Efficacy of Clozapine Versus Second-Generation Antipsychotics in People With Treatment-Resistant Schizophrenia
This IPD meta-analysis found a small and uncertain advantage of other second-generation antipsychotics, mainly olanzapine and risperidone, and so did not provide evidence for superior efficacy of clozapine compared with other second-generation antipsychotics in treatment-resistant schizophrenia. It is limited by unavailability of IPD for some studies, uncaptured sources of variance, and uncertainty due to premature study discontinuation.
Summary
A Systematic Review and Individual Patient Data Meta-Analysis
[Posted 7/Apr/2025]
AUDIENCE: Psychiatry, Family Medicine
KEY FINDINGS: This IPD meta-analysis found a small and uncertain advantage of other second-generation antipsychotics, mainly olanzapine and risperidone, and so did not provide evidence for superior efficacy of clozapine compared with other second-generation antipsychotics in treatment-resistant schizophrenia. It is limited by unavailability of IPD for some studies, uncaptured sources of variance, and uncertainty due to premature study discontinuation. Given the side-effects of clozapine, the observed uncertainty regarding clozapine's superiority warrants prudent use and further research.
BACKGROUND: Clozapine is recommended by national and international guidelines for people with treatment-resistant schizophrenia. However, available meta-analyses of randomised controlled trials have not shown superior efficacy of clozapine when compared with other second-generation antipsychotics, with heterogeneity identified between the original studies. Authors aimed to use individual patient data (IPD) to account for potential reasons of variability and to synthesise an adjusted estimate for the difference in efficacy between clozapine and other second-generation antipsychotics for treatment-resistant schizophrenia.
DETAILS: In this systematic review and IPD meta-analysis, authors searched the Cochrane Schizophrenia Group's Study-Based Register from inception to Jan 24, 2024, and previous reviews for blinded randomised controlled trials comparing clozapine with other second-generation antipsychotics in participants with treatment-resistant schizophrenia. Trials were eligible if they included patients with treatment-resistant schizophrenia and had a duration of at least 6 weeks. IPD were requested from trial investigators. The primary outcome was change in overall schizophrenia symptoms as measured by the Positive and Negative Syndrome Scale (PANSS) between clozapine and other second-generation antipsychotics after 6-8 weeks of treatment. The effect size measure for the primary outcome was mean difference with 95% credible interval (CrI). Authors fitted a Bayesian random-effects IPD meta-regression model that included duration of illness, baseline severity, and sex as potential prognostic factors or treatment effect modifiers. Confidence in the evidence was assessed using Grading of Recommendations, Assessment, Development, and Evaluation (GRADE). People with lived experience of mental illness were involved in this study. Authors screened 13 876 references and included 19 studies with data for 1599 participants; IPD were available for 12 of 19 trials (n=1052; mean age 37.67 years [SD 11.24; range 10-66]; 348 [33.08%] women and 704 [66.92%] men). Data on ethnicity were not available. The estimated mean difference in change from baseline PANSS total score was -0.64 points (95% CrI -3.97 to 2.63; τ=2.68) in favour of other second-generation antipsychotics. Shorter duration of illness and higher baseline severity were prognostic factors associated with a larger reduction in symptoms, but neither those factors nor sex were found to modify the relative effect between clozapine and other second-generation antipsychotics. The confidence in the evidence was graded as very low.
Our Most Popular Resources
Copyright © The Author(s). Published by Elsevier Ltd. All rights reserved.
Source: Schneider-Thoma, J., Hamza, T., Chalkoi, K., et al. (2025). Efficacy of Clozapine Versus Second-Generation Antipsychotics in People With Treatment-Resistant Schizophrenia: A Systematic Review and Individual Patient Data Meta-Analysis. The Lancet Psychiatry. 2025; 12(4): 254-265. Published: April, 2025. DOI: 10.1016/S2215-0366(25)00001-X.
Depressive Symptoms Associated With Cognitive Impairment in Cerebral Amyloid Angiopathy
A study of 168 adults found that patients with cerebral amyloid angiopathy had substantially more depressive symptoms and poorer cognitive performance than cognitively normal controls. Possible depression was associated with impairment in episodic memory, executive function, and processing speed, and partially mediated the relationship between CAA and cognition. Greater depressive symptoms were also associated with MRI markers of cortical and small-vessel brain injury.
