Electroconvulsive therapy (ECT) is associated with early benefits and with high response and remission rates in patients with depression; recovery from depression may, in turn, carry short- and long-term benefits. This article examines observational data on short- and long-term all-cause mortality, nonsuicide mortality, and suicide mortality following treatment of depression with ECT. To frame the subject in its proper context, a very large meta-analysis found that, relative to nondepressed or general population controls, depression was associated with a doubled risk of all-cause mortality, a tenfold risk of suicide mortality, and an increased risk of mortality in the presence of a wide range of medical comorbidities. All-cause mortality risks were also higher in psychotic depression relative to nonpsychotic depression and in treatment-resistant depression relative to depression that was not treatment-resistant. Three meta-analyses on mortality risks following ECT were published in 2025; these had partially, but not fully, overlapping datasets. The overall impression from these meta-analyses was that ECT-treated depressed cohorts were at lower risk of all-cause mortality, nonsuicide mortality, and natural cause mortality relative to comparison cohorts receiving treatments other than ECT. The all-cause mortality benefit was evident early as well as during long-term follow up. ECT-treated cohorts were also at lower risk of suicide mortality, though this finding appeared to be limited to the initial months posttreatment. Possible explanations for the findings are considered. Confounding by indication and confounding by severity of indication may also play a role, though more against ECT than in favor of ECT. Although cause-effect relationships cannot be asserted from observational studies, these findings encourage the use of ECT in depressed subjects for whom ECT is indicated. However, these findings cannot be extrapolated to all depressed samples.
Objective: To evaluate the benefit of pharmacotherapies for adults with co-occurring stimulant use disorder (StUD) and attention-deficit/hyperactivity disorder (ADHD) using network meta-analysis. Data Sources: Searches were conducted of PubMed, Embase, Scopus, Web of Science, and ClinicalTrials.gov from inception to February 2026, without language restrictions. Study Selection: Of 4,152 studies retrieved, 6 were included. These evaluated pharmacologic treatments in co-occurring StUD and ADHD, reporting stimulant use parameters and ADHD symptom-related outcomes. We excluded studies not including both disorders, reviews, and abstracts. Data Extraction: Data extracted included continuous abstinence from stimulants, negative urine toxicologies, and ADHD severity. Pharmacotherapies included methylphenidate (MPH), mixed amphetamine salt (MAS), and bupropion. Standardized mean differences (SMDs) or odds ratios (ORs) were calculated; treatment ranking probabilities were assessed using P-scores. Results: Higher-dose MPH and MAS were associated with superior outcomes. For continuous abstinence, MAS produced the greatest benefit versus placebo (OR=8.45; 95% CI, 2.55-27.98; P=.0005), with the 80-mg dose ranking highest in the network analysis (P-score=0.846). Similarly, pharmacotherapy increased the odds of negative urine tests (OR=1.65; 95% CI, 1.01-2.71; P=.05), and the highest MAS dose again ranked first (P-score=0.890). Regarding improvement in ADHD symptom severity (SMD=-0.59; 95% CI, -0.94 to -0.23; P=.001), the greatest reduction was observed with MPH 180 mg (P-score=0.899). Safety profiles for pharmacotherapies were comparable with placebo. Conclusions: Stimulant-based pharmacotherapies, particularly higher-dose MPH and MAS, were associated with superior outcomes for both stimulant-use indicators and ADHD symptoms. These findings support consideration of optimized stimulant dosing when treating co-occurring StUD and ADHD, though further trials are warranted to refine clinical recommendations.
