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Adding antidepressants raises serious rhythm risk Starting selective serotonin reuptake inhibitor antidepressants while taking an antipsychotic was linked to higher risk of dangerous heart rhythm problems or sudden death, though events were rare.
*Retrospective cohort study (target-trial emulation); Level 2b (OCEBM).

Citation

Chien H-T, Lin S-W, Kung T-J, et al. Ventricular Arrhythmia and Sudden Death Risk With Concomitant Antipsychotic and Selective Serotonin Reuptake Inhibitor Use. JAMA Network Open. 2026;9(4):e266028. doi:10.1001/jamanetworkopen.2026.6028

Background

Antipsychotics and some antidepressants can affect the heart’s electrical system. Whether combining them increases dangerous rhythm problems or sudden death has had limited real-world evidence.

Patients

Adults (18+) with a recorded psychotic disorder starting an outpatient antipsychotic in the US (2010-2023) or Taiwan (2010-2021); excluded if they used these antidepressants in the prior year or had prior dangerous rhythm problems or sudden death.

Intervention

Starting a selective serotonin reuptake inhibitor antidepressant within 52 weeks after antipsychotic start.

Control

Continuing antipsychotic treatment without starting that antidepressant class.

Outcome

First dangerous heart rhythm problem or sudden death (combined outcome).

Follow-up Period

Up to 1 year.

Results

Comparison US relative risk over time (95% CI) Taiwan relative risk over time (95% CI)
Any selective serotonin reuptake inhibitor antidepressant added vs not added (primary) 1.51 (1.04-2.19) 3.32 (2.26-4.88)
Citalopram or escitalopram added vs not added 2.20 (1.39-3.46) 2.84 (1.75-4.62)
Other drugs in this antidepressant class added vs not added NS 2.85 (1.79-4.54)
NS = not statistically significant.

Absolute risk was low: about 0.1% (US) and 0.2% (Taiwan). The reported absolute differences were roughly 1 per 10,000 (US) and 3 per 10,000 (Taiwan), implying approximate numbers needed to harm of 10,000 and 3,333, respectively.

Limitations

Observational claims data may miss important risk factors (for example, smoking or detailed clinical measurements). Events were rare, limiting precision and drug-by-drug comparisons. The combined outcome cannot show whether rhythm problems or sudden death drove results. Death recording in US data was incomplete after 2015, and intention-to-treat estimates were smaller than per-protocol estimates.

Funding

Taiwan National Science and Technology Council grant; Xin Chen Foundation scholarship; no funder role.

Clinical Application

When adding these antidepressants to antipsychotics, prefer lower-risk options and monitor closely (electrocardiogram, electrolytes), especially early and during dose changes.

