Targeting Toll-like Receptor 4/Nuclear Factor-κB and Nrf2/Heme Oxygenase-1 Crosstalk via Trimetazidine Alleviates Lipopolysaccharide-Induced Depressive-like Behaviors in Mice.

Depression is a global psychiatric illness that imposes a substantial economic burden. Unfortunately, traditional antidepressants induce many side effects which limit patient compliance thus, exploring alternative therapies with fewer adverse effects became urgent. This study aimed to investigate the effect of trimetazidine (TMZ); a well-known anti-ischemic drug in lipopolysaccharide (LPS) mouse model of depression focusing on its ability to regulate toll-like receptor 4 (TLR4)/nuclear factor-κB (NF-κB) as well as nuclear factor erythroid 2 related factor 2 (Nrf2)/ heme oxygenase-1 (HO-1) signaling pathways. Male Swiss albino mice were injected with LPS (500 µg/kg, i.p) every other day alone or parallel with oral doses of either escitalopram (Esc) (10 mg/kg/day) or TMZ (20 mg/kg/day) for 14 days. Treatment with TMZ attenuated LPS-induced animals' despair with reduced immobility time inforced swimming test. TMZ also diminished LPS- induced neuro-inflammation via inhibition of TLR4/NF-κB pathway contrary to Nrf2/HO-1 cascade activation with consequent increase in reduced glutathione (GSH) and HO-1 levels whereas the pro-inflammatory cytokines; tumor necrosis factor-α (TNF-α) and interleukin (IL)-1ß were evidently reduced. Besides, TMZ replenished brain serotonin levels via serotonin transporter (SERT) inhibition. Thus, TMZ hindered LPS-induced neuro-inflammation, oxidative stress, serotonin deficiency besides its anti-apoptotic effect which was reflected by decreased caspase-3 level. Neuroprotective effects of TMZ were confirmed by the histological photomicrographs which showed prominent neuronal survival. Here we showed that TMZ is an affluent nominee for depression management via targeting TLR4/NF-κB and Nrf2/HO-1 pathways. Future research addressing TMZ-antidepressant activity in humans is mandatory to enroll it as a novel therapeutic strategy for depression.

Psychotropic drug prescribing before and during the COVID-19 pandemic among people with depressive and anxiety disorders: a multinational network study.

BACKGROUND: People with mental health conditions were potentially more vulnerable than others to the neuropsychiatric effects of the COVID-19 pandemic and the global efforts taken to contain it. The aim of this multinational study was to examine the changes in psychotropic drug prescribing during the pandemic among people with depressive and anxiety disorders. METHODS: This study included electronic medical records and claims data from nine databases in six countries (France, Germany, Italy, the UK, South Korea, and the USA) of patients with a diagnosis of depressive or anxiety disorders between 2016 and 2021. The outcomes were monthly prevalence rates of antidepressant, antipsychotic, and anxiolytic drug prescribing. The associations between the pandemic and psychotropic drug prescribing were examined with interrupted time series analyses for the total sample and stratified by sex and age group. People with lived experience were not involved in the research and writing process. FINDINGS: Between Jan 1, 2016 and Dec 31, 2020, an average of 16 567 914 patients with depressive disorders (10 820 956 females [65·31%] and 5 746 958 males [34·69%]) and 15 988 451 patients with anxiety disorders (10 688 788 females [66·85%] and 5 299 663 males [33·15%]) were identified annually. Most patients with depressive disorders and anxiety disorders were aged 45-64 years. Ethnicity data were not available. Two distinct trends in prescribing rates were identified. The first pattern shows an initial surge at the start of the pandemic (eg, antipsychotics among patients with depressive disorders in MDCD_US (rate ratio [RR] 1·077, 95% CI 1·055-1·100), followed by a gradual decline towards the counterfactual level (RR 0·990, 95% CI 0·988-0·992). The second pattern, observed in four databases for anxiolytics among patients with depressive disorders and two for antipsychotics among patients with anxiety disorders, shows an immediate increase (eg, antipsychotics among patients with anxiety disorders in IQVIA_UK: RR 1·467, 95% CI 1·282-1·675) without a subsequent change in slope (RR 0·985, 95% CI 0·969-1·003). In MDCD_US and IQVIA_US, the anxiolytic prescribing rate continued to increase among patients younger than 25 years for both disorders. INTERPRETATION: The study reveals persistently elevated rates of psychotropic drug prescriptions beyond the initial phase of the pandemic. These findings underscore the importance of enhanced mental health support and emphasise the need for regular review of psychotropic drug use among this patient group in the post-pandemic era. FUNDING: University Grants Committee, Research Grants Council, The Government of the Hong Kong Special Administrative Region.

