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Antipsychotic drugs frequently cause metabolic complications in people with schizophrenia spectrum disorders, increasing cardiovascular morbidity and contributing to premature mortality; nutraceutical and phytotherapeutic agents may offer accessible adjunctive strategies, but their efficacy in this setting remains uncertain. We conducted a systematic review and meta-analysis (PROSPERO: CRD42024616494) of randomized controlled trials comparing nutraceuticals/phytotherapics with placebo in adults (18-65 years) with schizophrenia spectrum disorders receiving antipsychotics, including interventions lasting at least 4 weeks. Primary outcomes were body weight change and all-cause treatment discontinuation; secondary outcomes included lipid profile, glucose homeostasis, blood pressure, and anthropometric measures. Two independent reviewers extracted data and assessed study quality using the Cochrane Risk of Bias 2 tool, and meta-analyses primarily used random-effects models. Twenty-one trials (1,426 participants) evaluating 16 interventions were included. Omega-3 fatty acids, probiotics combined with dietary fibers, and Liuyu decoction were each associated with reduced body weight versus placebo, while alpha-lipoic acid showed consistent triglyceride reductions across two independent trials and berberine reduced systolic blood pressure. Discontinuation rates did not differ between groups, but risk of bias was frequently substantial, mainly due to blinding limitations and missing data handling. Overall, alpha-lipoic acid for hypertriglyceridemia and berberine for hypertension have the most consistent multi-trial support, whereas single-trial findings for omega-3s, probiotic combinations, and traditional Chinese medicine preparations require replication; heterogeneity and methodological weaknesses currently preclude broad clinical recommendations, though selected nutraceuticals may be considered for specific metabolic targets.
This study aimed to evaluate the impact of treatment with long-acting injectable antipsychotics on direct healthcare costs in a programme for patients with recent-onset psychosis. This was an observational, retrospective study. We included all patients admitted to the programme (from July 2015 to April 2020). All costs were recorded and three groups were compared: those receiving oral antipsychotics; those receiving oral treatment initially but subsequently switching before long-acting injectable antipsychotics; and those receiving after long-acting injectable antipsychotics. A total of 136 patients were included: 68 patients in the oral antipsychotics group and 34 patients in each of the other two groups. The average total healthcare cost per person/y was €11,347 in the oral antipsychotics group, €49,001 in the before long-acting injectable antipsychotics group, and €27,170 in the after long-acting injectable antipsychotics group. The comparisons between the first group and the other two were significant and between the after long-acting injectable antipsychotics vs before long-acting injectable antipsychotics groups (p<0.01, Mann-Whitney U test). These differences were related to the costs of psychiatric admissions, with an average per person/y of €2,252 (oral antipsychotics group), €22,947 (before long-acting injectable antipsychotics group) and only €777 in the after long-acting injectable antipsychotics group. The only prior clinical or demographic distinction between the three groups was the presence of substance abuse disorder, 41.2% in the oral treatment group vs. 70.6% in the long-acting injectable antipsychotics group (p=0.003 X 2 Pearson 99%; confidence interval: 0.002-0.005). In patients with recent-onset psychosis and comorbid substance abuse disorder, treatment with long-acting injectable antipsychotics, despite the higher cost of this medication, may be associated with a reduction in total direct healthcare costs. In our study, it saves €21,831 per patient/y.