Top Journal Rankings - July 2026

790 abstracts scored across 7 criteria. Click any article to expand criterion scores.
1. 8.4
Opioid agonist treatment and risk of mortality in French primary care: a nationwide, retrospective cohort study.
Overall: A very large national primary-care cohort links being on opioid agonist treatment—especially buprenorphine—to substantially lower mortality with precise estimates, though residual confounding and unreported harms limit causal certainty.
View 6 Criterion Scores
Primary-Care Relevance & Applicability 9.0
Directly evaluates opioid agonist treatment in a large national primary-care context, addressing a common, high-stakes outpatient management decision.
Validity, Bias Control & Precision 7.0
Very large, nationwide cohort with time-dependent exposure modeling and adjustment for multiple covariates plus tight confidence intervals, but the retrospective nonrandomized design leaves substantial potential for confounding/indication bias (noted by authors).
Patient-Oriented Outcomes 10.0
Primary endpoint is all-cause mortality with longer-term mortality and cause-specific deaths as secondary outcomes, all highly patient-important.
Magnitude of Net Benefit 9.0
Associations suggest a large mortality reduction while on OAT (e.g., adjusted HR 0.41 at 1 year with sizable absolute risk difference); harms and treatment burden are not quantified in the abstract, limiting full net-benefit accounting.
Implementability & Practicality 8.0
Intervention is standard medication treatment (not a specialized procedure) and explicitly studied in primary care; however, the abstract does not address operational barriers (access, monitoring, adherence, diversion risk, or policy constraints).
Practice-Changing Potential 7.5
The scale and consistency of mortality associations across time and causes could meaningfully reinforce and expand OAT use in routine care, but observational design and possible indication bias may temper immediate changes in practice or policy.
2. 7.8
Digital Self-Management of Symptoms and Quality of Life for Patients With Advanced Cancer: A Randomized Clinical Trial.
Overall: A large multicenter RCT reports improved quality of life and fewer unplanned hospitalizations with app-based symptom monitoring plus nurse follow-up, supporting a clinically meaningful, plausible-to-implement supportive care strategy, though setting, resource needs, and unreported harms/burden limit certainty about broad routine adoption.
View 6 Criterion Scores
Primary-Care Relevance & Applicability 7.0
Targets community-dwelling adults with advanced cancer and aims to reduce symptom burden and acute care use, which overlaps with generalist care and care coordination, but the intervention was delivered via palliative care clinics rather than typical primary-care settings.
Validity, Bias Control & Precision 8.5
Large multicenter randomized clinical trial (n=1214) with prespecified outcomes and 95% CIs reported; effect estimates are reasonably precise for the main outcomes, though blinding and attrition details are not provided in the abstract.
Patient-Oriented Outcomes 8.5
Primary outcome is health-related quality of life (EQ-5D-5L) and secondary outcomes include ED visits and hospitalizations—clearly patient-important outcomes; self-efficacy and ECOG are supportive but less direct.
Magnitude of Net Benefit 7.5
Shows meaningful between-group differences favoring the intervention for HRQOL and reduced unplanned hospitalization episodes/inpatient days; ED visits were not significantly different, and the abstract does not report harms, adverse effects, or patient/caregiver burden from app use.
Implementability & Practicality 7.0
Requires weekly digital symptom reporting, automated guidance, and nurse-led follow-up for alerts—feasible but implies staffing/workflow needs, technology access, and ongoing monitoring infrastructure that may limit easy scale-up in all settings.
Practice-Changing Potential 8.0
High-quality evidence that an app-plus-nurse follow-up model can maintain quality of life and reduce hospital use in advanced cancer could influence palliative/supportive care pathways, though generalizability beyond the studied clinic-based system and missing harms/burden data may temper immediate widespread adoption.
3. 7.7
Efficacy of Antiinflammatory Therapies for Adults With Non-Cystic Fibrosis Bronchiectasis: A Systematic Review and Network Meta-Analysis.
Overall: A relatively large, registered network meta-analysis of RCTs shows patient-important reductions in bronchiectasis exacerbations with macrolides and DPP-1 inhibitors and minimal reported harms, though some key estimates (notably severe exacerbations with macrolides) are imprecise and newer-agent practicality is less clear from the abstract.
View 6 Criterion Scores
Primary-Care Relevance & Applicability 7.0
Bronchiectasis is commonly co-managed in outpatient settings, and reducing exacerbations is a practical decision point, but CT-confirmed bronchiectasis and escalation to newer agents often involves specialist pathways.