Stimulant, Antidepressant, and Opioid Telehealth Prescription Trends Between 2019 and 2022.

This cross-sectional study examines the rates of in-person and telehealth prescriptions for stimulants, antidepressants, and opioids before and during the COVID-19 pandemic.

Psychedelic-assisted therapy for treating anxiety, depression, and existential distress in people with life-threatening diseases.

BACKGROUND: Psychedelic-assisted therapy refers to a group of therapeutic practices involving psychedelics taken under therapeutic supervision from physicians, psychologists, and others. It has been hypothesised that psychedelic-assisted therapy may reduce symptoms of anxiety, depression, and existential distress in patients facing life-threatening diseases (e.g. cancer). However, these substances are illegal in most countries and have been associated with potential risks. OBJECTIVES: To assess the benefits and harms of psychedelic-assisted therapy compared to placebo or active comparators (e.g. antidepressants) for treatment of anxiety, depression, and existential distress in people with life-threatening diseases. SEARCH METHODS: We searched CENTRAL, MEDLINE, Embase, and two trial registers on 30 March 2024. In addition, we undertook reference checking, citation searching, and contact with study authors to identify additional studies. We used no language or date restrictions. SELECTION CRITERIA: We included randomised controlled trials (RCTs), with no restrictions regarding comorbidity, sex, or ethnicity. Interventions comprised a substance-induced psychedelic experience preceded by preparatory therapeutic sessions and followed by integrative therapeutic sessions. DATA COLLECTION AND ANALYSIS: We used the standard methodological procedures expected by Cochrane. MAIN RESULTS: We included six studies in the review, which evaluated two different interventions: psychedelic-assisted therapy with classical psychedelics (psilocybin ('magic mushrooms') and lysergic acid diethylamide (LSD)), and psychedelic-assisted therapy with 3,4-methylenedioxymethamphetamine (MDMA or 'Ecstasy'). The studies randomised 149 participants with life-threatening diseases and analysed data for 140 of them. The age range of participants was 36 to 64 years. The studies lasted between 6 and 12 months, and were conducted in outpatient settings in the USA and in Switzerland. Drug companies were not involved in study funding, but funding was provided by organisations that promote psychedelic-assisted therapy. Primary outcomes (at 1 to 12 weeks) Anxiety Psychedelic-assisted therapy using classical psychedelics (psilocybin, LSD) may result in a reduction in anxiety when compared to active placebo (or low-dose psychedelic): State Trait Anxiety Inventory (STAI-Trait, scale 20 to 80) mean difference (MD) -8.41, 95% CI -12.92 to -3.89; STAI-State (scale 20 to 80) MD -9.04, 95% CI -13.87 to -4.21; 5 studies, 122 participants; low-certainty evidence. The effect of psychedelic-assisted therapy using MDMA on anxiety, compared to placebo, is very uncertain: STAI-T MD -14.70, 95% CI -29.45 to 0.05; STAI-S MD -16.10, 95% CI -33.03 to 0.83; 1 study, 18 participants; very low certainty evidence. Depression Psychedelic-assisted therapy using classical psychedelics (psilocybin, LSD) may result in a reduction in depression when compared to active placebo (or low-dose psychedelic): Beck Depression Inventory (BDI, scale 0 to 63) MD -4.92, 95% CI -8.97 to -0.87; 4 studies, 112 participants; standardised mean difference (SMD) -0.43, 95% CI -0.79 to -0.06; 5 studies, 122 participants; low-certainty evidence. The effect of psychedelic-assisted