Objective: Bipolar disorder (BD) greatly increases the risk of suicide. While lithium is recognized for reducing suicide and suicidal behaviors, evidence regarding its association with suicidal ideation remains limited. This study evaluated lithium's association with reduced suicidal ideation and behaviors among adolescents and adults with BD in China. Method: This multicenter, retrospective cohort study included participants aged 12-45 years from 15 psychiatric centers across mainland China who met DSM-IV criteria for BD, recruited between April 19, 2024, and November 30, 2024. Patients receiving lithium for ≥80% of the first 6 months in the preceding year formed the lithium group; those without lithium exposure served as controls. The primary outcome was suicidal ideation assessed by the Columbia-Suicide Severity Rating Scale; secondary outcomes included suicidal behaviors, nonsuicidal self-injury (NSSI), and aggression. Results: Of 603 screened patients, 585 (290 lithium; 295 controls) met inclusion criteria. At 1-year follow-up, lithium use was significantly associated with a lower likelihood of suicidal ideation (adjusted odds ratio [aOR] = 0.57, 95% CI = 0.38-0.86, P = .008) and suicidal behaviors (aOR= 0.60, 95% CI = 0.39-0.90, P = .02). No difference was observed in NSSI, while lithium users reported lower hostility scores (P = .01). Subgroup analyses indicated more pronounced protective associations among females, adults, higher-income individuals, and those without comorbid anxiety, rapid cycling, or predominantly depressive episodes, regardless of psychotic symptoms. Conclusions: Lithium was associated with a 40% lower risk of suicidal ideation and reduced suicidal behaviors in BD. These findings reinforce lithium as a first-line treatment for suicide prevention and highlight its comprehensive antisuicidal role-from lower rates of ideation to fewer behaviors-supporting confident, evidence-based clinical use.
Objective: Although the "Life's Essential 8" (LE8) proposed by the American Heart Association is a useful tool for assessing individuals' lifestyles and cardiovascular health, its relationship with suicidal behavior remains poorly understood. This study analyzed the relationship between LE8 levels and suicide mortality. Methods: This cohort study included 54,382 adults in South Korea who were matched to the National Death Registry between 2007 and 2022. The LE8 score, which ranges from 0 to 100, was calculated using 4 health behaviors and 4 biometric health factors. LE8 levels were classified into poor (0-49), intermediate (50-79), and ideal (80-100). Suicide mortality was defined as death due to intentional self-harm (ICD codes: X60-X84). Cox regressions were employed to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). Results: Among participants, 19.7% (n=10,703), 68.7% (n=37,346), and 11.6% (n=6,333) had ideal, intermediate, and poor LE8 scores, respectively. The median follow-up was 9.67 years, and the suicide mortality rate was 0.28 per 1,000 person-years. Compared with participants with an ideal LE8 score, those with a poor LE8 score had a higher risk of suicide mortality (HR: 2.49, 95% CI: 1.06-5.82), while the association for the intermediate LE8 score was not clear (HR: 1.83, 95% CI: 0.91-3.72). Additionally, among the subdimensions of the LE8 construct, the score for health behaviors had a stronger association with suicide mortality than did the score for biometric health factors. Conclusion: This cohort study found that poor LE8 scores were associated with a higher suicide risk among Korean adults.
Background: Clinical trials for antidepressants inform prescribing practices and clinical guidelines, but the demographic composition of the trial participants affects the generalizability. For this reason, the sex, race, and ethnicity reporting and participant composition in US antidepressant trials must be investigated. Methods: We searched ClinicalTrials.gov for completed US antidepressant trials conducted between January 1, 1993, and September 1, 2025. Data on trial characteristics and the reporting of sex, race, and ethnicity were extracted (n=166 trials). Normality of the observed trial-level sex distributions was assessed using the Shapiro-Wilk test. Paired t tests or Wilcoxon signed-rank tests were conducted to assess representation adequacy compared to annual state census data. Results: Sex was reported by 90.36% of trials, race by 39.16%, and ethnicity by 33.13%. Across trials reporting race or ethnicity, pooled participant proportions showed underrepresentation of Asian (4.13% vs 5.67% census, P<.001), American Indian/Alaska Native (AIAN, 0.44% vs 0.89%, P<.001), multiracial (1.90% vs 2.26%, P=.031), and Hispanic/Latino participants (12.42% vs 17.20%, P<.001). Across trials, female participants accounted for 58.27% of participants, which was significantly higher than the state-level benchmark but significantly lower than the benchmark female proportion among antidepressant users (P<.001). Conclusions: Reporting gaps persist and multiple minority racial/ethnic groups remain underrepresented in US antidepressant trials, limiting generalizability. Clearer reporting standards and targeted recruitment strategies are needed.
