Immunopharmacology

ImportanceMicrodosing psychedelics, including lysergic acid diethylamide (LSD), has gained attention for its potential benefits in several psychiatric disorders, including attention-deficit/hyperactivity disorder (ADHD). However, LSD’s efficacy in reducing ADHD symptoms remains unknown.ObjectiveTo determine the safety and efficacy of repeated low doses of LSD in reducing ADHD symptoms compared with placebo.Design, Setting, and ParticipantsThis was a 6-week, multicenter, double-blind, placebo-controlled, parallel-group phase 2A randomized clinical trial conducted between December 17, 2021, and December 4, 2023. Data were analyzed from March 22, 2024, to August 19, 2024. Outpatient treatment was provided at 2 centers: University Hospital in Basel, Switzerland, and Maastricht University in the Netherlands. Adults aged 18 to 65 years with a prior ADHD diagnosis who presented with moderate to severe symptoms (Adult Investigator Symptom Rating Scale [AISRS] score ≥26 and Clinical Global Impression Severity score ≥4) were eligible for inclusion. Key exclusion criteria included selected current major psychiatric or somatic disorders and the use of potentially interacting medications.InterventionParticipants received either LSD (20 μg) or placebo twice weekly for 6 weeks (total of 12 doses).Main Outcome and MeasuresThe primary outcome was the change in ADHD symptoms from baseline to week 6, assessed by the AISRS and analyzed with a mixed-effects model for repeated measures.ResultsA total of 53 participants were randomized to LSD (n = 27) or placebo (n = 26). Mean (SD) participant age was 37 (12) years, and 22 participants (42%) were female. The LSD group presented a mean AISRS improvement of −7.1 points (95% CI, −10.1 to −4.0). The placebo group presented a mean AISRS improvement of −8.9 points (95% CI, −12.0 to −5.8), with no difference between groups. LSD was physically safe and psychologically well tolerated overall.Conclusions and RelevanceIn this randomized clinical trial, repeated low-dose LSD administration was safe in an outpatient setting, but it was not more efficacious than placebo in reducing ADHD symptoms.Trial RegistrationClinicalTrials.gov Identifier: NCT05200936

ImportanceStimulants are increasingly prescribed for US adults. Whether such prescribing is associated with misuse and prescription stimulant use disorder (PSUD) is less understood.ObjectivesTo examine (1) sex- and age-specific trends in the number of persons dispensed stimulants and trends in dispensed prescription stimulants by prescriber specialty in 2019 through 2022; (2) prevalence of misuse and PSUD by use of prescription amphetamine-type stimulants (hereafter referred to as amphetamines) and methylphenidate; and (3) PSUD prevalence and sociodemographic and behavioral health correlates among persons using prescription stimulants with and without prescription stimulant misuse.Design, Setting, and ParticipantsThis cross-sectional survey study used the 2019-2022 IQVIA Total Patient Tracker and National Prescription Audit New to Brand databases and the 2021-2022 National Surveys on Drug Use and Health (NSDUH) (community-dwelling 18- to 64-year-old individuals). Data analysis was performed from March to April 2024.ExposurePast-year use of prescription stimulants.Main Outcomes and MeasuresPSUD using DSM-5 criteria.ResultsOf the sampled 83 762 adults aged 18 to 64 years, 33.8% (unweighted) were aged 18 to 25 years, 53.0% (unweighted) were aged 26 to 49 years, and 56.0% (unweighted) were women. Among those using prescription stimulants, 25.3% (95% CI, 23.8%-26.8%) reported misuse, and 9.0% (95% CI, 8.0%-10.0%) had PSUD. Among those with PSUD, 72.9% (95% CI, 68.3%-77.6%) solely used their own prescribed stimulants, 87.1% (95% CI, 82.3%-90.8%) used amphetamines, 42.5% (95% CI, 36.6%-48.5%) reported no misuse, and 63.6% (95% CI, 56.8%-69.8%) had mild PSUD. Individuals using amphetamines, compared with those using methylphenidate, had higher prevalence ratios of misuse (3.1 [95% CI, 2.2-4.3]) and PSUD (2.2 [95% CI, 1.3-3.8]). The largest increase in the number of individuals dispensed prescription stimulants was among women aged 35 to 64 years, from 1.2 million in quarter 1 of 2019 to 1.7 million in quarter 4 of 2022 (average quarterly percentage change, 2.6% [95% CI, 2.1%-3.1%]). The prevalence of prescription stimulant misuse was lower among women aged 35 to 64 years using these medications (13.7% [95% CI, 11.1%-16.8%]) than other sex- and age-specific subgroups (ranging from 22.0% [95% CI, 17.9%-26.7%] for men aged 35-64 years to 36.8% [95% CI, 32.6%-41.2%] for women aged 18-25 years).Conclusions and RelevanceHigh prevalence of prescription stimulant misuse and PSUD (regardless of misuse status) suggests the importance of ensuring clinically appropriate use and of screening for and treating PSUD among all adults prescribed stimulants, especially those using amphetamines. Findings may suggest potential progress in addressing the mental health care gap for middle-aged women and the need for evidence-based clinical guidance and training on benefits and risks of prescription stimulants for adults.