therapy using MDMA on depression, compared to placebo, is very uncertain: BDI-II (scale: 0 to 63) MD -6.30, 95% CI -16.93 to 4.33; 1 study, 18 participants; very low certainty evidence. Existential distress Psychedelic-assisted therapy using classical psychedelics (psilocybin, LSD) compared to active placebo (or low-dose psychedelic) may result in a reduction in demoralisation, one of the most common measures of existential distress, but the evidence is very uncertain (Demoralisation Scale, 1 study, 28 participants): post treatment scores, placebo group 39.6 (SEM 3.4), psilocybin group 18.8 (3.6), P ≤ 0.01). Evidence from other measures of existential distress was mixed. Existential distress was not measured in people receiving psychedelic-assisted therapy with MDMA. Secondary outcomes (at 1 to 12 weeks) Quality of life When classical psychedelics were used, one study had inconclusive results and two reported improved quality of life, but the evidence is very uncertain. MDMA did not improve quality of life measures, but the evidence is also very uncertain. Spirituality Participants receiving psychedelic-assisted therapy with classical psychedelics rated their experience as being spiritually significant (2 studies), but the evidence is very uncertain. Spirituality was not assessed in participants receiving MDMA. Adverse events No treatment-related serious adverse events or adverse events grade 3/4 were reported. Common minor to moderate adverse events for classical psychedelics were elevated blood pressure, nausea, anxiety, emotional distress, and psychotic-like symptoms (e.g. pseudo-hallucination where the participant is aware they are hallucinating); for MDMA, common minor to moderate adverse events were anxiety, dry mouth, jaw clenching, and headaches. Symptoms subsided when drug effects wore off or up to one week later. Certainty of the evidence Although all six studies had intended to blind participants, personnel, and assessors, blinding could not be achieved as this is very difficult in studies investigating psychedelics. Using GRADE criteria, we judged the certainty of evidence to be low to very low, mainly due to high risk of bias and imprecision (small sample size). AUTHORS' CONCLUSIONS: Implications for practice Psychedelic-assisted therapy with classical psychedelics (psilocybin, LSD) may be effective for treating anxiety, depression, and possibly existential distress, in people facing a life-threatening disease. Psychedelic-assisted therapy seemed to be well tolerated, with no treatment-emergent serious adverse events reported in the studies included in this review. However, the certainty of evidence is low to very low, which means that we cannot be sure about these results, and they might be changed by future research. At the time of this review (2024), psychedelic drugs are illegal in many countries. Implications for research The risk of bias due to 'unblinding' (participants being aware of which intervention they are receiving) could be reduced by measuring expectation bias, checking blinding has been maintained before cross-over, and using active placebos. More studies with larger sample sizes are needed to reduce imprecision. As the US Drug Enforcement Administration (DEA) currently classifies psychedelics as Schedule I substances (i.e. having no accepted medical use and a high potential for abuse), research involving these drugs is restricted, but is steadily increasing.

Acute treatment residual depression symptoms and functional impairment among depressive patients of different age groups and education levels in China: A prospective, multicenter, randomized study.

