Journal of Clinical Psychiatry最新文献

Objective: To test esmethadone (REL-1017) as adjunctive treatment in patients with major depressive disorder (MDD) and inadequate response to standard antidepressants.

Methods: In this phase 3, double-blind, placebo-controlled trial, outpatients with MDD (DSM-5) were randomized to daily oral esmethadone (75 mg on day 1, followed by 25 mg daily on days 2 through 28) or placebo between December 2020 and December 2022. The primary efficacy measure was change from baseline (CFB) to day 28 in the Montgomery-Asberg Depression Rating Scale (MADRS) score. The intent-to-treat (ITT) population included all randomized participants. The per-protocol (PP) population included completers without major protocol deviations impacting assessment. Post hoc analyses included participants with severe depression (baseline MADRS score ≥35).

Results: For the ITT analysis (n = 227), mean CFB was 15.1 (SD 11.3) for esmethadone (n = 113) and 12.9 (SD 10.4) for placebo (n = 114), with a mean difference (MD) of 2.3, which was not statistically significant (P = .154; Cohen effect size [ES] = 0.21). Remission rates were 22.1% and 13.2% (P = .076), and response rates were 39.8% and 27.2% (P = .044) with esmethadone and placebo, respectively. For the PP analysis (n = 198), mean CFB was 15.6 (SD 11.2) for esmethadone (n = 101) and 12.5 (SD 9.9) for placebo (n = 97), with an MD of 3.1 (P = .051; ES =0.29). In post hoc analyses of patients with baseline MADRS ≥35 in the ITT population (n = 112), MD was 6.9; P = .0059; ES = 0.57, and for the PP population (n = 98), MD was 7.9; P = .0015; ES = 0.69. Adverse events (AEs) were predominantly mild or moderate and transient, with no significant differences between groups.

Conclusions: The primary end point was not met. Esmethadone showed stronger efficacy in PP than in ITT analyses, with the discrepancy not attributable to AEs impacting treatment adherence. Significant efficacy occurred in post hoc analyses of patients with severe depression. Esmethadone was well tolerated, consistent with prior studies.

Trial Registration: ClinicalTrials.gov identifier: NCT04688164.

Objective: Few national estimates are available on the prevalence of tobacco use disorder (TUD) in the United States (US), and most trials exclusively assess daily smoking rather than TUD. We examined the prevalence and trends in cigarette smoking with vs without TUD among adults.

Methods: Data came from the 2010-2021 National Survey on Drug Use and Health (n = 483,982), a cross sectional, US representative dataset. A TUD composite variable was created based on established definitions (eg, DSM-5 symptoms). Weighted prevalence of past 30-day cigarette smoking, daily smoking (30/30 days) and nondaily smoking (<30/30 days) with and without TUD, was calculated annually.

Results: In 2021, the prevalence of past 30- day overall cigarette smoking was 17%; 11% reported daily cigarette smoking, whereas 6% reported nondaily cigarette smoking. Only 1% of the population reported daily smoking without TUD, whereas 10% reported daily smoking with TUD. Two percent of the population reported nondaily smoking without TUD, and 4% of the population reported nondaily smoking with TUD. Daily smoking with TUD and nondaily smoking with and without TUD decreased significantly from 2010 to 2021 (all P's < .001). US adults reporting TUD symptoms (vs not) were more likely to be older, identify as White, have lower income and less education, and have a substance use disorder.

Conclusions: The prevalence of daily cigarette smoking with TUD was 10× higher than the prevalence of daily cigarette smoking without TUD. Twice as many US adults with nondaily smoking reported TUD than no TUD, illustrating that daily smoking is not necessary for TUD.

Objective: The effectiveness of antidepressant treatment for mood disorders is often limited by either a poor response or the emergence of adverse effects. These complications often necessitate multiple drug trials. This clinical challenge intensifies during pregnancy, when medications must be selected to improve the likelihood of response and optimize reproductive outcomes. We determined the distribution of common pharmacogenetic variants, metabolizer phenotypes, past medication responses, and side effects in childbearing-aged individuals seeking treatment in a tertiary care perinatal mental health clinic.

Methods: Sixty treatment-seeking women (based on sex at birth) with DSM-5- defined bipolar disorder (n = 28) or major depressive disorder (n = 32) provided DNA samples and completed psychiatric diagnostic and severity assessments between April 2014 and December 2017. Samples were genotyped for single-nucleotide variants in drug metabolizing enzyme genes of commonly prescribed antidepressants (cytochrome P450 [CYP] 1A2, 2B6, 2C9, 2C19, 2D6, 3A4, and 3A5), and the frequency of normative metabolizer status was compared to reference populations data from Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines. The Antidepressant Treatment History Form was used to record historic medication trials and side effects.

Results: A significantly greater proportion of extensive metabolizers for CYP2B6 was observed in the study population when compared to CPIC population frequency databases in Caucasians (0.64 vs 0.43 [95% CI: 0.49-0.76]; P value = .006) and African Americans (0.71 vs 0.33 [95% CI: 0.29-0.96]; P value = .045). No significant association was found between metabolizer phenotype and the likelihood of a medication side effect.

