagnosis (HR 1.65 [95% CI, 1.30-2.08]). October 2021 to January 2022 (HR, 1.12 [95% CI, 1.06-1.18]) and January to April 2022 (HR, 1.08 [95% CI, 1.01-1.14]). Similar temporal patterns were observed for antidepressant and anxiolytic prescriptions, when the control group was patients with bone fracture, when anxiety and depressive disorders were considered separately, when recurrent depressive disorder was tested, and when the test period was extended to 6 months. COVID-19 patients ≥65 years old demonstrated greatest absolute risk at the start of the pandemic (6.8%), which remained consistently higher throughout the study period (HR, 1.20 [95% CI, 1.13-1.27]), and overall, women with COVID-19 had greater risk than men (HR 1.35 [95% CI 1.30-1.40])., (© 2024. The Author(s).)

Objective: The authors examined whether machine-learning models could be used to analyze data from electronic health records (EHRs) to predict patients' responses to antidepressant medications., Methods: EHR data from a Washington State health system identified patients ages ≥13 years who started an antidepressant medication in 2016 in a community practice setting and had a baseline Patient Health Questionnaire-9 (PHQ-9) score of ≥10 and at least one PHQ-9 score recorded 14-180 days later. Potential predictors of a response to antidepressants were extracted from the EHR and included demographic characteristics, psychiatric and substance use diagnoses, past psychiatric medication use, mental health service use, and past PHQ-9 scores. Random-forest and penalized regression analyses were used to build models predicting follow-up PHQ-9 score and a favorable treatment response (≥50% improvement in score)., Results: Among 2,469 patients starting antidepressant medication treatment, the mean±SD baseline PHQ-9 score was 17.3±4.5, and the mean lowest follow-up score was 9.2±5.9. Outcome data were available for 72% of the patients. About 48% of the patients had a favorable treatment response. The best-fitting random-forest models yielded a correlation between predicted and observed follow-up scores of 0.38 (95% CI=0.32-0.45) and an area under the receiver operating characteristic curve for a favorable response of 0.57 (95% CI=0.52-0.61). Results were similar for penalized regression models and for models predicting last PHQ-9 score during follow-up., Conclusions: Prediction models using EHR data were not accurate enough to inform recommendations for or against starting antidepressant medication. Personalization of depression treatment should instead rely on systematic assessment of early outcomes., Competing Interests: The authors report no financial relationships with commercial interests.

Competing Interests: Competing interests: The BMJ has judged that there are no disqualifying financial ties to commercial companies. The authors declare the following other interests: none. Further details of The BMJ policy on financial interests is here: https://www.bmj.com/sites/default/files/attachments/resources/2016/03/16-current-bmj-education-coi-form.pdf.