OBJECTIVE: A prospective, multicenter, randomized study evaluated the efficacy of major depressive disorder (MDD) patients after 2-3 months of acute treatment based on the dual factors of education and age. METHODS: This study classified the included patients into four groups using two classification parameters: age (≤45 years, vs. >45 years) and education years (≤12 vs. >12). We analyzed age, gender, marital status, personal income, depression onset history, medication use, and follow-up across various groups. We evaluated residual somatic symptoms and social functioning in depression patients was conducted using the 16-item Quick Inventory of Depressive Symptomatology Self-report (QIDS-SR16), the Patient Health Questionnaire-15 (PHQ15), and the Sheehan Disability Scale (SDS). RESULTS: In China, 16 hospitals, 553 depression patients, and 428 fulfilled the inclusion criteria. Baseline patient data revealed significant differences among the different age groups in gender, marital status, income, first onset age, physical illness, combination of antipsychotics, and benzodiazepines use (all p < .05). Statistically significant differences were observed in overall comparisons among the four groups, encompassing the QIDS-SR16 score, PHQ15 score, and various SDS parameters (all p < .05). However, no statistically significant differences (all p > .05) were found in residual somatic symptoms and social functioning parameters between different education levels (≤12 years vs. >12 years) at baseline, 3 months, and 6 months, based on total scores on the scale. Repeated measures mixed model indicates that the QIDS-SR16 assessment indicates statistical differences among various marital statuses, income levels, medical histories, and antipsychotic medication use (p < .05). Furthermore, PHQ-15 and SDS assessments reveal statistical differences between single and married/cohabiting statuses, physical comorbidities, 3 and 6 months follow-ups compared to baseline (p < .05). CONCLUSION: This study indicates that compared to depressive patients >45 years old, those ≤45 years old often exhibit more residual depression, somatic symptoms, and severe social functional impairment; patients' education levels less influence this trend.

Antidepressant Effects of Ginsenoside Rc on L-Alpha-Aminoadipic Acid-Induced Astrocytic Ablation and Neuroinflammation in Mice.

Depression is a prevalent and debilitating mental disorder that affects millions worldwide. Current treatments, such as antidepressants targeting the serotonergic system, have limitations, including delayed onset of action and high rates of treatment resistance, necessitating novel therapeutic strategies. Ginsenoside Rc (G-Rc) has shown potential anti-inflammatory and neuroprotective effects, but its antidepressant properties remain unexplored. This study investigated the antidepressant effects of G-Rc in an L-alpha-aminoadipic acid (L-AAA)-induced mouse model of depression, which mimics the astrocytic pathology and neuroinflammation observed in major depressive disorder. Mice were administered G-Rc, vehicle, or imipramine orally after L-AAA injection into the prefrontal cortex. G-Rc significantly reduced the immobility time in forced swimming and tail suspension tests compared to vehicle treatment, with more pronounced effects than imipramine. It also attenuated the expression of pro-inflammatory cytokines (TNF-α, IL-6, TGF-ß, lipocalin-2) and alleviated astrocytic degeneration, as indicated by increased GFAP and decreased IBA-1 levels. Additionally, G-Rc modulated apoptosis-related proteins, decreasing caspase-3 and increasing Bcl-2 levels compared to the L-AAA-treated group. These findings suggest that G-Rc exerts antidepressant effects by regulating neuroinflammation, astrocyte-microglia crosstalk, and apoptotic pathways in the prefrontal cortex, highlighting its potential as a novel therapeutic agent for depression.

Trajectories of perinatal depression among women living with HIV in Uganda.