Validity, Bias Control & Precision 8.5
Systematic review and network meta-analysis of randomized controlled trials (31 RCTs; N=4,092) with a registered protocol and effect estimates with CIs; some important imprecision is explicitly noted for severe exacerbations with macrolides.
Patient-Oriented Outcomes 8.5
Primary outcome (overall and severe exacerbation rates) is clearly patient-important; quality of life and functional capacity are included as secondary outcomes (though not fully reported in the abstract).
Magnitude of Net Benefit 8.0
Meaningful relative reductions in overall exacerbations are reported for macrolides (RR 0.44) and DPP-1 inhibitors (RR 0.73), with DPP-1 also reducing severe exacerbations (RR 0.70) and only trivial/small adverse events and discontinuations described.
Implementability & Practicality 7.0
Macrolides are widely available and straightforward to prescribe; DPP-1 inhibitors are less established in routine practice and may involve access/cost barriers not addressed in the abstract.
Practice-Changing Potential 7.0
Supports macrolides (already used in many settings) and suggests DPP-1 inhibitors as an additional option; the evidence appears moderate certainty for key findings but may still require guideline adoption and real-world uptake.
4. 7.6
One- versus two-sample fecal immunochemical testing for colorectal cancer screening: a systematic review and meta-analysis of participation, diagnostic performance, and cost-effectiveness.
Overall: This registered systematic review/meta-analysis in a common screening domain suggests one-sample FIT may improve participation and reduce colonoscopy burden with favorable cost-effectiveness, but limited reporting on study quality/precision and few patient-outcome endpoints beyond cancer detection moderate certainty and impact.
View 6 Criterion Scores
Primary-Care Relevance & Applicability 9.0
Directly addresses colorectal cancer screening strategy (FIT sampling) and downstream colonoscopy demand—core primary-care and population-screening decisions.
Validity, Bias Control & Precision 6.5
Systematic review/meta-analysis with prospective PROSPERO registration and large combined sample (n=45,888), but only five studies and the abstract reports p-values without 95% CIs or study quality/heterogeneity details, limiting confidence in precision and bias control.
Patient-Oriented Outcomes 6.0
Includes colorectal cancer detection (patient-important) and participation, but much of the comparison centers on test-performance metrics (sensitivity/specificity/PPV) and advanced neoplasia/adenoma rather than outcomes like mortality or morbidity.
Magnitude of Net Benefit 7.0
Findings suggest 1-FIT modestly improves participation and substantially reduces colonoscopy demand with favorable economic evaluations, while 2-FIT increases sensitivity/CRC detection but at the cost of more colonoscopies; absolute effect sizes are not provided.
Implementability & Practicality 9.0
Both strategies use widely available FIT; one-sample collection is simpler and likely less burdensome, and the abstract explicitly links results to colonoscopy capacity constraints and cost-effectiveness.
Practice-Changing Potential 8.0
Provides comparative evidence and an explicit recommendation favoring 1-FIT in resource-constrained settings, which could influence screening program protocols and primary-care workflows, though reliance on limited studies and lack of absolute effects may temper immediate change.
5. 7.5
Leisure-Time Physical Activity Is Associated With Reduced Risks of Mortality in Adults With General or Abdominal Obesity in Mexico.
Overall: A very large prospective Mexican cohort links higher leisure-time physical activity with lower mortality among adults with general/abdominal obesity, using patient-important outcomes and precise estimates, but observational confounding limits causal certainty and the findings mainly reinforce current lifestyle counseling rather than redefine care.
View 6 Criterion Scores
Primary-Care Relevance & Applicability 8.5
Addresses a very common primary-care problem (obesity) and a routine counseling/behavior target (leisure-time physical activity) linked to major outcomes.
Validity, Bias Control & Precision 6.5
Large, long prospective cohort with measured anthropometrics and adjusted Cox models, but exposure is self-reported activity and residual confounding/healthy-user bias remains likely in an observational design.
Patient-Oriented Outcomes 9.5
Uses hard patient-important endpoints: all-cause mortality and cause-specific cardiovascular and cancer mortality with many events over long follow-up.
Magnitude of Net Benefit 6.0
Reports attenuation of mortality risk (e.g., HR 1.40 to 1.18 for obesity class II with higher activity), suggesting clinically meaningful benefit, but absolute risk reduction and potential harms/burdens are not quantified.
Implementability & Practicality 9.0