Ethnopharmacological Relevance: Jiao-tai-wan (JTW), a classic herbal formula of traditional Chinese medicine recorded in Han Shi Yi Tong, has been used to alleviate sleep disorders since ancient times. In modern pharmacological research, JTW has been adopted for treating diabetes mellitus and even exerts antidepressant effects. However, the potential mechanisms deserve further elucidation., Aim of the Study: The prevalence of diabetes mellitus combined with depressive disorder (DD) is continuing to increase, yet it is currently under-recognized and its treatment remains inadequate. The present study aims to explore the underlying therapeutics and mechanisms of JTW on DD., Materials and Methods: Chronic restraint stress was used on db/db mice to construct a mouse model of DD. The therapeutic effects of JTW were assessed by glucolipid metabolic indexes, behavioral tests, and depression-related neurotransmitter levels. The inflammatory status and cell apoptosis of different mice were investigated and the changes in the cAMP/PKA/CREB pathway were detected. Combining the results of fingerprinting with molecular docking, the active components of JTW were screened. A cellular model was constructed by intervention of glucose combined with corticosterone (CORT). The levels of apoptosis and depression-related neurotransmitters in HT-22 cells were examined, and the changes in the cAMP/PKA/CREB pathway were tested. Finally, the activator and inhibitor of the PKA protein were used for reverse validation experiments., Results: JTW could improve the impaired glucose tolerance, lipid metabolism disorders, and depression-like symptoms in DD mice. Meanwhile, JTW could alleviate the inflammatory status, suppress the microglia activation, and improve hippocampal neuron apoptosis in DD mice. The dual effects of JTW might be associated with the activation of the cAMP/PKA/CREB pathway. Berberine (Ber) was identified for the in vitro experiment, it could reverse the apoptosis of HT-22 cells and up-regulate the depression-related neurotransmitter levels, and the effects of Ber were related to the activation of the cAMP/PKA/CREB pathway as well., Conclusion: JTW could exert both hypoglycemic and antidepressant effects through activating the cAMP/PKA/CREB signaling pathway, its active component, Ber, could improve the damage to HT-22 cells induced by glucose combined with CORT via the activation of the cAMP/PKA/CREB pathway. Ber may be one of the effective components of the dual effects of JTW., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Recent developments suggest that neurosteroids may achieve rapid antidepressant effects. As such, neurosteroidogenesis mediated by the translocator protein 18 kDa (TSPO) might constitute a promising option for the treatment of depression. Therefore, the current clinical trial aims to get the first evidence of whether TPSO ligands promote rapid antidepressant effects. Furthermore, we study which mechanisms of action, e.g., modulation of distinct neuronal networks, neurosteroidogenesis, endocrinological mechanisms, TSPO expression or microbiome composition, contribute to their putative antidepressant effects., Methods: This is a randomized, placebo-controlled, double-blind single-center trial of 2-week treatment with the TSPO ligand etifoxine versus placebo in depressive patients. Main eligibility criteria: male or female individuals aged 18 to 65 years with unipolar/bipolar depressive disorder with no other psychiatric main diagnosis or acute neurological/somatic disorder or drug/alcohol dependence during their lifetime. The primary endpoint is the time point at which 50% of the maximal effect has occurred (ET50) estimated by the scores of the Hamilton Depression Scale (HAMD-21). A total of 20 patients per group are needed to detect changes of therapeutic efficacy about 5% and changes of ET50 about 10% with a power of 70%. Assuming a drop-out rate of 10-20%, 50 patients will be randomized in total. The study will be conducted at the Department of Psychiatry and Psychotherapy of the University of Regensburg., Discussion: This study will provide a first proof-of-concept on the potential of the TSPO ligand etifoxine in the treatment of depressive disorders., Trial Registration: Clinical Trials Register (EudraCT number: 2021-006773-38 , registration date: 14 September 2022) and German Register of Clinical Studies (DRKS number: DRKS00031099 , registration date: 23 January 2023)., (© 2024. The Author(s).)