Background: Perinatal depression affects one-third of pregnant women living with HIV (WLH). We examined patterns of treatment response to a novel stepped model of depression care among WLH with perinatal depression in Uganda. Methods: As part of the Maternal Depression Treatment in HIV (M-DEPTH) cluster randomised controlled trial, 191 women were enrolled across four antenatal care clinics assigned to provide stepped care including behavioural and antidepressant therapy (ADT), and another 200 across four clinics assigned to provide usual care. They were assessed for depression severity using the Patient Health Questionnaire (PHQ-9) at enrolment and multiple times over 12 months of follow-up. We used repeated measures latent class analysis (LCA) to identify discrete trajectories of depression symptoms, while multinomial regression analyses measured correlates of class membership. Results: The LCA identified three trajectories among those in the treatment group: mildly depressed individuals who improved (MiD-I) (n = 143, 75%), moderately depressed individuals who improved (MoD-I) (n = 33, 17%), and moderately depressed individuals who remained depressed (MoD-R) (n = 15, 8%). Membership in MiD-I was associated with lower levels of intimate partner violence at baseline (P = 0.04) and month 6 (P < 0.001), and less recent trauma exposure (P = 0.03) at baseline. At month 6, social support was lowest in MoD-R, while the degree of negative problem-solving orientation was highest (both P < 0.001) in this class. The LCA also identified three trajectories among those in the usual care comparison group: mildly depressed (MiD) (n = 62, 31%), moderately depressed (MoD) (n = 71, 35%), and seriously depressed (SiD) (n = 67, 34%), with each experiencing slight improvement. Recent traumas at baseline were highest in SiD (P < 0.001); this group also reported the lowest positive problem-solving orientation and highest negative problem-solving orientation (P < 0.001) at baseline. Conclusions: Depression symptom trajectories among women with perinatal depression are related to modifiable factors such as problem-solving orientation and interpersonal dynamics, with the latter including intimate partner violence and social support. Most treatment recipients were characterised by trajectories indicating recovery from depression. Registration: ClinicalTrials.Gov (NCT03892915).

NMC-4 Ameliorates Depression-Like Behavior and Neuroinflammation Caused by Chronic Unpredictable Mild Stress.

Depression is a prevalent mental disorder, but the side effects of antidepressants also make depressed patients resistant. Effective and safe antidepressants should be developed from traditional herbs, with the aim of reducing the side effects of antidepressants and improving the efficacy of drugs. In this study, the new macamide compound-4 (NMC-4) was synthesized for the first time, addressing the problem of difficult extraction, isolation, and low content of natural macamide. NMC-4 was characterized using mass spectrometry, nuclear magnetic resonance, and infrared spectroscopy. The protective effect of NMC-4 against cell injury was demonstrated to be stronger than that of natural macamide (N-benzylhexadecanamide, XA) using a PC12 cell injury model. The study explored the effects of NMC-4 on chronic unpredictable mild stress (CUMS)-induced depressive symptoms. NMC-4 significantly improved depressive-like behaviors. NMC-4 ameliorated CUMS-induced depressive-like behaviors by mitigating neuroinflammation and modulating the NF-κB/Nrf2 and BDNF/PI3K/Akt pathways.

Polish standard of treatment with racemic ketamine for patients with depressive disorders developed by a Working Group appointed by the National Consultant in the field of psychiatry. / Polski standard leczenia racemiczna ketamina pacjentów z zaburzeniami depresyjnymi opracowany przez zespól roboczy powolany przez Konsultanta Krajowegow dziedzinie psychiatrii.

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.

Epigenetic mechanisms of rapid-acting antidepressants.

BACKGROUND: Rapid-acting antidepressants (RAADs), including dissociative anesthetics, psychedelics, and empathogens, elicit rapid and sustained therapeutic improvements in psychiatric disorders by purportedly modulating neuroplasticity, neurotransmission, and immunity. These outcomes may be mediated by, or result in, an acute and/or sustained entrainment of epigenetic processes, which remodel chromatin structure and alter DNA accessibility to regulate gene expression. METHODS: In this perspective, we present an overview of the known mechanisms, knowledge gaps, and future directions surrounding the epigenetic effects of RAADs, with a focus on the regulation of stress-responsive DNA and brain regions, and on the comparison with conventional antidepressants. MAIN BODY: Preliminary correlative evidence indicates that administration of RAADs is accompanied by epigenetic effects which are similar to those elicited by conventional antidepressants. These include changes in DNA methylation, post-translational modifications of histones, and differential regulation of non-coding RNAs in stress-responsive chromatin areas involved in neurotrophism, neurotransmission, and immunomodulation, in stress-responsive brain regions. Whether these epigenetic changes causally contribute to the therapeutic effects of RAADs, are a consequence thereof, or are unrelated, remains unknown. Moreover, the potential cell type-specificity and mechanisms involved are yet to be fully elucidated. Candidate mechanisms include neuronal activity- and serotonin and Tropomyosine Receptor Kinase B (TRKB) signaling-mediated epigenetic changes, and direct interaction with DNA, histones, or chromatin remodeling complexes. CONCLUSION: Correlative evidence suggests that epigenetic changes induced by RAADs accompany therapeutic and side effects, although causation, mechanisms, and cell type-specificity remain largely unknown. Addressing these research gaps may lead to the development of novel neuroepigenetics-based precision therapeutics.