Leisure-time physical activity counseling/prescription is broadly feasible in routine outpatient care with minimal equipment and low direct medical risk.
Practice-Changing Potential 5.5
Supports and strengthens existing advice to increase activity in obesity, but as observational evidence without a tested intervention it is less likely to change practice on its own.
6. 7.5
Exposure to Systemic Antimicrobials During Pregnancy and Risk of Miscarriage: A Population-Based Registry Study.
Overall: A large, methodologically careful registry cohort provides clinically relevant, patient-oriented miscarriage risk estimates by antimicrobial, but observational confounding limits certainty about causal harm and the size of actionable risk.
View 6 Criterion Scores
Primary-Care Relevance & Applicability 8.5
Antibiotic prescribing in early pregnancy is a common outpatient/primary-care decision, and the study directly addresses miscarriage risk by specific agents.
Validity, Bias Control & Precision 7.0
Very large, population-based registry cohort with time-varying exposure modeling, lag to reduce reverse causation, competing-risk handling, and bias analyses; however, it remains observational with likely residual confounding by indication (explicitly raised by authors).
Patient-Oriented Outcomes 9.0
Miscarriage and gestational age at miscarriage are clearly patient-important outcomes captured via multiple linked registries.
Magnitude of Net Benefit 6.0
Several antimicrobials show elevated relative risks (e.g., HR ~1.5–2.0), but the abstract emphasizes these associations may be driven by underlying infection and provides no absolute risk differences, limiting confidence in clinical impact.
Implementability & Practicality 8.0
Findings can be applied immediately to counseling and antibiotic selection in routine care without new tests, equipment, or complex workflows.
Practice-Changing Potential 6.5
Reassurance for commonly used agents (nitrofurantoin, pivmecillinam, amoxicillin) and caution for others could influence prescribing, but noncausal explanations and lack of absolute effects temper how strongly it should change practice.
7. 7.5
Pharmacological interventions for ADHD: a systematic review and dose-effect network meta-analysis.
Overall: A large, well-conducted RCT-based network meta-analysis provides actionable dosing-plateau and tolerability signals for common ADHD medications, but relies mainly on symptom scales and gives limited absolute effect quantification in the abstract.
View 6 Criterion Scores
Primary-Care Relevance & Applicability 8.0
ADHD medication selection and dose titration are common outpatient decisions relevant to generalists and shared-care models; includes both children/adolescents and adults across many drugs.
Validity, Bias Control & Precision 9.0
Systematic review and dose-effect network meta-analysis of double-blind RCTs with preregistration, risk-of-bias assessment, transitivity checks, and sensitivity analyses; large total sample, though some high-dose estimates had wide credible intervals.
Patient-Oriented Outcomes 6.5
Primary outcome is symptom efficacy on validated clinical scales (important but still scale-based), and tolerability is discontinuation due to adverse events; no direct functional, quality-of-life, or long-term outcomes reported in the abstract.
Magnitude of Net Benefit 6.0
Findings suggest clinically useful plateaus and dose-related discontinuation risks that could reduce harm from excessive escalation, but the abstract does not provide clear absolute effect sizes (e.g., NNT/ARD) for benefit or harm.
Implementability & Practicality 8.0
Applies to routinely used oral ADHD medications and directly informs day-to-day titration decisions without requiring new tests, equipment, or specialist-only infrastructure.
Practice-Changing Potential 7.5
Could meaningfully influence dosing strategies by discouraging ineffective escalation and highlighting thresholds where adverse-event discontinuation rises, with potential guideline impact; lack of explicit absolute benefits/harms tempers immediate 'do this Monday' clarity.
8. 7.5
Twenty-Three-Year Benefits of Sigmoidoscopy Screening for Colorectal Cancer : A Randomized Trial.
Overall: A very large randomized trial with long-term, patient-important outcomes shows sustained but modest absolute benefit from once-only sigmoidoscopy—mainly in men—while providing limited information on harms and practical tradeoffs.
View 6 Criterion Scores
Primary-Care Relevance & Applicability 9.0
Addresses a core primary-care decision (population CRC screening) in average-risk adults aged 50–64, with outcomes that matter to prevention practice.
Validity, Bias Control & Precision 9.0
Large randomized trial with intention-to-screen analysis and very long follow-up; effect estimates are precise with narrow confidence intervals, though participation was ~60–65% and registry follow-up is the main stated limitation.
Patient-Oriented Outcomes 9.0