Post-traumatic stress disorder (PTSD) and depressive disorders represent two significant mental health challenges with substantial global prevalence. These are debilitating conditions characterized by persistent, often comorbid, symptoms that severely impact an individual's quality of life. Both PTSD and depressive disorders are often precipitated by exposure to traumatic events or chronic stress. The profound impact of PTSD and depressive disorders on individuals and society necessitates a comprehensive exploration of their shared and distinct pathophysiological features. Although the activation of the stress system is essential for maintaining homeostasis, the ability to recover from it after diminishing the threat stimulus is also equally important. However, little is known about the main reasons for individuals' differential susceptibility to external stressful stimuli. The solution to this question can be found by delving into the interplay of stress with the cognitive and emotional processing of traumatic incidents at the molecular level. Evidence suggests that dysregulation in these signalling cascades may contribute to the persistence and severity of PTSD and depressive symptoms. The treatment strategies available for this disorder are antidepressants, which have shown good efficiency in normalizing symptom severity; however, their efficacy is limited in most individuals. This calls for the exploration and development of innovative medications to address the treatment of PTSD. This review delves into the intricate crosstalk among multiple signalling pathways implicated in the development and manifestation of these mental health conditions. By unravelling the complexities of crosstalk among multiple signalling pathways, this review aims to contribute to the broader knowledge base, providing insights that could inform the development of targeted interventions for individuals grappling with the challenges of PTSD and depressive disorders., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: While depression has been associated with alterations in the hypothalamic-pituitary adrenal (HPA) axis function, there is still controversy regarding the nature and extent of the dysfunction, such as in the debate about hypercortisolism vs. hypocortisolism. It may therefore be necessary to understand whether and how HPA axis function in depression is linked to mRNA expression of key genes regulating this system., Methods: We studied 163 depressed outpatients, most of whom were chronically ill, and 181 healthy controls. Blood mRNA expression levels of NR3C1 (including GRα, GRβ, and GR-P isoforms), FKBP4, and FKBP5 were measured at baseline. HPA axis feedback sensitivity was measured by the dexamethasone (Dex)/corticotropin-releasing hormone (CRH) test. The association between mRNA expression levels and HPA axis feedback sensitivity was examined., Results: Compared to controls, patients showed significantly higher expression of GRα and lower expression of FKBP5, and higher post-Dex cortisol levels, even after controlling for age and sex. FKBP5 expression was significantly positively correlated with cortisol levels in patients, while GRα expression was significantly negatively correlated with cortisol levels in controls., Limitations: Most patients were taking psychotropic medications. The large number of correlation tests may have caused type I errors., Conclusions: The tripartite relationship between depression, mRNA expression of GR and FKBP5, and HPA axis function suggests that the altered gene expression affects HPA axis dysregulation and, as a result, impacts the development and/or illness course of depressive disorder. The combination of increased GRα expression and decreased FKBP5 expression may serve as a biomarker for chronic depression., Competing Interests: Declaration of competing interest None., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Depression is detrimental to partnership stability. However, it remains unclear if and how the duration and timing of depression affect the risk of family dissolution., Methods: We conducted a Danish register-based cohort study of newly-formed cohabiting and married couples in 2008 and 2009, who were followed from the second year after family formation. Depressive episodes were defined by individual-level prescription patterns of antidepressant drugs (ATC codes N06A) in either partner. Family dissolution was characterized by the discontinuation of a shared residential address. Using Longitudinal Targeted Minimum Loss-based Estimation, we estimated the risk of family dissolution after 5 years of follow-up under various lengths and timings of depressive episodes., Results: There were 102,335 families included. The covariate-adjusted risk of family dissolution in families without depressive episodes was 30.0 % (95 % CI 29.6-30.4 %) and 35.5 % (95 % CI 29.5-41.5 %) in families with at least one depressive episode during follow-up. The risk of family dissolution increased with the duration of depressive episodes to 42.2 % (95 % CI 40.8-43.6 %) for five coherent years of depression. Depression shortly after family formation carried higher risk of family dissolution; this risk was 42.3 % (95 % CI 38.4-46.3 %) for depression experienced in the first year of family formation versus 32.9 % (95 % CI 31.8-34.0 %) in the fifth year of family formation., Limitations: Proxy measures of depression by antidepressant prescriptions fails to identify milder depression. Annual measures of family dissolution precluded more fine-grained analyses of time-intervals., Conclusions: Depression is disruptive to family stability, particularly with longer duration and early onset after family formation., Competing Interests: Declaration of competing interest All authors KL, HCWR, MGM, GAH, KBM, JWD and TMO declare no known conflicts of interest that may influence the work reported in this paper. We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this paper in consistent with those guidelines., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Purpose: This post hoc analysis investigated whether a patient's underlying psychiatric disease (schizophrenia/schizoaffective disorder [SCHZ] or bipolar disorder/depressive disorder [MOOD]) influenced the efficacy or safety of valbenazine for tardive dyskinesia (TD) in an Asian population., Methods: We analyzed data from J-KINECT, a multicenter, phase II/III, randomized, double-blind study, which consisted of a 6-week placebo-controlled period followed by a 42-week extension where Japanese patients with TD received once-daily 40- or 80-mg valbenazine. We compared the change from baseline in Abnormal Involuntary Movement Scale total score and Clinical Global Impression of TD score between patients with SCHZ and those with MOOD, and incidence of treatment-emergent adverse events., Results: Of 256 patients included in the placebo-controlled period, 211 continued to the long-term extension. The mean change from baseline in Abnormal Involuntary Movement Scale total score at week 6 (95% confidence interval) was -1.8 (-3.2 to -0.5) and -3.3 (-4.7 to -1.9) in the valbenazine 40- and 80-mg groups, respectively (SCHZ group), and -2.4 (-3.9 to -0.9) and -3.5 (-5.1 to -1.9) in the valbenazine 40- and 80-mg groups, respectively (MOOD group), demonstrating improvement at either dose level over placebo, regardless of the underlying disease. These results were maintained to week 48, and improvements of Clinical Global Impression of TD scores were similar. There were no notable differences in the incidence of serious or fatal treatment-emergent adverse events by underlying disease; differences in the incidence of worsening schizophrenia and depression were attributed to underlying disease progression., Conclusions: Safety and efficacy of long-term valbenazine therapy for TD did not vary according to underlying psychiatric disease., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc.)

Depressive disorders among children and adolescents impact the practice of many providers, in many specialties. These disorders contribute to illness and disability throughout the world, and they are a significant risk factor for suicide. Depression in these age groups can differ from those in adults, and early recognition along with proper treatment can lead to improved outcomes. It is important for clinicians to differentiate depression from other possible diagnoses such as anxiety disorders, attention deficit hyperactivity disorder (ADHD), and other mood disorders. Once the diagnosis of depression is established, the severity should be assessed to determine the most appropriate level of treatment. Outpatient treatment often starts with therapy, and if medications are indicated, the use of selectiveserotonin reuptake inhibitors (SSRIs) tend to be first-line., (Copyright© South Dakota State Medical Association.)

