Research Appraisals
Evidence-based critical appraisals of the latest medical research, systematically evaluated using Oxford CEBM methodology.
Showing 6 appraisals
Journal of affective disorders
Assessing symptom severity in patients with markedly treatment-resistant depression: Insights from the RECOVER trial
BACKGROUND: The performances of the Montgomery-Åsberg Depression Rating Scale (MADRS) and the Quick Inventory of Depressive Symptomatology-Clinician (QIDS-C) and Self-Report (QIDS-SR) ratings have never been evaluated in markedly treatment-resistant depression (TRD). RECOVER, a 12-month randomized, controlled trial, compared adjunctive active to adjunctive sham vagus nerve stimulation, provided data to address this knowledge gap, and to examine the basis for the differential sensitivities of these scales in detecting overall and between-treatment-group symptom changes. METHODS: We employed classical test and item response theory methods to characterize each scale. Effect sizes identified items that were most sensitive to change over time across treatments, best discriminated between the two treatments, and best detected at least a partial symptom response in clinician global ratings. RESULTS: All three inventories were unidimensional, with high retest reliability and strong internal consistency. MADRS total scores were less sensitive in detecting overall and between-treatment-group symptom differences. On each scale, five symptom domains-mood, energy/lassitude, interest/inability to feel, negative self-view/pessimism, and concentration-covaried most strongly with overall depression severity and had the largest effect sizes in detecting overall therapeutic change and between-group difference in efficacy. LIMITATIONS: These findings may not generalize to less treatment-resistant populations or to different treatments. The relative insensitivity of suicidal ideation, sleep, and appetite items may be due to study design or concomitant medications. CONCLUSION: The MADRS, QIDS-C, and QIDS-SR are suitable for use in markedly TRD. Whether sadness, energy, interest, guilt, and concentration are "core" symptoms that are especially sensitive to change deserves further study.
16 June 2026
Read appraisal →Journal of affective disorders
Brain aging in bipolar disorder using a neuroimaging and machine learning-derived metric: Findings from the ENIGMA BD Working Group.
BACKGROUND: Bipolar disorder (BD) is associated with clinical and biological markers of premature aging. In this largest study of brain age in BD to date, with 2919 participants, we compared brain-predicted age difference (brain-PAD) in individuals with BD and healthy comparison (HC) participants. Brain-PAD is a machine learning-estimated metric that quantifies the difference between an individual's predicted brain age and their chronological age, a potential clinical bio-signature of premature brain aging. Within individuals with BD, we also examined how medication and clinical characteristics were related to brain-PAD. METHODS: Age was predicted from 77 MRI measures of regional subcortical and lateral ventricle volumes, cortical thickness, and surface area for 1342 BD and 1577 HC adult participants, aged 18-75 yrs. old (μ = 37.2; SD = 12.3), from the curated ENIGMA Bipolar Disorder working group (ENIGMA-BD) and leveraging an ENIGMA machine learning model previously trained and validated using independent samples. Chronological age was subtracted from predicted age to produce an individual-level estimate known as brain-PAD. Linear mixed models (adjusting for sex and age as fixed effects and site as a random effect) were used to examine group differences and clinical associations. RESULTS: BD was associated with higher brain-PAD, compared to HC, primarily among older patients, as demonstrated by a significant age by diagnosis interaction (+0.05 [SE: 0.02] years). Individuals with BD on antiepileptic (AED) medications only (+3.20 [SE: 0.78] years) or on both AED and second-generation antipsychotics (SGA) (+3.74 [SE: 0.89] years) demonstrated greater brain-PAD compared to individuals who were not on any of the examined medications. Those taking lithium, whether alone or with AED and SGA independently, showed no difference in brain-PAD compared to individuals not taking any of the examined medications. However, individuals who were taking lithium showed lower brain-PAD compared to those on AED (-4.48 [SE: 0.84] years) or AED and SGA (-5.01 [SE:0.92] years). Individuals with a BD I subtype diagnosis had a higher brain-PAD (+1.50 [SE:0.55] years) compared to those with BDII or subtypes that are not otherwise specified (NOS). CONCLUSIONS: Results from this study suggest compounding effects of BD diagnosis and older age on brain-PAD, an ML-derived summary metric of structural alterations. Within BD, brain-PAD was differentially related to medication use, consistent with prior findings from ENIGMA-BD. Notably, AED use was generally related to more advanced brain age. Lithium use, alone or in combination with other medications, was not associated with advanced brain age, suggesting a possible neuroprotective effect of lithium. Brain-PAD as an ML-derived summary metric of structural alterations of the brain may provide clinical utility in assessing long-term holistic brain health to monitor the effectiveness of lifestyle modifications or treatments over time. LIMITATIONS: The cross-sectional nature of the study design and the limited granularity of the clinical data limit interpretation. Longitudinal studies with detailed chronicity data, medications and clinical measures overtime will improve brain-PAD modeling in BD.