INTRODUCTION: Lithium is a well-evidenced option for treatment-resistant unipolar depression. However, its use has globally declined over the past two decades and there is little evidence on exactly how unpopular the unipolar augmentation strategy is on the nosological characteristics of patients who still receive it and on primary agents. Real-world epidemiological studies can provide key relevant insights. METHODS: We analysed all ICD-10 unipolar depression prescriptions in Greece in the period between 1/2/2019 and 31/1/2020 and identified unipolar depression patients who were prescribed lithium. To benchmark lithium rates against those of other alternatives, we estimated quetiapine and aripiprazole prescription rates in unipolar depression. Logistic regression models were used to locate the diagnostic predictors of lithium prescription. Polypharmacy patterns and co-prescription of potentially interacting drugs were examined. RESULTS: Only 1,314 patients (0.174%) with unipolar depression were prescribed lithium, representing a small fraction of the assumed 30% of patients expected to have treatment-resistant depression. This was substantially lower than quetiapine (7.1%) and aripiprazole (1.1%) prescription rates for unipolar depression. Patients who were prescribed lithium were younger, more often men, and mostly managed by psychiatrists. More severe disorder profiles were apparent (24% vs. 6%), with psychotic symptoms and mixed symptomatology more prevalent. The sensitivity analysis showed that, after excluding patients prescribed lithium who received a diagnosis suggestive of bipolarity within the same period, only 785 patients (0.108%) consistently received unipolar diagnoses, with a further drop when other major diagnoses are factored in (0.08%). One in 13 people received a possibly interacting drug, especially thiazide diuretics. DISCUSSION: Despite strong evidence for augmentation in treatment-resistant unipolar depression, lithium prescription remains an underappreciated treatment option. In Greece, it is reserved for severe cases, together with selective serotonin reuptake inhibitors/serotonin and norepinephrine reuptake inhibitors and atypical antipsychotics. Possible reasons include a perception of alternatives as safer, further complicated by supply issues.
Randomised clinical trials with the same study design for granting a marketing authorisation are used to draw up depression guidelines. These randomised clinical trials have several limitations. These include that depression of the participants in these randomised clinical trials is heterogeneous to varying degrees and the natural resilience mechanism is insufficiently controlled. It is preferable to base antidepressant treatment guidelines on the results of pragmatic trials by a fixed group of primary and secondary care reporters in drug treatment-naive patients.
Acute stress, potentially mediated by the stress-induced release of cortisol, affects decision-making processes. In the brain, cortisol activates two different types of receptors: the glucocorticoid receptor (GR) and the mineralocorticoid receptor (MR), each with different functional profiles. While previous studies suggest specific effects for MR and GR, the role of both receptor types in decision-making is insufficiently investigated.In this study, stress-induced effects of cortisol on decision-making processes were investigated after pharmacological receptor blockade of the MR (spironolactone, 300 mg) or the GR (mifepristone, 600 mg) in 318 healthy men (M=25.42, SD=5.01). After single-dose administration, participants were subjected to a social-evaluative stress task (Trier Social Stress Test, TSST), which reliably activates the HPA-axis, or a non-stressful control task (pTSST). Participants were randomly assigned to one study group: pTSST-placebo, TSST-placebo, TSST-spironolactone, or TSST-mifepristone. Subsequently, participants completed the Iowa Gambling Task (IGT) as an outcome measure. A mediation analysis was conducted to investigate direct effects of experimental manipulation in this study and indirect effects mediated by cortisol levels. The evidence for stress effects on decisions under ambiguity was positive.While stressed participants exhibited higher risk-taking, this was not the case in the TSST-spironolactone group, although this group had the most pronounced cortisol stress response. Thus, cortisol did not mediate this effect.The stress effect on decision-making was attenuated when MR was blocked. This corresponds to previous findings of increased risk-taking after MR activation and highlights a functional differentiation of both receptors for this domain.
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Previous studies suggest a problem in the care of long-term patients in psychiatry, i.e., patients with long hospitalizations and no indication for acute inpatient treatment. Long stays are often associated with treatment resistance, for which evidence-based guideline recommendations exist for patients with schizophrenia. The aim of this study is to assess and characterize long-term patients in German psychiatric clinics and analyze the implementation of guideline recommendations for treatment-resistant schizophrenia. An anonymous online questionnaire was distributed to the management of 218 acute psychiatric clinics in Germany. The survey covered structural characteristics of the clinic, the number and diagnoses of long-term patients, and the implementation of guideline recommendations for patients with treatment-resistant schizophrenia. At the time of the survey, two-thirds of the responding clinics were treating long-term patients. Over 60% (n=45) of these patients had a diagnosis from the schizophrenia spectrum, with an average length of stay of 267 days. A total of 82.2% of patients with schizophrenia received antipsychotic therapy, 53% received clozapine, and 15.6% received electroconvulsive therapy. The most common reason for not receiving clozapine and electroconvulsive therapy was lack of consent. The survey confirms the unresolved problem of long-term patients in acute psychiatric clinics. In addition to demands for improved care structures for people with severe and chronic mental illnesses, the quality of acute psychiatric treatment (guideline adherence) must also be questioned. From an ethical viewpoint, short-term nonvoluntary measures aimed at restoring capacity to consent need to be weighed up against long-term or even permanent detention.