KEY FINDINGS: People with CAA in this study had substantially more depressive symptoms and poorer cognitive performance than cognitively normal controls. Depressive symptoms explained a small but significant portion of the association between CAA and impairment in episodic memory and executive function, suggesting that mood symptoms may contribute to cognitive difficulties in CAA. Greater depressive symptom severity was also associated with MRI markers of cortical and small-vessel brain injury. Because the study was cross-sectional, the findings do not establish whether CAA-related brain injury causes depression or whether depressive symptoms contribute to subsequent cognitive decline.
BACKGROUND: Cerebral amyloid angiopathy (CAA), a small-vessel disease characterized by β-amyloid deposition in cerebral vessel walls, is associated with cognitive impairment and dementia. Depression can independently affect memory and executive function, but the relationship between depressive symptoms, CAA-related brain injury, and cognition has been less clearly defined. This study examined whether depressive symptoms were associated with cognitive performance in people with CAA and whether depression helped explain the relationship between CAA and cognitive impairment.
DETAILS: Researchers analyzed baseline data from a prospective longitudinal cohort recruited through memory and stroke-prevention clinics at two Canadian centers. The analysis included adults aged ≥55 years with probable CAA and cognitively normal controls. Cognitive performance was evaluated across episodic memory, executive function, and processing speed, while depressive symptoms were assessed using the 15-item Geriatric Depression Scale (GDS-15). A score ≥5 was classified as "possible depression." The primary analysis included 168 participants: 85 with CAA and 83 cognitively normal controls. The mean age was 73.5 years among participants with CAA and 68.8 years among controls. Additional analyses exam-ined relationships between depressive symptoms and CAA-related MRI markers in 81 participants with CAA.
Our Most Popular Resources
Participants with CAA had substantially higher odds of possible depression than controls, with an odds ratio of 15.71 (95% CI, 4.26-80.05; P<0.001). Their GDS-15 scores were also 2.71 times higher than those of controls (95% CI, 2.10-3.51; P<0.001). Possible depression was associated with poorer performance across all three cognitive domains. After adjustment for age, sex, and education, associations were observed for episodic memory (β=-1.03; 95% CI, -1.53 to -0.53; P<0.001), executive function (β=-1.11; 95% CI, -1.65 to -0.58; P<0.001), and processing speed (β=-0.73; 95% CI, -1.24 to -0.21; P=0.006). Mediation analysis suggested that depressive symptoms accounted for 11% of the association between CAA and episodic memory and 9% of the association between CAA and executive function. No significant mediation was observed for processing speed, where depression accounted for approximately 2% of the association.
Among participants with CAA, greater depressive symptom severity was also associated with lower mean cortical thickness, cortical superficial siderosis, and a higher CAA-related small-vessel disease burden. Specifically, the count ratio was 1.33 (95% CI, 1.09-1.62; P=0.005) per SD decrease in cortical thickness, 2.04 (95% CI, 1.35-3.09; P<0.001) for cortical superficial siderosis, and 1.16 (95% CI, 1.00-1.35; P=0.047) for higher CAA small-vessel disease score.
Copyright © Skyscape. All rights reserved.
Source: Nukala, N., Muir, R. T., Beaudin, A. E., et al. Associations Between Cerebral Amyloid Angiopathy, Cognitive Impairment, and Depressive Symptoms. Neurology. 2026; 107(5): e218354. Published: September, 2026. DOI: 10.1212/WNL.0000000000218354.
Real-World Study Finds No Significant Difference in Heart Failure Risk Between Biosimilar and Reference Trastuzumab
In real-world practice, trastuzumab biosimilars were not associated with a statistically significant increase in heart failure compared with reference trastuzumab, supporting their cardiac safety. However, older age, anthracycline use, and greater comorbidity burden remain important risk factors, and larger studies are needed to assess cardiac safety differences among individual biosimilars.
KEY FINDINGS: In this large real-world cohort of patients with early-stage HER2-positive breast cancer, biosimilar trastuzumab use increased markedly between 2018 and 2024 without a statistically significant difference in heart failure risk compared with reference trastuzumab. Overall heart failure occurred in 5.9% of the study population. Comorbidity burden and older age were associated with higher heart failure risk, emphasizing the importance of cardiovascular risk assessment during HER2-directed therapy. Because this was a retrospective claims-based study, longer follow-up and additional real-world studies are needed to further evaluate long-term cardiac outcomes.
BACKGROUND: Trastuzumab is an important treatment for HER2-positive breast cancer, but cardiac dysfunction, including heart failure, remains a recognized safety concern. Biosimilar trastuzumab products have expanded treatment access and may reduce costs, although real-world data comparing their cardiac safety with the reference product remain limited. This study evaluated the uptake of biosimilar trastuzumab and compared heart failure risk between patients receiving biosimilar and reference trastuzumab in routine clinical practice.