Background: Maternal elevated glucocorticoid levels during pregnancy can affect the developing fetus, permanently altering the structure and function of its brain throughout life. Excessive action of these hormones is known to contribute to psychiatric disorders, including depression., Materials: The study was performed in a rat model of depression based on prenatal administration of dexamethasone (DEX) in late pregnancy (0.1 mg/kg, days 14-21). We evaluated the effects of prenatal DEX treatment on the cognition and bioenergetic signaling pathways in the brain of adult male rats, in the frontal cortex and hippocampus, and in response to stress in adulthood, using behavioral and biochemical test batteries., Results: We revealed cognitive deficits in rats prenatally treated with DEX. At the molecular level, a decrease in the orexin A and orexin B levels and downregulation of the AMPK-SIRT1-PGC1α transduction pathway in the frontal cortex of these animals were observed. In the hippocampus, a decreased expression of orexin B was found and changes in the MR/GR ratio were demonstrated. Furthermore, an increase in HDAC5 level triggered by the prenatal DEX treatment in both brain structures and a decrease in MeCP2 level in the hippocampus were reported., Conclusions: Our study demonstrated that prenatal DEX treatment is associated with cognitive dysfunction and alterations in various proteins leading to metabolic changes in the frontal cortex, while in the hippocampus adaptation mechanisms were activated. The presented results imply that different pathophysiological metabolic processes may be involved in depression development, which may be useful in the search for novel therapies., (© 2024. The Author(s).)

Background: Brain tumors represent a disease that causes both physical and psychological distress for those affected. The pharmacological treatment of depressive symptoms in particular has not been sufficiently researched in these patients. Depression can severely affect the quality of life and has an impact on the course of the disease., Objective: The aim of this work is to describe the diagnosis and treatment of depressive symptoms in brain tumor patients., Material and Methods: For this work a comprehensive literature search was conducted to identify relevant studies addressing the topic of depressive symptoms in brain tumors. The included studies were critically appraised to ensure their quality and relevance., Results: The review of the literature revealed that depressive symptoms are a common complication in brain tumor patients. It was found that there are no studies to date on the efficacy of antidepressant medications in brain tumor patients., Discussion: The results of this work highlight the need to pay increased attention to mental health in brain tumor patients. It is important that healthcare professionals identify depression in these patients at an early stage and provide appropriate interventions to improve their quality of life. Future research should focus on further exploring the mechanisms behind the association between brain tumors and depression in order to develop targeted and effective intervention options., (© 2023. The Author(s), under exclusive licence to Springer Medizin Verlag GmbH, ein Teil von Springer Nature.)