Medical cannabis, nabiximols, dronabinol and nabilone are used for various medical conditions. Despite their pronounced pharmacokinetic variability and complex concentration-effect relationships, therapeutic drug monitoring recommendations are lacking. We aimed to identify therapeutic reference ranges based on blood concentration-clinical effect relationships. Studies reporting blood concentrations and clinical effects/adverse effects or assessing cannabinoid receptors 1 and 2 occupancy were selected through a systematic literature search in the MEDLINE database via PubMed. Twenty-three articles were selected for vaporized/smoked medical cannabis, three for nabiximols, nine for dronabinol and one for nabilone. No article was identified for delta-9-tetrahydrocannabinol-dominant cannabis extracts. For vaporized/smoked medical cannabis, an orienting therapeutic reference range of 15-30 ng/mL delta-9-tetrahydrocannabinol was identified for pain reduction in diabetic peripheral neuropathy, while concentrations of <20 ng/mL delta-9-tetrahydrocannabinol were significantly correlated with intraocular pressure reduction and 7.5-10 ng/mL with improvement of tic symptoms. Half-maximum effective concentrations of 7-29 ng/mL delta-9-tetrahydrocannabinol were reported for "high" effects. For nabiximols, a preliminary therapeutic reference range of 1-10 ng/mL delta-9-tetrahydrocannabinol was determined for treating neuropathic pain and spasticity in adults with multiple sclerosis. For chemotherapy-induced nausea and vomiting, a preliminary therapeutic reference range of 1-5 ng/mL for nabilone and 5-15 ng/mL delta-9-tetrahydrocannabinol for dronabinol was assessed. In conclusion, relatively low concentrations may be sufficient to achieve therapeutic effects across all substances studied, with medical cannabis demonstrating these effects at lower concentrations than typically observed in recreational use. Nevertheless, adverse effects at therapeutic reference ranges cannot be excluded.
Clozapine is an effective antipsychotic used in treatment-resistant schizophrenia, but high serum levels may increase side effects. This study aimed to examine the efficacy and tolerability profile of clozapine in a naturalistic setting. The impact of multiple factors, specifically CYP1A2 genotypes, smoking, and fluvoxamine coadministration, on CYP1A2 enzyme activity was assessed as a secondary exploratory end point. In this prospective, observational study, 32 patients receiving stable clozapine therapy were observed over a 24-hour period at the Central Institute for Mental Health, Mannheim. Clozapine blood levels were measured via liquid chromatography-mass spectrometry and the MyCare Clozapine Assay. Clozapine levels above 600 ng/mL were not associated with increased clinical efficacy but were linked to more side effects. Sleep quality was generally poor, and daytime sedation was frequent. While coadministration with the CYP1A2 inhibitor fluvoxamine led to a dose-corrected increase in clozapine levels of approximately 50%; smoking reduced clozapine (-36%) and norclozapine (-32%) levels. Clozapine levels above the therapeutic reference range may not provide additional benefits and could increase side effects. Therapeutic drug monitoring is an essential clinical practice tool, especially when using comedication or in smokers. Overall, these findings should be interpreted as exploratory and supportive of existing therapeutic guidance because of the small sample size and naturalistic study design.
Electrocardiographic changes indicating a significantly increased risk of adverse cardiac effects, such as heart-rate corrected QT interval prolongation, are rare during antidepressant treatment; however, systematic analyses are lacking. Therefore, our study aimed at investigating the relationship between heart-rate corrected QT interval changes and both dosage and serum levels of escitalopram and venlafaxine in a well-characterized study sample.Two hundred seven depressed patients received escitalopram (10-20 mg/d) for 4 weeks. Non-responders were switched to high-dose venlafaxine (150-375 mg/d) for an additional 4 weeks of treatment. Serum concentrations were measured weekly and electrocardiograms were recorded at baseline, day 28 and day 56. Risk factors for heart-rate corrected QT interval prolongation were included as covariates in the analysis.Escitalopram did not significantly affect heart-rate corrected QT intervals. Switching to high-dose venlafaxine resulted in a significant increase of mean QT intervals from day 29 to day 56 (p=0.007), more pronounced in men (interaction p=0.038). Heart-rate corrected QT interval prolongation occurred in 5% of patients after escitalopram and 12% after venlafaxine; notably, 12 patients experienced critical prolongations, all with higher rates of known risk factors. No correlation between serum concentrations and heart-rate corrected QT intervals were observed.Our findings indicate that escitalopram does not affect heart-rate corrected QT intervals, whereas venlafaxine is associated with a modest but significant heart-rate corrected QT interval prolongation, particularly in males. Although infrequent, critical prolongations highlight the need for individualized risk assessment, especially in patients with risk factors. The lack of correlation with serum concentrations suggests that pharmacokinetic monitoring alone may not reliably predict cardiac risk. Our results underscore the importance of electrocardiogram monitoring with attention to sex-specific and clinical risk profiles.