15 June 2026
Read appraisal →BMC psychiatry
Olanzapine effectiveness on weight gain in anorexia nervosa patients: systematic review and meta-analysis
BACKGROUND: Anorexia nervosa (AN) is a complex psychiatric disorder marked by extreme caloric restriction, intense fear of weight gain, and distorted body image perception. Not only influence physical health, but it also creates serious psychological burdens. Treatment of AN is especially daunting due to its multi-dimensional nature. Recent research indicates that a pharmacological approach, such as the prescription of atypical antipsychotics like Olanzapine, may help treat both the nutritional deficiency and psychological distress related to the disorder. By allowing an individual gain weight and potentially reducing comorbid depression and anxiety, Olanzapine can be a valuable add-on to standard treatments. AIM: This study aims to investigate the effectiveness of Olanzapine in causing weight gain among anorexia nervosa patients. Based on comparisons of results in a number of clinical trials, the study aims at establishing the effect of Olanzapine on weight restoration and investigating any accompanying shift in the psychological state of the patients. METHOD: A comprehensive literature search was performed on Medline, ClinicalTrials.gov, Scopus, and the Cochrane Database of Systematic Reviews for all records from the earliest date available through to August 22, 2024. Randomized controlled trials of olanzapine treatment in anorexia nervosa were included. Studies were screened, and data were extracted. Risk of bias was assessed with the Cochrane risk-of-bias tool. Records for meta-analysis were combined in a random-effects model to calculate effect sizes, and heterogeneity was quantified with the I2 statistic. RESULT: 207 records were found, 159 of which were excluded after title and abstract screening. After full-text review, seven RCTs were found. These trials involving 152 patients assessed the impact of olanzapine on weight gain in anorexia nervosa. Meta-analysis of 4 studies (91 patients) showed a mean difference in BMI of 1.68 kg/m² (95% CI: 0.82, 4.18) in favor of olanzapine but not statistically significant (p = 0.19), with high heterogeneity (I² = 94%). Sensitivity analysis reduced the heterogeneity to 28% but not the effect size. CONCLUSION: Although olanzapine showed a numerically greater weight gain compared to control conditions, the pooled effect did not reach statistical significance and was associated with substantial heterogeneity. Therefore, current evidence remains inconclusive. Olanzapine may be considered in selected cases, particularly where psychological comorbidities are prominent, but larger and methodologically robust trials are needed before routine clinical use can be recommended. CLINICAL TRIAL NUMBER: Not Applicable.
21 May 2026
Read appraisal →Psychological medicine
Risk factors associated with blood dyscrasia during clozapine treatment: a systematic review and meta-analysis
Clozapine is the only effective treatment for treatment-resistant schizophrenia, but concerns over blood dyscrasia and need for monitoring limit its use. Evidence suggests many hematological abnormalities may result from surveillance bias, with agranulocytosis being the primary adverse effect directly induced by clozapine. This systematic review (PROSPERO: CRD42024487199) investigates non-genetic risk factors associated with blood dyscrasia during clozapine treatment, focusing on neutropenia and agranulocytosis. Random-effect meta-analyses were performed on studies reporting quantitative risk data. Due to inconsistent neutropenia definitions, analyses used absolute neutrophil count (ANC) thresholds of <2000/mm3, <1500/mm3, and <500/mm3. Forty-four studies were included in the systematic review, 15 in meta-analyses. No significant association was found between agranulocytosis and female gender (OR = 1.48, 95% CI: 0.92-2.38; p = 0.106) or age (pooled standardized mean difference [SMD] = 0.32, 95% CI: -0.26 to 0.90, p = 0.285), whilst a modest inverse association with clozapine dose (SMD = -0.32, 95%CI: -0.50 to -0.14, p < 0.001) and baseline white cell count (SMD = -0.21, 95%CI: -0.40 to -0.03, p = 0.026) was found. Neutropenia (ANC < 2000/mm3) was positively associated with concomitant psychotropic use (OR = 2.15, 95% CI: 1.13-4.07, p = 0.019). Clozapine rechallenge studies revealed no significant associations with gender, age, duration of initial clozapine trial, or length of discontinuation period prior to rechallenge. No strong predictors of clozapine-associated blood dyscrasia were identified. Findings may be limited by study variability, surveillance bias, and lack of consistent differentiation between agranulocytosis and milder neutropenia, highlighting limitations in current evidence.
13 May 2026
Read appraisal →Journal of affective disorders
Exploring temperamental and clinical predictors of lithium treatment outcomes in bipolar disorder using diverse machine learning approaches
BACKGROUND: Lithium is a core treatment for bipolar disorder (BD), yet clinical response varies across patients. Testing accessible predictors of lithium response is critical for personalization strategies in real-world settings. METHODS: In this cross-sectional study, 179 individuals with BD were assessed using a broad range of standardized clinical instruments and the Brief TEMPS-M to evaluate affective temperaments. Lithium response was retrospectively classified via the Alda Scale. Multivariate linear regressions and three supervised machine learning classifiers (random forest, elastic net, and XGBoost) were applied to identify predictors of treatment response. Class imbalance was addressed by down-sampling during training. RESULTS: Responders (12.3 % of participants) were more likely to be employed, diagnosed with BD-II, had fewer lifetime depressive and hypomanic episodes, fewer suicide attempts, and significantly lower anxious temperament scores. In multivariable models, lifetime psychotic and mixed features, as well as higher counts of hypomanic and manic episodes, were independently associated with poorer lithium response. Machine learning models confirmed the importance of these variables, possibly with remarkably high predictive validity (random forest AUC = 1.00; elastic net and XGBoost F1 = 0.86). Hyperthymic temperament was positively associated with lithium response, whereas cyclothymic and depressive traits were associated with poorer lithium response. CONCLUSIONS: The present exploratory study should be intended as a primer for larger samples and more balanced replication studies employing reliable machine learning techniques, allowing for firm conclusions about suggestive clinical predictors of lithium response in BD, and their complex interaction.
16 Apr 2026
Read appraisal →European journal of clinical pharmacology
Clozapine prescribing in treatment-resistant schizophrenia - an updated systematic literature review of barriers and facilitators among clinicians
BACKGROUND: Increased rates of clozapine prescribing are essential to improving timely patient access within treatment-resistant schizophrenia (TRS) management. The extent of geographical variation in its use suggests it is possible to develop interventions to increase clinician engagement. To inform intervention development, a contemporary review of barriers and facilitators to increased clozapine prescribing is required. We aimed to conduct a systematic review of research addressing barriers and facilitators to clozapine prescribing among clinicians within TRS management. METHODS: The review was conducted in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. PubMed, Embase, CINAHL, and PsycINFO were searched from inception to July 2025. Results were synthesized qualitatively. RESULTS: Fifteen studies were included. Barriers related to clinicians, patients and carers, and healthcare institutions. Primary clinician-related barriers included insufficient knowledge of, and confidence in, managing clozapine treatment and the associated administrative burden. Primary patient-related barriers included concerns regarding patients' willingness to consistently adhere to clozapine treatment and associated monitoring requirements. A lack of dedicated systems of care to facilitate clozapine initiation and shared community care were the leading institutional barriers. Major facilitators included improved education for clinicians, access to point-of-care testing, and increased availability of dedicated clozapine clinics. CONCLUSION: Most barriers to systematically increasing clozapine prescribing rates are beyond the influence of individual prescribers. Instead, structural interventions focusing on (i) reducing the administrative burden associated with establishing clozapine treatment, (ii) increasing access to standardised training and supervision opportunities, and (iii) providing longitudinal support to clinicians when managing clozapine treatment, are required.
13 Apr 2026
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