ImportanceBariatric surgery, once the criterion standard in obesity treatment, has a small but concerning association with increased suicidality. Glucagon-like peptide 1 receptor agonists (GLP-1 RAs), originally developed to treat diabetes, now provide substantial efficacy in the treatment of obesity. However, concerns of risk of suicidality with these medicines have been raised.ObjectiveTo evaluate the risk of suicidality and self-harm in randomized, placebo-controlled trials of GLP-1 RAs in adults with diabetes or obesity.Data SourcesMEDLINE, Embase, ClinicalTrials.gov, and Cochrane databases were systematically searched from inception to August 29, 2023.Study SelectionReports of randomized clinical trials (RCTs) lasting 6 or more months comparing GLP-1 RAs with placebo for the treatment of diabetes or obesity published in peer-reviewed journals were identified. Two independent reviewers screened all search-identified studies for inclusion. Records of outcomes were queried from primary papers, ClinicalTrials.gov entries, and corresponding authors.Data Extraction and SynthesisTwo independent researchers abstracted data and assessed data quality and validity using PRISMA guidelines. Data were pooled using random-effects models.Main Outcomes and MeasuresPooled incidence of completed or attempted suicide, occurrences of suicidal ideation, or self-harm.ResultsA total of 27 of 144 RCTs meeting inclusion criteria systematically recorded suicide and/or self-harm-related events and included 32 357 individuals receiving GLP-1 RAs and 27 046 treated with placebo, over 74 740 and 68 095 person-years of follow-up, respectively. Event incidence was very low in the GLP-1 RA (0.044 per 100 person-years) and placebo (0.040 per 100 person-years) groups, with no statistically significant difference (rate ratio [RR], 0.76; 95% CI, 0.48-1.21; P = .24). Subgroup analyses did not suggest differences in outcomes based on diabetes status or GLP-1 RA used. Five studies were considered at risk of bias due to the loss of more than 5% of participants to follow-up. Otherwise, studies were not found to be heterogeneous nor at high risk of bias.Conclusions and RelevanceThere is unlikely to be an increase in the very low incidence of suicide-related adverse events among individuals receiving GLP-1 RAs within the context of RCTs. While these findings may further ease concerns about these adverse effects, continued monitoring is warranted to identify particular patients who may be at risk as extended use of GLP-1 RAs expands.

ImportanceExpectancy effects are significant confounding factors in psychiatric randomized clinical trials (RCTs), potentially affecting the interpretation of study results. This narrative review is the first, to our knowledge, to explore the relationship between expectancy effects, compromised blinding integrity, and the effects of active treatment/placebo in psychiatric RCTs. Additionally, we present statistical and experimental approaches that may help mitigate the confounding impact of expectancy effects. The review concludes with recommendations to enhance the reliability of RCTs in psychiatry.ObservationsThe placebo response comprises both specific and nonspecific elements, with expectation being a key specific component. Evidence from experimental and clinical studies suggests that expectancy can influence treatment responses in RCTs. Blinding integrity may be compromised by perceived treatment efficacy and adverse effects, introducing bias into outcome assessments. Treatment expectations can lead to unblinding during RCTs, and meta-analytic data from studies in the fields of psychedelics and anxiety disorders indicate that this can influence effect sizes. Therefore, controlling for expectancy effects is essential when interpreting RCT results. Novel statistical methods, though still in need of further validation, offer strategies to address this issue. Another approach may involve experimental medicine models, which aim to develop objective improvement markers (readouts) less affected by expectancy effects.Conclusions and RelevanceExpectancy effects represent a significant confound in psychiatric RCTs. We recommend collecting data on treatment expectations alongside monitoring blinding integrity to more accurately interpret study results. Additionally, developing objective readouts that are less confounded by expectancy effects offers another promising avenue for mitigating these confounding influences in psychiatric RCTs.

