Longitudinal Trajectory of the Link Between Ventral Striatum and Depression in Adolescence
The connectivity strength of the VS within the reward network showed distinct patterns of association with depressive disorders and anhedonia from mid to late adolescence, suggesting that the role of this circuitry in depression changes with age.
KEY FINDINGS: The connectivity strength of the VS within the reward network showed distinct patterns of association with depressive disorders and anhedonia from mid to late adolescence, suggesting that the role of this circuitry in depression changes with age. This study replicates, in an independent sample, the association between the VS and depression previously reported in younger adolescents. The findings suggest a role of VS connectivityrw in anhedonia but not in low mood.
BACKGROUND: Research in adolescent depression has found aberrant intrinsic functional connectivity (iFC) among the ventral striatum (VS) and several brain regions implicated in reward processing. The present study probes this question by taking advantage of the availability of data from a large youth cohort, the IMAGEN Consortium.
DETAILS: iFC data from 303 adolescents (48% of them female) were used to examine associations of VS connectivity at baseline (at age 14) with depressive disorders at baseline and at 2-year (N=250) and 4-year (N=219) follow-ups. Eleven regions of interest, key nodes of the reward system, were used to probe the reward network and calculate the connectivity strength of the VS within this network (VS connectivityrw). The main analyses assessed associations of VS connectivityrw with depressive disorders, anhedonia, and low mood using logistic regression. Autoregressive models accounting for carryover effects over time were conducted to further evaluate these brain-behavior associations. Higher right VS connectivityrw was associated with higher probability of depressive disorders at baseline (odds ratio=2.65, 95% CI=1.40, 5.05). This finding was confirmed in the autoregressive model, adjusting for carryover effects of the depressive disorders across the three time points. VS connectivityrw was not predictive of depressive disorders at follow-up assessments. Longitudinal associations between VS connectivityrw and anhedonia emerged in the structural equation model: left VS connectivityrw was associated with anhedonia at 2 years (odds ratio=2.20, 95% CI=1.54, 3.14), and right VS connectivityrw was linked to anhedonia at 4 years (odds ratio=1.87, 95% CI=1.09, 3.21). VS connectivityrw did not predict low mood at any time point in the structural equation model.
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Source: Pan, P. M., Sato, J. R., Martinot, M. P.,, et al. (2022). Longitudinal Trajectory of the Link Between Ventral Striatum and Depression in Adolescence. Am J Psychiatry. 2022; 179(7): 470-481. Published: July, 2022. DOI: 10.1176/appi.ajp.20081180.
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.
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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.
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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.
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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.
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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.
Self-Sampling HPV Testing Increases Cervical Cancer Screening Uptake in Primary Care
A Singapore randomized trial found that offering HPV self-sampling increased cervical cancer screening uptake from 42.8% to 56.6%. More than half of screened women chose self-sampling, suggesting that flexible screening options may help reach women who otherwise remain unscreened.
KEY FINDINGS: Offering HPV self-sampling as an additional screening option substantially increased cervical cancer screening participation and high-risk HPV detection compared with clinician sampling alone in this Singapore primary care population. The benefit was particularly relevant to women who had never previously undergone screening, suggesting that providing greater choice and convenience may help reach populations that are otherwise difficult to engage. More than half of screened women in the intervention group selected self-sampling, indicating substantial acceptance of this approach. However, lower uptake among women with less educational attainment highlights the need for targeted education and engagement strategies when implementing self-sampling programs.
BACKGROUND: Cervical cancer screening remains suboptimal in Singapore, where clinician-collected HPV testing has been the standard approach. Concerns related to discomfort, privacy, embarrassment, or the clinical setting may discourage some women from participating in screening. This pragmatic randomized controlled trial evaluated whether offering self-sampling for HPV DNA testing alongside clinician sampling could increase cervical cancer screening uptake and detection of high-risk human papillomavirus (HPV) compared with clinician sampling alone.