Conclusion: Pharmacogenomic testing may have value for personalized prescribing in individuals capable of or considering pregnancy.

Objectives: Women veterans are more likely than men veterans to receive medications that Department of Veterans Affairs clinical practice guidelines recommend against to treat posttraumatic stress disorder (PTSD). To understand this difference, we examined potential confounders in incident prescribing of guideline discordant medications (GDMs) in veterans with PTSD.

Methods: Veterans receiving care for PTSD during 2020 were identified using Veterans Health Administration administrative data. PTSD diagnosis was established by the presence of at least 1 ICD-10 coded outpatient encounter or inpatient hospitalization during the calendar year 2020. Incident GDM prescribing was assessed during 2021, including benzodiazepines, antipsychotics, select anticonvulsants, and select antidepressants. Log-binomial regression was used to estimate the difference in risk for GDM initiation between men and women, adjusted for patient, prescriber, and facility-level covariates, and to identify key confounding variables.

Results: Of 704,699 veterans with PTSD, 16.9% of women and 10.1% of men initiated a GDM, an increased risk of 67% for women [relative risk (RR) = 1.67; 95% CI, 1.65-1.70]. After adjustment, the gender difference decreased to 1.22 (95% CI, 1.20-1.24) in a fully specified model. Three key confounding variables were identified: bipolar disorder (RR = 1.60; 95% CI, 1.57-1.63), age (<40 years: RR = 1.20 [1.18-1.22]; 40-54 years: RR = 1.13 [1.11-1.16]; ≥65 years: RR = 0.64 [0.62-0.65]), and count of distinct psychiatric medications prescribed in the prior year (RR = 1.14; 1.13-1.14).

Conclusions: Women veterans with PTSD were 67% more likely to initiate a GDM, where more than half of this effect was explained by bipolar disorder, age, and prior psychiatric medication. After adjustment, women veterans remained at 22% greater risk for an incident GDM, suggesting that other factors remain unidentified and warrant further investigation.

The age-standardized global prevalence of epilepsy is about 0.3% in women. Seizures are associated with morbidity and mortality risks; so, women with epilepsy (WWE) are usually advised antiepileptic drug (AED) treatment even during pregnancy. Women may also knowingly or unknowingly be exposed during pregnancy to AEDs advised for other on- or off-label indications. In this context, a meta-analysis of 35 adverse gestational outcomes examined in 76 observational studies found that WWE were at increased risk of most of the adverse outcomes, regardless of gestational exposure to AEDs. AEDs, especially in polytherapy, further increased at least a few of the gestational risks, including risks of congenital conditions, neonatal intensive care unit admission, small for gestational age, low birth weight, and neonatal/infant death (it is unclear whether the lack of statistical significance for the remaining risks was because AED exposure was truly limited to these risks or whether the nonsignificant analyses were underpowered). Reassuringly, the increases in risk were mostly in the small to modest range. This meta-analysis pooled unadjusted risks (which would probably be larger than adjusted risks), so readers are informed about expected findings in the population but not about cause-effect relationships that may be cautiously hypothesized from adjusted analyses. A take-home message is that, because of the wide range of outcomes for which risk is increased, WWE should be closely monitored and followed all through pregnancy, regardless of treatment with AEDs. This article also provides readers with suggestions on how to critically interpret literature with regard to 8 matters: confounding by indication and confounding by severity of indication, as specific to the indication for AED prescription; unadjusted and adjusted analyses; the base rate of an outcome in the population; the examination of multiple outcomes; the uniform direction of findings; the sample numbers; the timing of AED exposure; and self-fulfilling prophecies.

Objective: To determine the objective cognitive effects of electroconvulsive therapy (ECT) in treatment-resistant schizophrenia (TRS).

Data Sources: A database search of MEDLINE, PsycINFO, and Embase was conducted on September 22, 2022, using the search terms "schizophrenia" and "electroconvulsive therapy." The search was limited to the articles published from 1985 to present, in English, and human studies.

Study Selection: A total of 4293 articles were identified. After screening by title and full text, 17 articles met eligibility criteria. Controlled, open-label, and retrospective studies of acute, maintenance, or continuation ECT were included. An objective cognitive measure(s) had to be the primary or secondary outcome of the study, with no other interventions administered, besides standard-of-care treatment (ie, antipsychotics).

Data Extraction: Data regarding the study design, type of ECT provided, cognitive outcome measures, and change in cognitive performance pre- to post-ECT were extracted. Results are presented as a narrative review.

Results: Overall, ECT was not associated with any significant cognitive deficits in participants with TRS across the domains of global cognition, attention, language, visuospatial function, and executive function. Findings for immediate effects on memory were equivocal, but the majority of studies found no change or an improvement in memory after treatment.

Conclusions: The current evidence supports the conclusion that ECT does not have negative long-term effects on cognition among patients with TRS. Larger, sham-controlled trials are needed to support these conclusions. All studies in this review assessed ECT adjunct to antipsychotics; therefore, the cognitive effects of ECT independent of antipsychotics remain unclear.