ImportancePeripheral (blood-based) biomarkers for psychiatric illness could benefit diagnosis and treatment, but research to date has typically been low throughput, and traditional case-control studies are subject to potential confounds of treatment and other exposures. Large-scale 2-sample mendelian randomization (MR) can examine the potentially causal impact of circulating proteins on neuropsychiatric phenotypes without these confounds.ObjectiveTo identify circulating proteins associated with risk for schizophrenia (SCZ), bipolar disorder (BD), and major depressive disorder (MDD) as well as cognitive task performance (CTP).Design, Setting, and ParticipantsIn a 2-sample MR design, significant proteomic quantitative trait loci were used as candidate instruments, obtained from 2 large-scale plasma proteomics datasets: the UK Biobank Pharma Proteomics Project (2923 proteins per 34 557 UK individuals) and deCODE Genetics (4719 proteins per 35 559 Icelandic individuals). Data analysis was performed from November 2023 to November 2024.ExposureGenetic influence on circulating levels of proteins in plasma.Main Outcomes and MeasuresOutcome measures were summary statistics drawn from recent large-scale genome-wide association studies for SCZ (67 323 cases and 93 456 controls), BD (40 463 cases and 313 436 controls), MDD (166 773 cases and 507 679 controls), and CTP (215 333 individuals). MR was carried out for each phenotype, and proteins that showed statistically significant (Bonferroni-corrected P < .05) associations from MR analysis were used for pathway, protein-protein interaction, drug target enrichment, and potential druggability analysis for each outcome phenotype separately.ResultsMR analysis revealed 113 Bonferroni-corrected associations (46 novel) involving 91 proteins across the 4 outcome phenotypes. Immune-related proteins, such as interleukins and complement factors, showed pleiotropic effects across multiple outcome phenotypes. Drug target enrichment analysis provided support for repurposing of anti-inflammatory agents for SCZ, amantadine for BD, retinoic acid for MDD, and duloxetine for CTP.Conclusions and RelevanceIdentifying potentially causal effects of circulating proteins on neuropsychiatric phenotypes suggests potential biomarkers and offers insights for the development of innovative therapeutic strategies. The study also reveals pleiotropic effects of many proteins across different phenotypes, indicating shared etiology among serious psychiatric conditions and cognition.