DETAILS: The open-label, 2-arm randomized controlled trial used a Zelen design and was conducted across National Healthcare Group Polyclinics in Singapore. Women aged 30-69 years who were due for cervical cancer screening were randomly assigned 1:1 to an intervention group or usual care. Women in the intervention group were offered clinician sampling followed by self-sampling if they did not choose clinician sampling, whereas women receiving usual care were offered clinician sampling alone. The primary outcome was detection of high-risk HPV DNA, with screening uptake as the secondary outcome.
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Between August 2024 and February 2025, 650 women were randomized, with 640 participants included in the final analysis, 320 in each group. Subgroup analyses evaluated outcomes according to previous screening history, while multivariable analyses examined factors associated with screening choices.
High-risk HPV detection was significantly greater when self-sampling was offered alongside clinician sampling than with clinician sampling alone: 3.1% versus 0.3%, respectively, representing an absolute difference of 2.8% (95% CI, 0.8-4.8; P<.001). The higher detection rate was driven by greater screening participation, with screening uptake reaching 56.6% in the intervention group compared with 42.8% with usual care, an absolute difference of 13.8% (95% CI, 6.0-21.4; P<.001).
The increase in screening uptake was particularly evident among women who had no previous screening and those with a regular screening history. Among women who underwent screening in the intervention group, 56.4% selected self-sampling. Lower educational attainment was associated with lower odds of choosing self-sampling rather than declining screening altogether.
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Source: Ng, X. R., Quek, I. P., Pereira, M. J., et al. Effect of Self-Sampling HPV DNA Testing on Cervical Cancer Screening in Singapore's Primary Care: Pragmatic Randomized Controlled Trial Annals of Family Medicine.. 2026; 24(4): 291-300. Published: July, 2026. DOI: 10.1370/afm.250683.
Long-Term Outcomes of Azacitidine, Venetoclax, and Gilteritinib in Newly Diagnosed FLT3-Mutated Acute Myeloid Leukemia
In a phase II study of 30 patients with newly diagnosed FLT3-mutated AML, azacitidine, venetoclax, and gilteritinib produced a 96% CR/CRi rate. At a median follow-up of 41.5 months, median RFS and OS were 23.4 and 29.7 months, with 3-year rates of 43% and 46%, respectively. Baseline RAS pathway mutations were associated with poorer outcomes, while 67% of evaluable relapses lacked detectable FLT3 mutations. The triplet produced durable remissions but frequently required treatment dose or duration reductions because of myelosuppression.
KEY FINDINGS: In this phase II study, azacitidine, venetoclax, and gilteritinib produced high remission rates and encouraging long-term survival in patients with newly diagnosed FLT3-mutated AML who were unfit for intensive chemotherapy. The 3-year RFS and OS rates were 43% and 46%, respectively, although outcomes were less favorable in patients with FLT3-ITD mutations and baseline RAS pathway mutations. Most evaluable relapses were FLT3-negative, suggesting that resistance may involve mechanisms beyond persistent FLT3-mutated disease. Dose or duration reductions were frequently required during consolidation, primarily reflecting the challenge of managing myelosuppression. Randomized studies are needed to establish the role of this triplet regimen relative to current standard approaches.
BACKGROUND: Relapse after frontline azacitidine and venetoclax remains a major challenge in patients with FLT3-mutated acute myeloid leukemia (AML), with relapse often associated with expansion of FLT3-mutated clones. This phase II study evaluated the long-term efficacy and safety of adding the FLT3 inhibitor gilteritinib to azacitidine and venetoclax in adults with newly diagnosed FLT3-mutated AML who were considered unfit for intensive chemotherapy.
DETAILS: Thirty patients with newly diagnosed FLT3-mutated AML were treated with the azacitidine, venetoclax, and gilteritinib triplet regimen. The median age was 71 years, and 22 (73%) patients had FLT3-ITD mutations. Fourteen patients (47%) proceeded to allogeneic hematopoietic stem cell transplantation in first remission. The median follow-up was 41.5 months.
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The complete remission or complete remission with incomplete hematologic recovery rate was 96%. Eleven patients (37%) subsequently relapsed, and among evaluable relapses, the FLT3 mutation was no longer detectable in 67%, indicating that relapse mechanisms were not necessarily driven by persistent FLT3-mutated disease.