Background: Intravenous racemic ketamine is a promising treatment for treatment-resistant depression. However, its clinical utility compared with intranasal esketamine and the other well-studied conventional pharmacological interventions (i.e., aripiprazole and lithium) as augmentative treatments for treatment-resistant unipolar depression in adults remains unclear. Therefore, we aimed to compare the efficacy, tolerability and acceptability of intravenous racemic ketamine with intranasal esketamine, aripiprazole and lithium under such conditions., Methods: The Cochrane Library, PubMed, CINHAL and ClinicalTrials.gov databases were systematically searched from their inception to 10 May 2023. Randomised controlled trials evaluating these drugs were included. A random-effects network meta-analysis was also performed., Results: In the primary analysis, all four drugs were significantly more effective than placebo. In addition, intravenous racemic ketamine was significantly more effective and acceptable than intranasal esketamine and aripiprazole. Intravenous racemic ketamine was not significantly different from placebo in tolerability, whereas intranasal esketamine and aripiprazole were significantly less tolerable than placebo. Lithium did not differ significantly from intravenous racemic ketamine in efficacy, tolerability and acceptability., Limitations: The sample size of patients treated with intravenous racemic ketamine was small., Conclusions: Intravenous racemic ketamine may be a better augmentative treatment for treatment-resistant unipolar depression than intranasal esketamine and aripiprazole. Whether intravenous racemic ketamine or lithium is superior is unclear currently. A larger head-to-head trial of intravenous racemic ketamine versus conventional augmentative treatments for treatment-resistant unipolar depression is needed., Competing Interests: Declaration of competing interest The Authors declare that there is no conflict of interest., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Background: Evidence-based use of antidepressant medications is of major clinical importance. We aimed to uncover precription patterns in a large cohort of patients with unipolar depression., Material and Methods: Using Danish nationwide registers, we identified individuals with a first-time hospital diagnosis of unipolar depression between January 1st, 2001, and December 31st, 2016. Redemeed prescriptions of antidepressants from five years before to five years after diagnosis were retreived. Lithium and relevant antipsychotics were included. Data were analyzed with descriptive statistics including sunburst plots. Cox regressions were used to rank the risk of treatment failure according to antidepressant category and depression severity, as measured by hazard ratios of drug shift., Results: The full study population consisted of 113,175 individuals. Selective Serotonin Reuptake Inhibitors was the predominantly prescribed first-line group, both before (55.4%) and after (47.7%) diagnosis and across depression severities. Changes of treatment strategy were frequent; 60.8%, 33.7%, and 17.1% reached a second, third, and fourth treatment trial after the hospital diagnosis, respectively. More than half of patients continued their pre-diagnosis antidepressant after diagnosis. The risk of change of treatment strategy was generally lower in mild-moderate depression and higher in severe depression, with tricyclic antidepressants carrying the highest risk in the former and the lowest risks in the latter. Overall, prescribing were often not in accordance with guidelines., Conclusion: These findings uncover a potential for improving the clinical care for patients with unipolar depression through optimization of the use of marketed antidepressants., (© 2023 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Objective: The primary aim of this study was to examine the association between the different predicted phenotypes of the polymorphic CYP2D6 gene and the prevalence of adverse drug reactions in patients suffering from depressive disorders. The secondary aim was to investigate if comedication with CYP2D6 inhibitors resulted in more adverse drug reactions due to phenoconversion., Methods: Between January 2012 and December 2021, 415 patients with a depressive disorder and insufficient treatment response in secondary psychiatric care were included in the naturalistic observational study Genes, Depression, and Suicidality (GEN-DS). The patients were subjected to a semistructured interview and diagnosed according to DSM-IV . Patients were also required to complete the self-rating version of the UKU Side Effect Rating Scale. All patients were genotyped for CYP2D6 and assigned a corresponding predicted CYP2D6 phenotype., Results: Out of the 415 patients, 147 patients with available genotyping and UKU scale results were also prescribed 1 or more drugs metabolized by CYP2D6. We did not find any evidence of an effect of the predicted CYP2D6 phenotype on the total burden of adverse drug reactions or in any of the specific symptom domains as measured with the UKU scale among these patients. We also investigated if comedication with 1 or more substances that inhibited the effect of the CYP2D6 enzyme resulted in more reported adverse drug reactions due to phenoconversion. Even though the rate of phenotypic PMs increased from 13 to 38 patients, we did not find any support for increased adverse drug reactions in this group., Conclusions: We did not find that CYP2D6 phenotype could predict the occurrence of adverse drug reactions in patients with depressive disorders in this naturalistic setting. However, information about CYP2D6 genotype may still be important in antidepressant treatment for the selection of appropriate drugs, for dosing recommendations of certain medications, or when the patient is suffering from severe adverse reactions., (© Copyright 2024 Physicians Postgraduate Press, Inc.)

The article reflects the results of a number of studies that demonstrate the therapeutic effectiveness of Recognan (citicoline) in anxiety-depressive and asthenic disorders against the background of somatic and neurological diseases, in the correction of post-stroke depression. Recent experimental animal studies prove the effect of citicoline on anxiety and depression. In the complex effect, Recognan potentiates the main pharmacological effect of antidepressants and anxiolytics. In some studies, a dose-dependent change in animal behavior has been observed in response to the analgesic and antidepressant effects of citicoline. The effectiveness of citicoline in combination with transcranial direct current stimulation in the treatment of depression has been shown. The analysis of these research materials allows us to recommend Recognan in the complex therapy of asthenic and anxiety-depressive disorders in response to such pathological conditions as anxiety, asthenia, depression.

The efficacy and safety of psychopharmacotherapy with antidepressants is of great medical importance. The search for clinical and biological predictors for choosing the optimal psychopharmacotherapy with antidepressants is actively underway all over the world. Research is mainly devoted to searching for associations of polymorphic gene variants with the efficacy and safety of therapy. However, information about a patient's genetic polymorphism is often insufficient to predict the efficacy and safety of a drug. Modern research on the personalization of pharmacotherapy should include, in addition to genetic, phenotypic biomarkers. This is important because genotyping, for example, cannot accurately predict the actual metabolic activity of an isoenzyme. To personalize therapy, a combination of methods is required to obtain the most complete profile of the efficacy and safety of the drug. Successful treatment of depression remains a challenge, and inter-individual differences in response to antidepressants are common. About half of patients with depressive disorders do not respond to the first attempt at antidepressant therapy. Serious side-effects of antidepressant pharmacotherapy and discontinuation of treatment due to their intolerance are associated with ineffective therapy. This review presents the results of the latest studies of «omics» biomarkers of the efficacy and safety of antidepressants.