IMPORTANCEMaternal inflammation during pregnancy has been associated with an increased risk of neurodevelopmental disorders (NDDs), such as attention-deficit/hyperactivity disorder (ADHD) and autism, and cognitive deficits in early childhood. However, little is known about the contributions of a wider range of inflammatory proteins to this risk.OBJECTIVETo determine whether maternal inflammatory proteins during pregnancy are associated with the risk of NDDs and executive functions (EF) in middle childhood and to identify protein patterns associated with NDDs and EF.DESIGN, SETTING, AND PARTICIPANTSThis was a 10-year follow-up cohort study of the Danish Copenhagen Prospective Studies on Asthma 2010 mother-child birth cohort, using plasma samples collected at week 24 in pregnancy, where 92 inflammatory proteins were assessed. NDDs and EF were assessed in the offspring at age 10 years, between January 2019 and December 2021. Mother-offspring dyads with available maternal prenatal inflammatory proteins during pregnancy and offspring NDD psychopathology data at follow-up were included. Data analyses took place between December 2023 and August 2024.EXPOSURESLevels of 92 inflammatory proteins from panel collected at week 24 during pregnancy.MAIN OUTCOMES AND MEASURESCategorical and dimensional psychopathology of NDDs (primary outcome) and EF (secondary outcome).RESULTSA total of 555 mothers (mean [SD] age, 32.4 [4.3] years) and their children (285 male [51%]) were included. The principal component analysis showed that higher levels of maternal inflammatory proteins depicted in principal component 1 were associated with a higher risk of any NDD (OR, 1.49; 95% CI, 1.15-1.94; P = .003), particularly autism (OR, 2.76; 95% CI, 1.45-5.63; P = .003) and ADHD with predominantly inattentive presentation (OR, 1.57; 95% CI, 1.05-2.39; P = .03). The single protein analysis showed that 18 of 92 proteins reached false discovery rate (FDR) 5% significance after adjustment. Vascular endothelial growth factor A, C-C motif chemokine ligand, CD5, interleukin 12B, fibroblast growth factor-23, and monocyte chemoattractant protein-1 emerged as top proteins associated with risk of NDDs. The sparse partial least squares approach identified 34 proteins associated with any NDD, and 39 with ADHD with predominantly inattentive presentation. There were no associations with EF after FDR correction.CONCLUSIONS AND RELEVANCEThe maternal inflammatory proteome during pregnancy was associated with NDDs risks in offspring at age 10 years. Further research is warranted to elucidate the specific pathways involving these proteins during pregnancy that could be targeted with prevention strategies to reduce risk of NDDs in children.

This Viewpoint discusses addressing women’s anger after trauma.

ImportanceIntermittent theta-burst stimulation (iTBS) is an established treatment for treatment-resistant depression (TRD). Sessions conducted more than once daily (ie, accelerated TBS [aTBS]) may enhance antidepressant effects. However, evidence is limited to small trials, and protocols are time-consuming and can require neuroimaging-based targeting.ObjectiveTo evaluate the efficacy and safety of a pragmatic aTBS protocol for TRD.Design, Setting, and ParticipantsThis triple-blinded, sham-controlled randomized clinical trial was conducted at a single center in São Paulo, Brazil, from July 2022 to June 2024, with a subsequent open-label phase. Patients aged 18 to 65 years with major depression, experiencing a TRD episode, and with a Hamilton Depression Rating Scale, 17-item (HDRS-17) score of 17 or higher were eligible for inclusion. Exclusion criteria were other psychiatric disorders (except anxiety), neurological conditions, and TBS contraindications.InterventionsParticipants received 45 active or sham stimulation sessions over 15 weekdays, with 3 iTBS sessions (1200 pulses each) per day, spaced 30 minutes apart and targeting the left dorsolateral prefrontal cortex using a craniometric approach. In the open-label phase, additional aTBS sessions were offered to achieve a response (≥50% HDRS-17 score improvement) if needed.Main Outcomes and MeasuresThe primary outcome was change in HDRS-17 score at week 5.ResultsOf 431 volunteers screened, 100 participants were enrolled and randomized to either sham or active aTBS. Mean (SD) participant age was 41.7 (8.8) years, and 84 participants (84%) were female. A total of 89 patients completed the study. In the intention-to-treat analysis, the mean change in HDRS-17 scores from baseline to the study end point was 5.57 (95% CI, 3.99-7.16) in the sham group and 9.68 (95% CI, 8.11-11.25) in the active group, corresponding to 31.87% and 54.7% score reductions, respectively, and a medium-to-large effect size (Cohen d, 0.65; 95% CI, 0.29-1.00; P < .001). Response and remission rates were also higher in the active group. Both interventions were well tolerated, but scalp pain was more frequent in the active group than the sham group (17.4% vs 4.4%). During the open-label phase, approximately 75% of patients received additional sessions.Conclusions and RelevanceIn this triple-blinded, sham-controlled randomized clinical trial, a pragmatic aTBS protocol using only 3 iTBS sessions per day and a nonexpensive, non-neuronavigated approach was found to be safe and effective for TRD.Trial RegistrationClinicalTrials.gov Identifier: NCT05388539

This Viewpoint explores the shift from the process-oriented concept of evidence-based practicing toward the development and distribution of evidence-based practices within the sphere of mental health care.