The increasing use of antidepressant combinations necessitates a deeper understanding of drug-drug interactions. This study investigated serum concentration-dependent CYP2D6 inhibition by bupropion (via hydroxybupropion) and doxepin at antidepressant doses, using venlafaxine and risperidone as victim drugs.Therapeutic drug monitoring data from inpatients at the University Hospital of Würzburg (2018-2023) were retrospectively analyzed across four interaction groups (hydroxybupropion-venlafaxine, doxepin-venlafaxine, doxepin-risperidone, and hydroxybupropion-risperidone) with controls lacking CYP2D6 inhibitors. Associations between inhibitor concentrations and victim drug levels were assessed linearly. Nonlinear regression (four-parameter logistic model) was applied to relate inhibitor concentrations to metabolite-to-parent ratios; when the model fit was adequate, the half-maximal inhibitory concentration/90% inhibitory concentration values were estimated. Receiver operating characteristic analysis identified inhibitor concentration thresholds for phenoconversion to poor metabolizer status.Hydroxybupropion and doxepin concentrations were positively associated with venlafaxine, risperidone, and venlafaxine active moiety levels (p ≤ 0.02). Adequate sigmoidal curve fitting demonstrated a concentration-dependent inverse association between inhibitor levels and metabolite-to-parent ratios for venlafaxine with hydroxybupropion and doxepin, and risperidone with hydroxybupropion, but not risperidone with doxepin. The half-maximal inhibitory concentration values were 120.4 ng/mL and 28.16 ng/mL for hydroxybupropion (venlafaxine and risperidone, respectively) and 24.4 ng/mL for doxepin (venlafaxine). Phenoconversion thresholds were identified for hydroxybupropion (venlafaxine: 328.5 ng/mL and risperidone: 110.5 ng/mL) and doxepin (venlafaxine: 35 ng/mL and risperidone: 70.5 ng/mL).Hydroxybupropion and doxepin exert serum concentration-dependent inhibition of CYP2D6 activity, significantly affecting the metabolism of venlafaxine and risperidone. These effects and a phenoconversion into poor metabolizer status were detectable at subtherapeutic hydroxybupropion and therapeutic antidepressant doxepin levels. Monitoring inhibitor and victim-drug concentrations may aid in managing clinically relevant CYP2D6-mediated interactions.