Objective: To evaluate and compare the obstetric risks associated with stimulant and nonstimulant medication use during pregnancy. Methods: This retrospective cohort study used TriNetX electronic health records from 894,986 pregnancies recorded between 2010 and 2023. Women aged 18-45 years were grouped by attention-deficit/hyperactivity disorder (ADHD) medication exposure during pregnancy: stimulant (n=3,465), nonstimulant (n=575), or no ADHD medication (n=890,946). Propensity score-based inverse probability of treatment weighting balanced demographic, substance use, medical, and mental health factors, including ADHD. Weighted logistic regression compared adverse pregnancy outcomes across groups. Results: Stimulant and nonstimulant use during pregnancy were both associated with increased risk for several obstetric complications compared to no medication, with increased-risk odds ratios ranging from 1.21 to 1.85 for stimulants and 1.12 to 5.70 for nonstimulants. Compared with nonstimulants, stimulants were associated with higher odds of placenta previa and large for gestational age but lower odds of gestational diabetes, placental abruption, intrauterine growth restriction, and preterm delivery. Conclusion: Stimulant and nonstimulant use during pregnancy were associated with increased obstetric risk. Given the observational electronic health record design, lack of an ADHD-unmedicated comparison group, and lack of adjustment for concomitant medication exposures, findings should be interpreted as potential safety signals rather than definitive causal estimates. Findings support individualized risk-benefit assessment and further research on ADHD treatment during pregnancy.
Ketamine can be administered in more than a dozen different ways for on-label and off-label indications. Oral ketamine, administered as a liquid repurposed from ketamine for injection, is one way in which ketamine is used to treat depression and chronic pain. Such repurposing may seem unorthodox but has been reported for at least the past 3 decades from many countries, including Canada, England, India, Israel, Japan, New Zealand, and the United States. Oral ketamine, thus administered, is noninvasive, and a safe and inexpensive option for medical practitioners who treat severe, suicidal, and/or treatment-resistant depression. It is safe because, when administered as a liquid in a glass of water or fruit juice, it can be sipped across 20-30 min; treatment-emergent dissociative, neurological, and other psychophysiological effects are thereby minimized. It is inexpensive because there are no costs associated with patented formulations, hospitalization, monitoring facilities, and additional personnel. Because of its simplicity, safety, and inexpensiveness, oral ketamine represents an opportunity for low-resource settings, especially in low- and middle-income countries. This article is intended to be a teaching article. It presents a brief theoretical background to the use of ketamine in the treatment of depression, justifies oral ketamine as an alternative to intranasal and intravenous routes of administration, explains clinical contexts in which the intervention can be used, and presents a detailed protocol for the use of oral ketamine. Matters considered are fitness for oral ketamine, consenting, facilities required, instructions on how to conduct the session, dosing, monitoring, ending the session, scheduling future sessions, continuation and maintenance therapy, domiciliary use, and many others. Drug interactions and concurrent medications are also discussed. This article is therefore a prescriber's guide to the use of oral racemic ketamine that could, it is hoped, make ketamine available in settings in which it is currently unavailable but needed.