Baseline Cognition Is Not Associated With Depression Outcomes in Vortioxetine for Major Depressive Disorder: Findings From Placebo-Controlled Trials.

Objective: Major depressive disorder (MDD) is a common psychiatric disorder for which pharmacologic standard-of-care treatments have limited efficacy, particularly among individuals with cognitive dysfunction. Cognitive dysfunction is observed in approximately 25%-50% of those with MDD, wherein response to standard-of-care medications is reduced. Vortioxetine is an approved antidepressant that has shown evidence of procognitive effects in patients. It is not known if it has greater clinical efficacy in MDD patients with cognitive dysfunction, a more difficult to treat population, than other antidepressants.Methods: This study was a reanalysis of 1,812 subjects with MDD across 4 placebo controlled trials. Baseline cognition was measured by the Digit Symbol Substitution Test (DSST), the primary measure used to demonstrate vortioxetine's procognitive effects in clinical studies. Analyses examined whether baseline cognitive function was associated with differences in treatment outcomes.Results: Baseline DSST did not predict placebo-adjusted treatment effects of vortioxetine on depressive symptoms (pooled Cohen d = -0.02, 95% CI = -0.12 to 0.07). Analyses of additional cognitive measures similarly did not predict placebo-adjusted treatment effects on depression (all 95% CI contained zero). Finally, analyses of trials with selective serotonin reuptake inhibitors (SSRIs)/serotonin and norepinephrine reuptake inhibitors (SNRIs) as active comparators also revealed no prediction of SSRI/SNRI adjusted treatment effects of vortioxetine on depression.Conclusions: These findings, taken together, suggest that cognitive function does not moderate depression outcomes in vortioxetine, with results comparable to other antidepressants.

Self-stigmatization and treatment preferences: Measuring the impact of treatment labels on choices for depression medications.

OBJECTIVE: To collect evidence on the possibility that patients with depression experience self-stigmatization based on label information for medications. METHODS: We developed a discrete-choice experiment (DCE) survey instrument that asked respondents to make choices between hypothetical treatments for major depressive disorder (MDD). We also included treatment type (antidepressants versus antipsychotics) and approved indications for the medication. The choice questions mimicked the information presented in product inserts and required systematic tradeoffs between treatment efficacy, treatment type, and indication. We calculated how many patients were willing to forgo efficacy to avoid treatments with information associated with self-stigmatization, and how much efficacy they were willing to forgo. We also evaluated the impact of contextualizing the treatment information to reduce self-stigmatization by randomizing respondents who received additional context. RESULTS: A total of 501 patients with MDD were recruited to complete the DCE survey. Respondents had well-defined preferences for treatment outcomes. Over 60% (63.4%) of respondents were found to be significantly affected by treatment indication. These respondents were willing to forgo about 2.5 percentage points in the chance of treatment efficacy to avoid treatments indicated for schizophrenia. We also find that some level of contextualization of the treatment details could help reduce the negative impact of treatment type and indications. CONCLUSIONS: Product-label treatment indication can potentially lead to patient self-stigmatization as shown by patients' avoidance of treatments that are also used to treat schizophrenia. While the effect appears to be relatively small, results suggests that the issue is likely pervasive.