The evidence on whether statin use affects cancer incidence is inconclusive and limited among apparently healthy older adults. This study emulated a target trial comparing statin initiators versus non-initiators, with further analyses stratified by statin lipophilicity. We conducted a target trial emulation using ASPREE (ASPirin in Reducing Events in the Elderly) and its extended observational data (ASPREE-XT). ASPREE was a placebo-controlled trial of low-dose aspirin in 19,114 older adults predominantly ≥70 years of age in Australia and the United States, who had no cardiovascular events, dementia, and independence-limiting physical disability at enrolment. We emulated a target trial of statin initiators versus non-initiators, following a prespecified target protocol. Key exclusion criteria were prior cardiovascular or cerebrovascular disease, high bleeding risk, conditions likely to limit 5-year survival, and anemia. The primary outcome was any-incident cancer and site-specific cancer, as adjudicated by an expert panel. Inverse probability weighting (IPW) was applied to adjust for predefined confounders including sociodemographic, clinical, and anthropometric factors, comorbidities, and co-medications to achieve balance between treatment groups. Participants were enrolled from March 01, 2010, to December 31, 2014, with follow-up to June 12, 2017, during the trial phase and then extended to January 08, 2022, as observational study. Of 12,557 eligible participants, 1596 (12.7%) initiated statin, including 882 (7.0% lipophilic and 714 (5.7%) hydrophilic statin. Over a median follow-up of 8.3 years (IQR; 6.5-9.5), the cumulative incidence of cancer per 1000 person-years was 16.0 (95% CI: [13.8-18.3]) in statin initiators and 21.6 (95% CI: [20.6-22.6]) in the non-initiators. Statin use was associated with a lower risk of cancer (Sub-distribution Hazard Ratio (SHR): 0.70 95% CI [0.59-0.82]), metastatic (SHR: 0.70 95% CI [0.52-0.93]) and non-metastatic (SHR: 0.71 95% CI [0.58-0.87]) cancers. This association remained significant for lipophilic statins (metastatic (SHR: 0.65 95% CI [0.45-0.94]) and non-metastatic (SHR: 0.64 95% CI [0.49-0.84]) cancers), but not for hydrophilic statins (metastatic (SHR: 0.77 95% CI [0.52-1.13]) and non-metastatic (SHR: 0.80 95% CI [0.61-1.06]) cancers). Among site-specific cancers, prostate cancer (SHR 0.67; 95% CI 0.47-0.95) and breast cancer (SHR 0.55; 95% CI 0.33-0.93) showed significant association. The estimated number needed to treat associated with statin use was 31 (95% CI: 25-47) for any cancer, 56 (95% CI: 44-87) metastatic cancer, and 72 (95% CI: 46-100) non-metastatic cancer over a median follow-up of 8.3 years. In this target trial emulation, statin use was associated with lower cancer incidence in older adults, with potential differences by cancer type and statin lipophilicity. These findings highlight the need for long-term randomised control trial to confirm this association. Potential for unmeasured confounding and bias due to the non-randomised observational design was a study limitation, and the inclusion of healthy participants may limit the generalizability of the findings. National Institute on Aging, National Cancer Institute, National Health and Medical Research Council of Australia, Monash University, Victorian Cancer Agency and Deakin University Postgraduate Research Scholarship.
The efficacy of antidepressants in mild depression remains debated. Despite guidelines recommending psychosocial interventions first, antidepressants are often initiated in real-world clinical practice. This study aimed to investigate the prescribing patterns of antidepressants at initial psychiatric consultations for patients with mild depression and to identify symptom-related factors influencing these prescribing decisions.A retrospective chart review was conducted on 1,508 outpatients diagnosed with depression at Kyorin University Hospital between 2020 and 2024. Among them, 171 patients met the criteria for mild depression, defined as a total score of 6-10 on the Quick Inventory of Depressive Symptomatology-Self Report. Independent t-tests and logistic regression analyses were performed to compare demographic and symptom-level characteristics between those who were prescribed antidepressants and those who were not.Of the 171 eligible patients, 28.1% were prescribed antidepressants at their first visit. No significant between-group differences were observed in demographics or overall symptom severity. The Quick Inventory of Depressive Symptomatology-Self Report item "increased weight" showed lower scores in the antidepressant group (0.1±0.4 vs 0.3±0.7, p=0.03), but this was not statistically significant after Benjamini-Hochberg false discovery rate correction and was also not statistically significant in logistic regression. Among participants prescribed monotherapy, no significant differences were found across antidepressant categories.Antidepressants were prescribed at the initial consultation in approximately 30% of patients with mild depression. No symptom item showed a clear, robust association with prescribing, suggesting that factors other than specific symptom profiles may play a more decisive role in real-world treatment selection.
Both patients and physicians are routinely exposed to the corporate promotion of artificial intelligence (AI) for healthcare products. Hype for AI products may impact both patient behavior and attitudes about healthcare. Corporate AI hype may intentionally overlook the known limitations associated with AI products and focus solely on potential benefits. As AI is increasingly integrated into medicine, physicians are also routinely subject to AI hype. As the promotion and use of AI products have grown dramatically in recent years, physicians should be aware of the potential benefits and risks of AI products despite the hype.