ImportanceSports gambling has become one of the most accessible forms of gambling in the United States, and recent research suggests that sports gambling coupled with frequent alcohol use may have deleterious health consequences.ObjectiveTo examine the trajectories of sports gambling frequency and alcohol-related problems over time and the associations between these trajectories.Design, Setting, and ParticipantsThis survey study was a 2-year longitudinal study conducted in the United States. Participants were recruited from a nonprobability internet panel from 2 sources: a large cross-section of adults matched and weighted to US Census norms and a specific oversample of sports-gambling adults. Recruitment began in spring 2022, and the last surveys concluded in spring 2024. To identify trajectories within sports gambling frequency and alcohol use problems, latent growth curve modeling was used.Main OutcomesAt each time point, the National Institute on Drug Abuse–modified Alcohol, Smoking, and Substance Involvement Screening Test 2 was used to assess alcohol-related problems and sports gambling frequency was assessed by a single item.ResultsThe cross-section of US adults (n = 2806) and oversample of sports-gambling adults (n = 1557) resulted in a total baseline sample of 4363 (mean [SD] age, 49.6 [16.2] years; 2243 men [51.4%] and 2120 women or nonbinary gender reported [48.6%]). Latent growth curve modeling revealed that alcohol problems decreased over time (slope = −0.059; 95% CI, −0.090 to −0.028). Sports gambling frequency did not show a significant trend over time (slope = −0.003; 95% CI, −0.053 to 0.047), though there was significant variance in this slope (variance = 0.024; 95% CI, 0.013 to 0.034). The trajectories of alcohol-related problems and sports gambling did not move independently, instead being highly positively correlated, suggesting that increases in one would correspond to increases in the other.Conclusions and RelevanceThis study found that over time, the trajectory of sports gambling frequency was associated with the trajectory of alcohol-related problems. Screening and treatment interventions are recommended for sport gamblers who also drink concurrently, especially because this group appears to be at an elevated risk for developing greater alcohol-related problems over time.

ImportanceThis study aims to provide robust evidence to support or challenge the immune hypothesis of schizophrenia.ObjectiveTo conduct a meta-analysis of reports on blood leukocyte subpopulations in schizophrenia vs healthy controls, examining disease- and treatment-related differences as well as potential confounders.Data SourcesSystematic database search for English and non-English peer-reviewed articles in PubMed, Web of Science, Scopus, and Cochrane Library databases, with the last search in January 2024.Study SelectionCross-sectional, case-control, and longitudinal studies comparing leukocyte numbers in patients with schizophrenia and healthy controls. After duplicates were removed, 3691 studies were identified for screening.Data Extraction and SynthesisData extraction and quality assessment were conducted following PRISMA and MOOSE guidelines. Data were independently extracted by 2 authors and pooled using random-effects models.Main Outcomes and MeasuresThe planned primary outcomes were differences in leukocyte subpopulation counts between individuals with schizophrenia and healthy controls to increase our understanding of the immune system dysfunction in schizophrenia.ResultsSixty-four relevant articles were identified (60 cross-sectional/case-control studies and 4 longitudinal studies) with data on leukocyte numbers from 26 349 individuals with schizophrenia and 16 379 healthy controls. Neutrophils (g = 0.69; 95% CI, 0.49 to 0.89; Bonferroni-adjusted P < .001; n = 40 951 [47 between-group comparisons]) and monocytes (g = 0.49; 95% CI, 0.24 to 0.75; Bonferroni-adjusted P < .001; n = 40 513 [44 between-group comparisons]) were higher in schizophrenia compared with control participants. Differences were greater in first-episode vs chronic schizophrenia and in patients who were not treated vs treated with antipsychotic medication. There were no significant differences in eosinophils (g = 0.02; 95% CI, −0.16 to 0.20; Bonferroni-adjusted P > .99; n = 3277 [18 between-group comparisons]), basophils (g = 0.14; 95% CI, −0.06 to 0.34; Bonferroni-adjusted P = .85; n = 2614 [13 between-group comparisons]), or lymphocytes (g = −0.08; 95% CI, −0.21 to 0.06; Bonferroni-adjusted P > .99; n = 41 693 [59 between-group comparisons]). Neutrophils decreased longitudinally (g = −0.30; 95% CI, −0.45 to −0.15; Bonferroni-adjusted P < .001; n = 896 [4 within-group comparisons]) and eosinophils increased longitudinally (g = 0.61; 95% CI, 0.52 to 0.71; Bonferroni-adjusted P < .001; n = 876 [3 within-group comparisons]) after successful treatment of acute psychosis.Conclusions and RelevanceOur findings of increased blood neutrophils and monocytes support the immune hypothesis of schizophrenia, particularly highlighting the role of innate immune activation. As these effects were more pronounced in early disease stages and also reflected clinical improvement, they may pave the way for innovative treatment strategies based on immunological and inflammatory pathways and help revolutionize the treatment landscape for schizophrenia.

ImportanceIn the 2020 Bostock v Clayton County decision, the US Supreme Court extended employment nondiscrimination protection to sexual minority adults. The health impacts of this ruling and similar policies related to sexual orientation–based discrimination are not currently known.ObjectiveTo estimate changes in mental health following the Bostock decision among sexual minority adults in states that gained employment nondiscrimination protection (intervention states) compared with those in states with protections already in place (control states).Design, Setting, and ParticipantsThis cross-sectional study used 2018-2022 data from the Behavioral Risk Factor Surveillance System and a difference-in-differences approach to evaluate changes in mental health after the Bostock decision by comparing sexual minority adults (aged ≥18 years and identifying as lesbian, gay, or bisexual) in 12 intervention states with those residing in 9 control states. Models were estimated for all participants and separately for employed participants. Data were analyzed between February and September 2024.ExposureResiding in a state that gained employment nondiscrimination protection after the Bostock decision.Main Outcomes and MeasuresThe primary outcome was number of poor mental health days during the past 30 days, and the secondary outcome was severe mental distress (defined as 14 or more past-month poor mental health days).ResultsOf 597 462 participants (306 365 in intervention states [77.7% aged 18-64 years and 22.3% aged ≥65 years; 51.7% female] and 291 097 in control states [77.5% aged 18-64 years and 22.5% aged ≥65 years; 50.6% female]), 5.1% in intervention states and 6.0% in control states self-identified as sexual minority adults. The mean (SE) number of past-month poor mental health days was unchanged after the Bostock decision among sexual minority adults in both intervention (from 8.70 [0.27] to 9.59 [0.24] days; adjusted difference, 0.57 [95% CI, −1.02 to 2.16] days) and control (from 8.53 [0.21] to 10.15 [0.20] days; adjusted difference, 1.17 [95% CI, −0.46 to 2.79] days) states, resulting in no differential change between the 2 groups (difference-in-differences, −0.60 days; 95% CI, −1.25 to 0.06 days). Among the subset of employed sexual minority adults, the mean (SE) number of poor mental health days did not change in intervention states (from 7.99 [0.38] to 8.83 [0.30] days; adjusted difference, 0.87 [95% CI, −0.49 to 2.22] days) but increased in control states (from 7.75 [0.27] to 9.75 [0.26] days; adjusted difference, 1.84 [95% CI, 0.44-3.24] days). These findings corresponded to a significant relative reduction in poor mental health days among employed sexual minority adults in intervention vs control states (difference-in-differences, −0.97 days; 95% CI, −1.74 to −0.21 days). Mean (SE) rates of severe mental distress increased less among employed sexual minority adults in intervention (from 26.35% [1.59%] to 29.92% [1.46%]; adjusted difference, 6.81% [95% CI, 2.20%-11.42%]) vs control (from 26.53% [1.27%] to 34.26% [1.16%]; adjusted difference, 10.30% [95% CI, 5.99%-14.61%) states, also corresponding to a significant relative reduction among employed sexual minority adults (difference-in-differences, −3.49%; 95% CI, −6.71% to −0.27%).Conclusions and RelevanceThese findings show significant relative reductions in past-month poor mental health days and severe mental distress among employed sexual minority adults after the implementation of a federal ban on employment discrimination based on sexual orientation. Larger and more consistent mental health benefits observed among sexual minority adults in the workforce underscore the importance of broadening protections to other social domains.