Potential deprescribing indications for antidepressants between 2012 and 2019: repeated cross-sectional analysis in two Scottish health boards.

BACKGROUND: Antidepressants have a pivotal role in the treatment of many psychiatric disorders, but there are concerns about long-term use and adverse effects. The objectives of this study were (1) to examine time trends in antidepressant use, (2) to estimate the prevalence of long-term and potential high-risk antidepressant use, and (3) to examine patient characteristics associated with potential deprescribing indications (PDIs) (i.e., simultaneous long-term and potential high-risk antidepressant use). METHODS: Repeated population-based cross-sectional study for all 609,299 people aged ≥ 18 years resident in the Tayside or Fife regions of Scotland. The prevalence of antidepressant use was examined on June 30th (index date) of each year from 2012 to 2019, while the prevalence of long-term and potential high-risk use as well as PDIs was assessed and compared on the same dates in 2012 and 2019. Binary logistic regression modeling was used to examine patient characteristics associated with PDIs. RESULTS: Antidepressant use increased by 27% from 12.0 to 15.3% among adult residents between 2012 and 2019. While the proportion of antidepressants users dispensed ≥ 1 antidepressant for > 2 years increased from 54.3 to 61.9% between 2012 and 2019, the proportion of antidepressant users triggering ≥ 1 indicator of potential high-risk use decreased slightly from 37.9 to 34.7%. In 2019, potential high-risk use most commonly related to indicators targeting fall risk (16.0%), cardiovascular risks (14.1%), insomnia (10.6%), and risk of orthostatic hypotension (8.6%). More than 1 in 4 (25.8%) antidepressant users had PDIs. The main risk factors associated with PDIs included increasing age (65-79, adjusted OR 14.12; 95% CI, 13.15-15.17), increasing number of drugs taken concomitantly (≥ 15 drugs, adjusted OR 7.37; 95% CI, 6.71-8.10), use of tricyclic antidepressants (≥ 50 mg) (adjusted OR 5.49; 95% CI, 5.02-6.01), and concomitant use of ≥ 2 antidepressants (adjusted OR 5.52; 95% CI, 5.20-5.85). CONCLUSIONS: Long-term and potential high-risk use of antidepressants is widespread, and potential deprescribing indications (PDIs) are increasing, suggesting the need for a critical review of their ongoing use by clinicians. If deemed necessary, future deprescribing interventions may use the criteria applied here for identification of patients with PDIs and for evaluating intervention effectiveness.

[Melatonergic antidepressant agomelatine: augmentation of antipsychotic drugs in treatment of post-schizophrenic depression]. / Melatoninergicheskii antidepressant agomelatin: augmentatsiya antipsikhotikov v terapii postshizofrenicheskikh depressii.

The article presents an analytical review of the data on the effectiveness of agomelatine as an augmentation of antipsychotics in the treatment of post-schizophrenic depression (PSD). The results of 5 published studies with a total sample size of 137 patients, the duration of therapy from 28 to 180 days with the appointment of agomelatin in combination with antipsychotics, including cases of additional use of drugs of other classes (normotimics, antidepressants, anxiolytics, anticholinergic correctors) were used. As a result, a pronounced effect was established in the indicators of respondents and patients in remission, combined with a favorable tolerability and safety profile, determining the prospects for the use of agomelatin in the therapy of PSD. Certain limitations in the methodology, including open and uncontrolled research design and small sample sizes, determine the relevance of systematic controlled trials to confirm the results obtained.

Effectiveness and safety of Arecae Semen compounds for patients with depression: a systematic review and meta-analysis.