Although pain and depression frequently co-occur, the relationship between depressive symptom severity and both the odds and duration of analgesic use remains underexplored. This study investigated the relationship between depressive symptoms and analgesic use, with particular attention to the duration of use. A cross-sectional analysis was conducted using data from the 2005-2018 National Health and Nutrition Examination Survey. Depressive symptoms were assessed using the Patient Health Questionnaire-9. A total of 36,023 participants (51.14% women) were included. Each 1-point increase in the Patient Health Questionnaire-9 score was associated with a higher likelihood of analgesic use (adjusted odds ratio=1.08 and 95% confidence interval: 1.07-1.09). Compared to individuals with minimal depressive symptoms, those with mild (adjusted odds ratio=1.66 and 95% confidence interval: 1.45-1.90), moderate (adjusted odds ratio=2.17 and 95% confidence interval: 1.77-2.67), and severe symptoms (adjusted odds ratio=2.97, 95% confidence interval: 2.41-3.67) had progressively higher odds of analgesic use. Overall, depressive symptoms were associated with more than twice the odds of analgesic use (adjusted odds ratio=2.13 and 95% confidence interval: 1.82-2.48). Higher Patient Health Questionnaire-9 scores were associated with increased odds of longer analgesic use (>15 d; adjusted odds ratio=1.05 and 95% confidence interval: 1.02-1.08), as was the presence of depressive symptoms (adjusted odds ratio=1.73 and 95% confidence interval: 1.21-2.48). This association was most pronounced among individuals with severe depressive symptoms (adjusted odds ratio=2.58 and 95% confidence interval: 1.46-4.57). Depressive symptoms were significantly associated with both increased likelihood and longer duration of analgesic use. These findings highlight the complex and potentially bidirectional relationship between pain and mental health, suggesting the need for integrated approaches to pain management and psychiatric care.
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Psilocybin, a classic psychedelic compound, has garnered renewed interest as a potential treatment for various psychiatric disorders. This review provides a comprehensive overview of psilocybin's history, recent clinical evidence, ongoing clinical trials, neuroimaging findings, and regulations. Historically used in spiritual and healing rituals, psilocybin was in the early 1970s subjected to strict legal restrictions that stalled research for decades. However, renewed scientific interest began in the 1990s, with studies demonstrating psilocybin's therapeutic potential for psychiatric disorders. Clinical trials have reported therapeutic effects of psilocybin in major depressive disorder (MDD), depressive symptoms associated with life-threatening illnesses, and in some substance use disorders. Moreover, several phase III clinical trials of psilocybin for depression are currently underway, though trial data for obsessive-compulsive disorder and bipolar depression are limited. Short-term side effects are reportedly generally mild and transient, but long-term effects still need further investigation. Neuroimaging research using magnetic resonance imaging and electroencephalography is still limited and focuses mainly on MDD. However, ongoing clinical trials include neuroimaging studies for psychiatric disorders beyond MDD, as well as positron emission tomography studies for MDD. Regulatory frameworks vary internationally. While many countries continue to classify psilocybin as a prohibited substance, use of psilocybin under controlled conditions is now permitted in Switzerland, parts of the United States, Canada, and Australia. Despite encouraging data, challenges remain, including the need for larger, blinded trials, standardized protocols, and clarification of long-term efficacy and safety. Psilocybin represents a novel therapeutic approach in psychiatric treatment, warranting further rigorous scientific and regulatory research.
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Bipolar disorders are amongst the most common, severe and chronic mental health conditions, often associated with unpredictable illness trajectories. Temperament, as a relatively stable however underutilized affective trait in clinical practice, has been proposed as a potential modifier of illness course in BD. The current study sought to classify and examine temperament as a predictive or distinguishing factor in the course of bipolar illness. Ninety-one initially euthymic individuals with BD I or II were followed for a period of two years. Latent profile analysis (LPA) was conducted based on self-reported temperament (TEMPS-A scale) and used to identify temperament-based subgroups. Longitudinal illness burden was measured using an adapted Morbidity Index (MI), and stepwise multiple regression was performed to test whether temperament classes predicted MI scores. The LPA identified three distinct classes: moderate-reactive, reactive-instable, and resilient-hyperthymic temperament. Individuals in the moderate-reactive (vs. the resilient-hyperthymic) class showed significantly higher MI scores, indicating a worse longitudinal illness course. Temperament classes - reflecting combinations of traits rather than single dimensions alone - may serve as clinically meaningful predictors of illness burden in BD. The potential improvement of incorporating temperament profiles into clinical assessment to identify high-risk patients and guide more tailored treatment approaches is discussed.