Reports colorectal cancer incidence and colorectal cancer mortality over 23 years, which are directly patient-important outcomes.
Magnitude of Net Benefit 6.0
Shows modest absolute reductions overall (notably in men: 1.7% lower CRC incidence and 0.8% lower CRC death over 23 years), minimal/no mortality benefit in women, and the abstract does not report harms or downstream burdens.
Implementability & Practicality 6.0
Once-only sigmoidoscopy is scalable but still requires endoscopy capacity, trained staff, and patient participation; adding FIT did not improve benefit in this trial.
Practice-Changing Potential 6.0
Supports long-term effectiveness and clarifies sex-specific benefit, but sigmoidoscopy screening efficacy is already established and the incremental impact is mainly in duration and subgroup detail.
9. 7.4
Adverse Effects and Treatment Discontinuation of Blood Pressure-Lowering Drugs and Combinations: A Network Meta-Analysis.
Overall: A large, methodologically strong network meta-analysis of double-blind RCTs provides precise, primary-care–relevant estimates of short-term antihypertensive tolerability, but effects are modest and limited to short-term discontinuation/symptom outcomes.
View 6 Criterion Scores
Primary-Care Relevance & Applicability 9.0
Hypertension drug choice and tolerability are daily primary-care decisions, and the analysis directly compares major first-line classes and common combinations.
Validity, Bias Control & Precision 8.5
Large network meta-analysis of 716 double-blind RCTs (159,362 participants) with independent extraction and reported credible intervals; still limited by trial-level network assumptions and short follow-up (4–26 weeks).
Patient-Oriented Outcomes 7.0
Primary outcome (discontinuation due to adverse events) and symptom AEs (dizziness, headache, edema, cough) are patient-relevant, but no long-term cardiovascular outcomes or quality-of-life measures are reported.
Magnitude of Net Benefit 6.0
Absolute differences in discontinuation vs placebo are small (about −1.2% to +1.7%), and dizziness increased across regimens, suggesting modest net effects on tolerability rather than large clinically transformative benefits.
Implementability & Practicality 8.0
Findings are readily actionable because they compare widely available antihypertensive classes and combinations without requiring specialized testing or infrastructure.
Practice-Changing Potential 6.0
May influence class/combination selection when tolerability is a key issue (e.g., favoring ARB-containing regimens), but short-term trial data and modest absolute effects limit immediate practice-changing impact.
10. 7.4
Kidney and Survival Benefits of Semaglutide in Diabetes With Chronic Kidney Disease: FLOW Trial Cardiovascular Subgroup Analyses.
Overall: A large randomized placebo-controlled trial subgroup analysis suggests semaglutide meaningfully lowers CKD progression events and may reduce all-cause mortality across cardiovascular-risk subgroups, but incomplete reporting of harms and reliance on subgroup estimates temper certainty and real-world impact.
View 6 Criterion Scores
Primary-Care Relevance & Applicability 8.0
Type 2 diabetes with CKD is common in primary care, and adding a GLP-1 RA is a generalist decision (often shared with endocrinology/nephrology), with subgroup results framed around cardiovascular risk profiles clinicians routinely consider.
Validity, Bias Control & Precision 8.0
Randomized placebo-controlled trial population with large sample size (≈3,533) and time-to-event estimates with CIs; however, these are cardiovascular subgroup analyses, and several CIs cross 1.0, reducing certainty for subgroup-specific estimates.
Patient-Oriented Outcomes 7.0
Includes all-cause mortality (patient-important) and a kidney composite that appears partly driven by eGFR decline (more surrogate) alongside advanced CKD thresholds; the abstract does not fully specify all components of the primary kidney endpoint.
Magnitude of Net Benefit 7.5
Kidney outcome reductions are clinically meaningful with reported NNTs of 13–22 over 3 years in key subgroups, and mortality HRs are ~0.71–0.82 with some statistically significant results; harms, discontinuation, and treatment burden are not presented in the abstract, limiting net-benefit confidence.
Implementability & Practicality 6.0
Once-weekly subcutaneous semaglutide is widely available but requires injections, titration/monitoring for adverse effects, and often faces cost and insurance authorization barriers, which can impede routine uptake in primary care.
Practice-Changing Potential 8.0
Adds randomized evidence for kidney and survival benefits in a high-risk, common population and suggests consistency across cardiovascular-risk strata, which can strengthen guideline recommendations and prescribing decisions, though it is still a subgroup-focused analysis.
Score Guide: 9-10 Exceptional 7-8 Strong 5-6 Moderate 3-4 Weak 1-2 Poor
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