BACKGROUND: Arecae Semen is a traditional herbal medicine widely used in the medical service and food industry, but in recent years, the carcinogenesis of edible Arecae Semen chewing has aroused comprehensive attention, therefore it is necessary to evaluate its medicinal properties. Increasing evidence has shown that Arecae Semen Compounds (ASC) possess antidepressant ability. This study aimed to evaluate the effectiveness and safety of ASC in the treatment of depression. METHODS: We retrieved articles in eight databases from their inception to May 2024. Randomized controlled trials (RCTs) comparing the effects of ASC alone or combined with routine treatment in patients with depression were identified. The Cochrane risk of bias (ROB) tool (ROB 2) was used for assessing the ROB in the included trials. Grading of Recommendations Assessment, Development, and Evaluation (GRADE) was used to assess the certainty of the evidence for the review outcomes. The outcomes included Hamilton depression rating scale (HAMD) scores, depression-related symptoms, serum dopamine levels, and adverse events. Stata 14.0 was used for data analysis calculating standardized mean difference (SMD) for continuous outcomes and relative risk (RR) for binary outcomes, both with 95% confidence intervals (CI). RESULTS: Nine RCTs involving 787 patients were included in this review. ASC lowered HAMD scores (SMD - 3.43, 95% CI - 5.24 to - 1.61; I2 = 95.2%, P < 0.001), alleviated depression-related symptoms, increased serum dopamine levels, and reduced the incidence of adverse events slightly (RR 0.18, 95% CI 0.04 to 0.77; I2 = 0, P = 0.775) compared with the control group. Publication bias might account for the asymmetrical presentation of funnel plots. Meta-regression analysis revealed that regarding HAMD scores, there was no significant relationship with duration, sample size, or treatment strategy. The evidence of the outcomes was of very low certainty. CONCLUSIONS: ASC may achieve better therapeutic effects, alleviate depression-related symptoms with a lower incidence of adverse events, and provide a potentially effective and safe complementary therapy for patients with depression. However, the evidence is very uncertain so further researches are required to validate our results and explore clinical implications of Arecae Semen in depth. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42022361150.

Pharmacoeconomic implications of preference toward reference- versus generic-brand antidepressants in primary care.

BACKGROUND: The prevalence of depression is gradually increasing worldwide with an increasing utilization of antidepressants. Nevertheless, despite their lower costs, generic-brand antidepressants were reported to be less prescribed. We aimed to examine the costs of reference- versus generic-brand antidepressant prescriptions in primary care practice. METHODS: This cross-sectional study included electronic prescriptions for adult patients that contained antidepressants (World Health Organization's Anatomical Therapeutic Chemical (ATC) code: N06A), which were generated by a systematically selected sample of primary care doctors (n = 1431) in Istanbul in 2016. We examined the drug groups preferred, the reference- versus generic-brand status, and pharmacotherapy costs. FINDINGS: The majority of the prescriptions were prescribed for women (71.8%), and the average age of the patients was 53.6 ± 16.2 years. In prescriptions with a depression-related indication (n = 40 497), the mean number and cost of drugs were 1.5 ± 1.0 and 22.7 ± 26.4 United States Dollar ($) per prescription, respectively. In these prescriptions, the mean number and cost of antidepressants per encounter were 1.1 ± 0.2 and $17.0 ± 13.2, respectively. Reference-brand antidepressants were preferred in 58.2% of depression-related prescriptions, where the mean cost per prescription was $18.3 ± 12.4. The mean cost per prescription of the generics, which constituted 41.8% of the antidepressants in prescriptions, was $15.1 ± 11.4. We found that if the generic version with the lowest cost was prescribed instead of the reference-brand, the mean cost per prescription would be $12.9 ± 11.2. CONCLUSIONS: Our study highlighted the substantial pharmacoeconomic impact of generic-brand antidepressant prescribing, whose preference over reference-brands could reduce the cost of antidepressant medication treatment by 17.5% in primary care, which could be approximately doubled if the cheapest generic antidepressant had been prescribed.