DETAILS: The investigators analyzed patients aged ≥18 years with breast cancer who received trastuzumab between 2018 and 2024 using the IQVIA PharMetrics Plus Closed Health Plan Claims database. Patients who underwent breast cancer surgery within the first year after diagnosis were considered to have early-stage disease. Individuals with a heart failure diagnosis before breast cancer surgery were excluded. Trastuzumab products were identified using Healthcare Common Procedure Coding System Level II codes, while heart failure was identified using International Classification of Diseases codes. The analysis used multivariable cause-specific Cox proportional hazards regression to evaluate the association between trastuzumab type and subsequent heart failure risk. The study included 5,135 patients, of whom 43.9% received reference trastuzumab.
Our Most Popular Resources
Use of biosimilar trastuzumab increased substantially during the study period, from 0% in 2018 to 71.3% in 2024 (P<0.001). Overall, heart failure occurred in 5.9% of patients, including 5.5% of those receiving reference trastuzumab and 6.3% of those receiving biosimilar trastuzumab (P=0.26). After adjustment for relevant factors, there was no statistically significant difference in heart failure risk between biosimilar and reference trastuzumab (adjusted HR, 1.16; 95% CI, 0.92-1.46). In contrast, patients with a Charlson Comorbidity Index score ≥2 had a higher heart failure risk than those with a score of 0 (adjusted HR, 1.52; 95% CI, 1.11-2.08). Older age was also associated with greater risk: compared with patients aged 18-54 years, the adjusted HR was 1.61 (95% CI, 1.19-2.19) for those aged 65-74 years and 1.95 (95% CI, 1.29-2.96) for those aged ≥75 years.
Copyright © Skyscape. All rights reserved.
Source: Jackson, I., Zhang, N., Sullivan, M., et al. Real-World Cardiotoxicity of Biosimilar versus Reference Trastuzumab in Early HER2-Positive Breast Cancer. JACC: CardioOncology. Published: September 10, 2026. DOI: 10.1016/j.jaccao.2026.07.009.
A Pragmatic SMART Study of Medication and CBT Sequencing in Pediatric Anxiety Disorders
Fluoxetine and exposure-based CBT showed broadly comparable improvement over 24 weeks. Among those remaining symptomatic, CBT followed by combination therapy showed the strongest overall improvement pattern.
KEY FINDINGS: In this pragmatic study of clinically complex and demographically diverse youths, fluoxetine and exposure-based CBT produced broadly comparable improvement in anxiety symptoms over 24 weeks. For patients who remained symptomatic after 12 weeks, adding the alternate treatment generally showed a tendency toward greater improvement than optimizing monotherapy, although the overall differences were small and did not establish combination therapy as superior on the primary outcome. The CBT→combination sequence produced the strongest overall pattern of improvement across anxiety severity and functional impairment measures. Treatment response also varied across racial and ethnic groups, with Non-Hispanic White youths showing greater benefit from fluoxetine-based treatment sequences on some parent- and youth-reported secondary outcomes, whereas racial and ethnic minority youths showed greater benefit from transition to combination therapy on selected measures.
BACKGROUND: Choosing between medication and cognitive-behavioral therapy (CBT) as the initial treatment for pediatric anxiety disorders, and determining how to proceed when symptoms persist, remains clinically challenging. This pragmatic randomized trial evaluated whether initiating treatment with fluoxetine or exposure-based CBT produced better outcomes and whether adding the alternate treatment was more effective than continuing the initial therapy when remission was not achieved after 12 weeks.
DETAILS: This 24-week, single-blind sequential multiple assignment randomized trial included 316 youths aged 8-17 years with DSM-5 anxiety disorders, significant anxiety symptoms, and functional impairment. Participants were initially randomized to 12 weeks of fluoxetine or weekly exposure-based "Coping Cat" CBT. Fluoxetine dosing ranged from 10 to 80 mg/day. Youths who did not achieve remission after 12 weeks were subsequently randomized to either optimization of their initial treatment or optimization plus addition of the other modality. Outcomes included youth- and parent-reported 41-item Screen for Child Anxiety Related Emotional Disorders (SCARED) scores and Childhood Anxiety Impact Scale (CAIS) scores. The study was conducted in primary care and community mental health settings and included youths with substantial sociodemographic disadvantage and co-occurring mental health conditions.