Medications used by lactating mothers appear in breast milk to varying extents and are ingested by the breastfed infant. The degree of exposure of infants to maternal medication is therefore a matter of concern. Key clinical considerations are the absolute exposure of the infant to the drug, the infant's age and capacity to metabolize the drug, and the possible effects of drug exposure in the infant. In this context, the relative infant dose (RID) is a useful construct that helps predict infant exposure without requiring infant blood sampling. By definition, the RID estimates the dose of drug that a breastfed infant ingests per day relative to the dose that the mother receives per day; dosing is standardized per kg body weight, and breast milk intake is standardized at 150 mL/kg/d. A drug with an RID that is <10% is conventionally considered to be compatible with breastfeeding; however, this interpretation is nuanced. This article explains the RID using a worked example. Clinically important issues in the derivation, interpretation, and application of the RID are discussed. Matters considered include how maternal weight and infant weight influence the estimated RID, the need to consider active metabolites, and study-related issues such as sample size and breast milk sampling. Special situations examined include intermittent drug dosing and rescue dosing, dosing with drugs that have long half-lives, use of prodrugs or long-acting injections, and use of drugs that may be problematic regardless of dose. Examples of the RID are provided for ketamine and its active metabolite norketamine, lurasidone, and viloxazine. Readers need to be aware that there is more to the RID than just the arbitrary 10% cutoff.
Background: Attention-deficit/hyperactivity disorder (ADHD) is increasingly recognized among women of reproductive age. Little is known about time trends in maternal ADHD, and treatment utilization in this group. Methods: We conducted a cross-sectional time series analysis of all obstetrical deliveries in Ontario, Canada, from 2002-2023 (medication data available from 2014). Maternal ADHD was defined by inpatient or outpatient diagnosis within 10 years preconception. Stimulant medication use (amphetamine, dextroamphetamine, lisdexamfetamine, methylphenidate) was assessed via prescription fills in the year before pregnancy, during pregnancy, and stratified by trimester. We described the annual proportions of pregnancies with preconception maternal ADHD diagnoses and stimulant use patterns in this group. Results: Of 2,327,110 included pregnancies, the proportion of pregnancies with maternal ADHD rose from 0.5% to 2.5% from 2002 to 2023. Between 2014 and 2023, stimulant use increased from 21.8% to 39.8% in the year prior to pregnancy and from 10.1% to 20.9% during pregnancy among those with ADHD. Methylphenidate predominated early in the study period, but increases over time were largely driven by lisdexamfetamine. Approximately 75% of those prescribed a stimulant in the year prior to conception discontinued it prior to, or in, the first trimester of pregnancy, with stable time trends. Conclusions: The 4-fold increase in maternal ADHD in pregnancy over a 20-year period and 2-fold increase in the use of stimulant medication before and during pregnancy in this group underline the need for clinical guidance on managing ADHD in pregnancy.
Objective: To evaluate pharmacokinetics of viloxazine extended-release (ER) in breast milk and plasma of healthy lactating women and calculate potential infant exposure. Methods: Healthy lactating women (N=15), who were ≥12 weeks postpartum, received viloxazine ER 600 mg/d (the maximum recommended adult dose, given as 3x200 mg capsules) for 3 days at the same time each morning. Pharmacokinetic parameters describing the timing and amount of viloxazine in plasma and breast milk were measured based on samples collected predose and for 24 hours postdose on Day 3.Measures of potential infant exposure were calculated, including estimated daily infant dose (EDID) and relative infant dose (RID; the percentage of the weight-adjusted maternal daily dose that an infant would likely receive through breast milk). Results: At steady state, the median Tmax, milk in breast milk for viloxazine ER was 5.53 h, and the geometric mean (coefficient of variation [CV]%) breast milk-to-plasma ratio was 0.338 (17.4), indicating limited partitioning of drug into breast milk. Using a standard estimate of 150 mL/kg/d infant milk intake, the geometric mean (CV%) EDID was 0.134 (34.4) mg/kg/d, yielding an RID of 1.53% (27.6)-a value indicating low infant exposure within the commonly accepted <5%-10% RID safety threshold. Mild treatment-related adverse events were reported by 80% of participants, most commonly somnolence (67%), nausea (20%), and dizziness (20%). No participants discontinued. Conclusion: Viloxazine transfer into breastmilk of healthy, lactating women following multiple, once-daily 600 mg viloxazine ER doses was low. Trial Registration: ClinicalTrials.gov identifier: NCT06259331.