The median relapse-free survival (RFS) was 23.4 months and median overall survival (OS) was 29.7 months. At 3 years, RFS was 43% and OS was 46%. Among patients with FLT3-ITD-mutated AML, median RFS and OS were 17.0 months and 21.8 months, respectively, with 3-year RFS and OS rates of 32% and 36%. Baseline RAS pathway mutations were associated with poorer outcomes.
Survival outcomes were similar regardless of whether patients underwent allogeneic hematopoietic stem cell transplantation in first remission. Among patients receiving at least one consolidation cycle, 68% required a reduction in the dose or duration of at least one study drug, highlighting the need to manage treatment-related myelosuppression during prolonged therapy.
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Source: Short, N. J., Kantarjian, H. M., Daver, N., et al. Long-Term Outcomes of Azacitidine, Venetoclax and Gilteritinib in Newly Diagnosed FLT3-Mutated AML. Blood Advances.. 2026; 10(17): 5743–5750. Published: May 27, 2026. DOI: 10.1182/bloodadvances.2026019841.
[Posted 2/Sep/2026]
AUDIENCE: Hematology, Oncology
KEY FINDINGS: In this phase II study, azacitidine, venetoclax, and gilteritinib produced high remission rates and encouraging long-term survival in patients with newly diagnosed FLT3-mutated AML who were unfit for intensive chemotherapy. The 3-year RFS and OS rates were 43% and 46%, respectively, although outcomes were less favorable in patients with FLT3-ITD mutations and baseline RAS pathway mutations. Most evaluable relapses were FLT3-negative, suggesting that resistance may involve mechanisms beyond persistent FLT3-mutated disease. Dose or duration reductions were frequently required during consolidation, primarily reflecting the challenge of managing myelosuppression. Randomized studies are needed to establish the role of this triplet regimen relative to current standard approaches.
BACKGROUND: Relapse after frontline azacitidine and venetoclax remains a major challenge in patients with FLT3-mutated acute myeloid leukemia (AML), with relapse often associated with expansion of FLT3-mutated clones. This phase II study evaluated the long-term efficacy and safety of adding the FLT3 inhibitor gilteritinib to azacitidine and venetoclax in adults with newly diagnosed FLT3-mutated AML who were considered unfit for intensive chemotherapy.
DETAILS: Thirty patients with newly diagnosed FLT3-mutated AML were treated with the azacitidine, venetoclax, and gilteritinib triplet regimen. The median age was 71 years, and 22 (73%) patients had FLT3-ITD mutations. Fourteen patients (47%) proceeded to allogeneic hematopoietic stem cell transplantation in first remission. The median follow-up was 41.5 months.
The complete remission or complete remission with incomplete hematologic recovery rate was 96%. Eleven patients (37%) subsequently relapsed, and among evaluable relapses, the FLT3 mutation was no longer detectable in 67%, indicating that relapse mechanisms were not necessarily driven by persistent FLT3-mutated disease.
The median relapse-free survival (RFS) was 23.4 months and median overall survival (OS) was 29.7 months. At 3 years, RFS was 43% and OS was 46%. Among patients with FLT3-ITD-mutated AML, median RFS and OS were 17.0 months and 21.8 months, respectively, with 3-year RFS and OS rates of 32% and 36%. Baseline RAS pathway mutations were associated with poorer outcomes.
Survival outcomes were similar regardless of whether patients underwent allogeneic hematopoietic stem cell transplantation in first remission. Among patients receiving at least one consolidation cycle, 68% required a reduction in the dose or duration of at least one study drug, highlighting the need to manage treatment-related myelosuppression during prolonged therapy.
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Source: Short, N. J., Kantarjian, H. M., Daver, N., et al. Long-Term Outcomes of Azacitidine, Venetoclax and Gilteritinib in Newly Diagnosed FLT3-Mutated AML. Blood Advances.. 2026; 10(17): 5743–5750. Published: May 27, 2026. DOI: 10.1182/bloodadvances.2026019841.
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