Our Most Popular Resources
Youth-reported SCARED scores decreased by 31.7% over 24 weeks, from 42.9 at baseline to 29.31 at study endpoint. Improvement did not differ significantly between initial fluoxetine and CBT, although CBT showed a nonsignificant numerical advantage, with a 24-week difference in mean group change of 1.45 (95% CI=-2.25, 5.16). Among participants who did not remit by week 12, combination treatment was not significantly superior to continued optimized monotherapy for youth-reported anxiety at week 24 (group difference in mean change from baseline: -2.74, 95% CI=-6.53, 1.05).
Exploratory analyses of treatment sequences found that CBT followed by combination therapy produced the greatest overall improvement across the primary and secondary outcomes, although youth-reported SCARED scores did not differ significantly between individual sequences at week 24. Parent-reported SCARED scores declined by 37.8%, from 38.9 to 24.2, over 24 weeks. Parent ratings showed faster improvement with initial fluoxetine at weeks 6 and 12, while youth-reported CAIS scores favored initial CBT by week 24. Reduced appetite was more frequent with medication during both treatment stages, occurring in 43.7% versus 32.3% during stage 1 (p<0.05) and in 17.3% with med→med, 3.6% with CBT→CBT, and 12.1% with combination treatment during stage 2 (p=0.013). Serious or unexpected adverse events were rare.
Copyright © Skyscape. All rights reserved.
Source: Peterson, B. S., West, A. E., Weersing, V. R., et al. A Pragmatic SMART Study of Medication and CBT Sequencing in Pediatric Anxiety Disorders: A Randomized Clinical Trial. American Journal of Psychiatry. 2026; 183(9): 668-681. Published: September, 2026. DOI: 10.1176/appi.ajp.20251037.
TMS Sites Associated With Nicotine Addiction Improvement Converge on a Common Brain Circuit
A study indicates that that TMS sites more strongly connected to a brain circuit linked to nicotine-addiction remission were associated with greater improvement in withdrawal symptoms. Data showed convergence between TMS and lesion-based brain circuits. The findings identify potential targets in the frontopolar, posterior parietal, lateral temporal, and superior frontal regions for future TMS research in nicotine addiction.
KEY FINDINGS: The findings indicate that brain regions associated with improvement in nicotine addiction through TMS and lesions converge on a common functional brain circuit. Rather than relying solely on stimulation of an individual anatomical region, connectivity with this circuit may help guide selection of TMS targets for nicotine addiction. The identified circuit provides a testable framework for future neuromodulation studies. However, the study demonstrates an association between TMS-site connectivity and withdrawal improvement and does not establish that targeting these regions will improve long-term smoking cessation outcomes.
BACKGROUND: Transcranial magnetic stimulation (TMS) is an established neuromodulation approach for smoking cessation, but the optimal brain region to target for nicotine addiction remains uncertain. Previous lesion-mapping research identified a brain circuit associated with remission of nicotine addiction. This study investigated whether TMS sites connected to that lesion-derived circuit were also associated with greater improvement in nicotine withdrawal symptoms.
DETAILS: The study included 72 participants with tobacco use disorder who abstained from smoking for at least 12 hours before TMS assessment. TMS was delivered to four left-hemisphere regions-the dorsolateral prefrontal cortex, superior frontal gyrus, posterior parietal cortex, and visual cortex-across separate sessions, producing a total of 243 stimulation sites.
Our Most Popular Resources
Nicotine withdrawal was assessed before and after each TMS session using the Shiffman-Jarvik Withdrawal Scale. The investigators used a normative functional-connectivity dataset derived from 1,000 healthy individuals to determine how strongly each stimulation site was connected with the previously identified lesion-based nicotine-addiction remission circuit. They then examined whether this connectivity predicted improvement in withdrawal symptoms.
Greater connectivity between the TMS stimulation site and the lesion-derived addiction-remission circuit was significantly associated with greater improvement in nicotine withdrawal symptoms. The association remained significant after adjustment for sex, baseline nicotine dependence, or both factors simultaneously.
A data-driven TMS circuit associated with withdrawal improvement showed substantial correspondence with the lesion-based remission circuit, with a Pearson correlation of r=-0.74. Combining the lesion and TMS findings identified potential therapeutic targets involving the frontopolar cortex, posterior parietal cortex, lateral temporal lobe, and superior frontal gyrus.
Copyright © Skyscape. All rights reserved.
Source: Khosravani, S., Drew, W., Apostol, M. R., et al. Convergence of TMS Sites and Lesion Locations Associated With Nicotine Addiction Improvement on a Common Brain Circuit.. American Journal of Psychiatry. 2026; 183(9): 646-656. Published: September, 2026. DOI: 10.1176/appi.ajp.20250855.
Specialty: