Antidepressant Monotherapy Research Articles

A Multicenter, Open-Label Study to Evaluate the Long-term Safety and Efficacy of Adjunctive Brexpiprazole 2 mg Daily in Japanese Patients with Major Depressive Disorder.

Inadequate response to antidepressant monotherapy is common among patients with major depressive disorder (MDD). The efficacy and safety of adjunctive brexpiprazole 2 mg/day has recently been confirmed during the 6-week, randomized, placebo-controlled phase 2/3 (BLESS) study, which evaluated brexpiprazole at 1 mg/day and 2 mg/day versus placebo as adjunctive therapy to antidepressant therapies in 740 Japanese patients with MDD and an inadequate response to antidepressant monotherapy. This study evaluated the long-term safety and efficacy of adjunctive fixed-dose brexpiprazole 2 mg/day in Japanese patients with MDD. An open-label, 52-week study enrolled rollover patients who completed the 6-week, double-blind, randomized, placebo-controlled phase 2/3 BLESS study (NCT03697603), and de novo patients aged ≥ 65 years. Patients were titrated to fixed-dose brexpiprazole 2 mg/day from Week 1. Safety assessments included treatment-emergent adverse events (TEAEs; primary outcome) and clinical and laboratory variables. Efficacy was assessed using the Montgomery-Åsberg Depression Rating Scale(MADRS), Clinical Global Impression-Improvement (CGI-I) scale, Hamilton Depression Rating Scale (HAM-D) 17-item total score, and Sheehan Disability Scale (SDS) score. In total, 247 patients [rollover, n = 216; de novo (previously unexposed), n = 31] were included in the safety/efficacy populations, and 138 (rollover, n = 132; de novo, n = 6; 55.9%) completed the study. Common TEAEs (incidence ≥ 10%) were weight gain [33.2% (n = 82)], akathisia [23.5% (n = 58)], nasopharyngitis [21.1% (n = 52)], and somnolence [10.5% (n = 26)]. TEAEs leading to treatment discontinuation occurred in 26.7% of patients receiving brexpiprazole and 58.1% of de novo patients. The mean (SD) increase in body weight from baseline to Week 52 [observed cases (OC)] was 4.2 (6.5) kg (n = 138); 44.5% (n = 110) had weight gain ≥ 7% at any postbaseline visit. There were no cases of tardive dyskinesia and no AEs related to suicide/suicide attempts. One death occurred (unknown cause), which was unrelated to study treatment. Improvements in the MADRS total score were observed from baseline over the course of the 52-week study [mean (SD) change at Week 52 (OC): - 7.3 (8.7)] for all patients receiving brexpiprazole. The overall MADRS response rate and remission rate in patients receiving brexpiprazole was 41.3% (n = 57) and 34.8% (n = 48), respectively, at Week 52 (OC). Improvements in CGI-S, HAM-D 17 item total score, and SDS mean scores were also observed from baseline over the 52-week study, with a mean (SD) change from baseline at Week 52 (OC) of - 0.8 (1.0), - 5.9 (6.3), and - 1.0 (2.2), respectively, indicating a sustained improvement in symptoms with long-term brexpiprazole treatment. This is the first study to evaluate the safety profile of brexpiprazole 2 mg/day in Japanese patients with MDD, including older adults, which is similar to previous reports, with no new safety risks, and continued efficacy over 52 weeks. ClinicalTrials.gov (NCT03737474; registered on 29 July 2018).

Bright Light Therapy for Nonseasonal Depressive Disorders

Seasonal humor disorders are prone to have a link with daylight exposure. However, the effect of external light on nonseasonal disorders remains unclear. Evidence is lacking for the validity of bright light therapy (BLT) as an adjunctive treatment for these patients. To assess BLT effectiveness as an adjunctive treatment for nonseasonal depressive disorders. In March 2024, a comprehensive search was performed of publications in the MEDLINE, Embase, and Cochrane databases for randomized clinical trials (RCTs) evaluating BLT effects in patients with nonseasonal depression. RCTs published since 2000 were eligible. Comparisons between BLT and dim red light or antidepressant monotherapy alone were considered for inclusion. Using the systematic review approach on RCTs published from January 1, 2000, through March 25, 2024, differences between patients treated with and without BLT were estimated using the Mantel-Haenszel method; heterogeneity was assessed using I2 statistics. Remission of symptoms, response to treatment rates, and depression scales were assessed. In this systematic review and meta-analysis of 11 unique trials with data from 858 patients (649 female [75.6%]), statistically significant better remission and response rates were found in the BLT group (remission: 40.7% vs 23.5%; odds ratio [OR], 2.42; 95% CI, 1.50-3.91; P <.001; I2 = 21%; response: 60.4% vs 38.6%; OR, 2.34; 95% CI, 1.46-3.75; P <.001; I2 = 41%). With BLT, subgroup analysis based on follow-up times also showed better remission (<4 weeks: 27.4% vs 9.2%; OR, 3.59; 95% CI, 1.45-8.88; P = .005; I2 = 0% and >4 weeks: 46.6% vs 29.1%; OR, 2.18; 95% CI, 1.19-4.00; P = .01; I2 = 47%) and response (<4 weeks: 55.6% vs 27.4%; OR, 3.65; 95% CI, 1.81-7.33; P <.001; I2 = 35% and >4 weeks: 63.0% vs 44.9%; OR, 1.79; 95% CI, 1.01-3.17; P = .04; I2 = 32%) rates. Results of this systematic review and meta-analysis reveal that BLT was an effective adjunctive treatment for nonseasonal depressive disorders. Additionally, results suggest that BLT may improve the response time to the initial treatment.

Exploring cariprazine as a treatment option for varied depression symptom clusters.

Major depressive disorder (MDD) is among the most prevalent psychiatric conditions and a leading cause of disability worldwide. MDD presents a diverse range of symptoms that significantly impact personal, societal, and economic dimensions. Despite the availability of numerous antidepressant treatments (ADTs) targeting different molecular mechanisms, a substantial proportion of patients experience inadequate response, presenting a considerable challenge in MDD management. As a result, adjunctive strategies, particularly involving atypical antipsychotics, are often employed to enhance treatment efficacy. Cariprazine, a D2/D3 partial agonist, is distinguished from other atypical antipsychotics by its selective action on the D3 receptor and its modulation of 5-HT1A, 5-HT2A, and alpha 1B receptors. This distinctive pharmacological profile warrants investigation into its potential effectiveness and tolerability across various symptom domains of MDD, including pleasure, interest, and motivation; mood and suicidality; sleep and appetite; fatigue; psychomotor activity and anxiety; and cognitive function. Preliminary evidence from animal studies and clinical trials suggests that cariprazine may improve motivation, anhedonia, and cognitive function symptoms. Cariprazine shows promise in alleviating mood-related symptoms, though its impact on anxiety and its effects on agitation and psychomotor retardation remains uncertain. Cariprazine may be particularly beneficial for patients with MDD exhibiting anhedonia, cognitive deficits, and possibly fatigue and hypersomnia. Evaluating cariprazine's efficacy across these symptom domains could reveal patterns that support more personalized treatment approaches for depression. Further research is essential to elucidate the role of cariprazine as an adjunctive therapy for adults with major depressive disorder who have an inadequate response to antidepressant monotherapy.

A multicenter retrospective study of antidepressant use in outpatient clinics in China pre- and post-COVID.

Analyzing antidepressant prescribing in real-world settings can provide clinicians and health policymakers valuable information. This epidemiological study examined the status and trends in antidepressant prescribing among the Chinese population from July 1, 2017, to June 30, 2022. A retrospective study was conducted in three hospitals. Data were collected 2.5 years before and 2.5 years after the onset of the COVID-19 pandemic. We analyzed the number of patients diagnosed with depression and their corresponding antidepressant prescriptions. Using the chi-square test, stratified analyses were performed to explore the characteristics of these prescriptions in different ages and sexes. The study included 124,355 patients and 400,840 antidepressant prescriptions. We observed fluctuating upward trends in the number of patients and antidepressant prescriptions. Post-COVID-19, the number of patients increased by 37.1% compared to the pre-pandemic period, and the number of antidepressant prescriptions rose by 88.3%. The three most frequently prescribed antidepressants for adolescents were sertraline, citalopram, and escitalopram. Among adults, citalopram, escitalopram, and sertraline were most common, while in older adults, citalopram, escitalopram, and mirtazapine were predominant. Male patients used mirtazapine, venlafaxine, paroxetine, bupropion, fluvoxamine, vortioxetine, and clomipramine more frequently compared to female patients, who were more likely to be prescribed citalopram, flupentixol/melitracen, agomelatine, and fluoxetine. Antidepressant monotherapy represented 76.6% of prescriptions, with the most common combination being antidepressants and anxiolytics. Over the past 5 years, both the number of patients and antidepressant prescriptions have shown upward trends, and the COVID-19 pandemic has impacted prescribing. Understanding the changes in antidepressant prescriptions can identify adherence to national guidelines.

Longitudinal invariance of the Patient Health Questionnaire-9 among patients receiving pharmacotherapy for major depressive disorder: A secondary analysis of clinical trial data.

Comparing self-reported symptom scores across time requires longitudinal measurement invariance (LMI), a psychometric property that means the measure is functioning identically across all time points. Despite its prominence as a measure of depression symptom severity in both research and health care, LMI has yet to be firmly established for the Patient Health Questionnaire-9 depression module (PHQ-9), particularly over the course of antidepressant pharmacotherapy. Accordingly, the objective of this study was to assess for LMI of the PHQ-9 during pharmacotherapy for major depressive disorder. This was a secondary analysis of data collected during a randomized controlled trial. A total of 1,944 veterans began antidepressant monotherapy and completed the PHQ-9 six times over 24 weeks of treatment. LMI was assessed using a series of four confirmatory factor analysis models that included all six time points, with estimated parameters increasingly constrained across models to test for different aspects of invariance. Root-mean-square error of approximation of the chi-square difference test values below 0.06 indicated the presence of LMI. Exploratory LMI analyses were also performed for separate sex, age, and race subgroups. Root-mean-square error of approximation of the chi-square difference test showed minimal change in model fits during invariance testing (≤ 0.06 for all steps), supporting full LMI for the PHQ-9. LMI was also supported for all tested veteran subgroups. As such, PHQ-9 sum scores can be compared across extended pharmacotherapy treatment durations. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Effectiveness and safety of Chaihu-Shugan-San for treating depression based on clinical cases: An updated systematic review and meta-analysis.

Chaihu-Shugan-San (CSS), a Traditional Chinese Medicine formula, has been widely used for treating depression since the Ming Dynasty, as recorded in Jingyue Quanshu, but its effectiveness and safety lack comprehensive and objective evaluation. Based on our meta-analysis, we aimed to adequately evaluate the efficacy and risk of CSS by considering the latest clinical literature. Multiple databases, including PubMed, Embase, Web of Science, SinoMed, China National Knowledge Infrastructure, Chongqing VIP, and Wanfang, were used to collect clinical data. The quality of the included clinical studies was assessed using the Cochrane Risk of Bias Tool, and the data were meta-analyzed using Review Manager 5.0 and Stata 17. The data were obtained from a genome-wide association study, and Mendelian randomization (MR) was performed using R Software 4.3.2 with the TwoSampleMR and MR Pleiotropy RESidual Sum and Outlier packages. A total of 15 studies with 1034 patients and 6 antidepressant drugs were included in this work. Meta-analyses revealed that drug combinations of CSS and antidepressants significantly improved depressive symptoms (weighted mean difference = -4.21; 95% confidence interval [CI]: -5.62--2.81), increased the effective rate (odds ratio [OR] = 3.82; 95% CI: 2.44-6.83), and reduced side effects (OR = -3.55; 95% CI: -5.66--1.43) compared with antidepressant monotherapy. Additionally, compared with antidepressant monotherapy, CSS alone exhibited fewer side effects (95% CI:-9.25--6.95). Like antidepressants, CSS also improved depressive symptoms (weighted mean difference = -0.05; 95% CI: -0.63--0.52) and increased the effective rate (OR = 1.07; 95% CI: 0.52-2.20). Additionally, MR was used to evaluate the safety of traditional antidepressants, as there was a causal association between amitriptyline and body mass index. This analysis demonstrated that compared with traditional antidepressants, CSS combined with antidepressants was more effective and safer for treating depressed patients. MR showed that a causal relationship may exist between amitriptyline and body mass index. Therefore, clinicians should carefully consider the advantages and potential drawbacks of Traditional Chinese Medicine and classic drugs to serve patients better.

A Randomized Controlled Trial Comparing the Quality of Life and Medication Adherence in Patients on Antidepressant Monotherapy.

Background and objectives The quality of life declines with the growing severity of major depressive disorder (MDD). In depressed people, medication adherence and the quality of life are mutually corrosive. These concerns spurred the investigation of relationships between treatment outcomes and adherence levels. Limited studies are looking at how vortioxetine, escitalopram, and vilazodone affect these parameters. We aimed to detect how the Short Form-36 (SF-36) had changed 16 weeks after the baseline. The connection between treatment results (as expressed by the Hamilton Depression Rating Scaleor HDRS) and medication adherence (as reflected by the MoriskyMedication Adherence Scale-8or MMAS-8) was also explored. Methods An open-label, randomized, three-arm trial with 96 MDD patients was conducted. For 16 weeks, the participants were put into three groups per a 1:1:1 ratio and administered tablets of vilazodone (20-40 mg/day), escitalopram (10-20 mg/day), or vortioxetine (5-20 mg/day). There were two test drugs: vilazodone and vortioxetine; the control was escitalopram. Four weeks apart, follow-up appointments were set after the baseline visit. The HDRS, mental and physical components of SF-36, and MMAS-8 scores were evaluated in the per-protocol (PP) population. Reduced HDRS scores were indicative of improved depression symptoms. Higher MMAS-8 and SF-36 scores indicated high drug adherence and enhanced quality of life. Our analysis used the Kruskal-Wallis test, the Bonferroni correction, and the Sankey diagram. In the Clinical Trial Registry-India (CTRI), we recorded this study prospectively (2022/07/043808). Results One hundred nine (81.34%) of the 134 individuals we examined were eligible. The PP population consisted of 96 (88.07%) of them who wrapped up the 16-week study. The mean age of the group was 46.3 ± 6.2 years. For each of the three groups, the SF-36 physical component scores revealed a median difference of 24.5 (23.8-26.0), 24.0 (22.8-25.3), and 27.0 (25.0-29.0) (p = 0.001). Accordingly, the mental components of their SF-36 scores showed a median difference of 32.0 (31.0-33.3), 31.0 (29.8-34.3), and 36.0 (33.0-38.0) (p = 0.001). A median difference of -15.0 (-16.0 to -14.0), -16.0 (-17.0 to -15.0), and -16.0 (-17.0 to -15.8) was observed in the HDRS scores after 16 weeks, with respect to the baseline (p < 0.001). The median MMAS-8 scores at 16 weeks were 6.0 (6.0-7.0), 6.8 (6.0-7.0), and 7.5 (6.5-8.0)(p = 0.031). The Sankey diagram illustrated the connection between better treatment results, increased medication compliance, and decreased symptoms of depression. Conclusion In comparison to vilazodone and escitalopram, vortioxetine demonstrated a statistically significant decrease in HDRS scores and an improvement in the physical and mental component scores of the SF-36. Clinical improvements were evident in the individuals' drug adherence levels. Larger-scale studies are advised to investigate the effects of these medications on the quality of life, medication adherence, and treatment outcomes.

Alcohol Consumption Is a Coping Mechanism for Male Patients with Severe Anxiety Disorders Treated with Antidepressants Monotherapy.

Background: Anxiety disorders are prevalent mental health conditions often accompanied by various comorbidities. The association between anxiety and liver disease, as well as fluctuations in blood sugar levels, highlights the importance of carefully evaluating patients with anxiety undergoing antidepressant therapy. The aim of this study was to conduct a comparative assessment of liver function and blood glucose levels in patients diagnosed with anxiety disorders while considering potential gender-specific differences. Methods: An analysis was conducted over a 24-month period. This study included 88 patients diagnosed with anxiety disorders, with symptoms severe enough to require hospitalization, aged 18 or older, undergoing antidepressant monotherapy, without any additional pathologies. Liver enzymes (AST, ALT, GGT), AST/ALT ratio, and blood glucose levels were measured and compared. Results: While no significant differences were found between antidepressant classes, increased GGT levels were observed in men older than 40 years compared to women of the same age, suggesting that alcohol consumption may be a coping mechanism for anxiety. This gender difference was not observed among young patients. Conclusions: Early detection of alcohol consumption is essential in patients with anxiety disorders in order to prevent alcohol-related liver damage and to adjust the management of both conditions accordingly.

155. Longitudinal Oral and Fecal Microbiome Alterations in Veterans With New Antidepressant Monotherapy for Major Depressive Disorder

155. Longitudinal Oral and Fecal Microbiome Alterations in Veterans With New Antidepressant Monotherapy for Major Depressive Disorder

Diagnosis and Treatment of Generalized Anxiety Disorder in Japan: Psychiatric Specialist Survey.

Generalized anxiety disorder (GAD) is a suboptimally managed chronic recurring psychiatric condition with a lifetime prevalence of 2.6% in Japan. We assessed the current status of GAD management in Japan. This was an observational, cross-sectional study conducted through an anonymous web-based survey in Japan from December 12-16, 2022. Psychiatrists and psychosomatic medicine physicians who agreed to participate and saw ≥10 outpatients in the previous month were eligible. Survey questionnaire comprised 37 single/multiple choice, numerical entry, or open-ended questions in Japanese. Among 509 participants (493 psychiatrists and 16 psychosomatic medicine physicians), 96.9% were aware of GAD. On average, 12.4 outpatients and 1.0 inpatient were diagnosed with GAD per physician per month. Of 433 physicians having patients diagnosed with GAD, 46.9% used operational diagnostic tools; among these, DSM-5 diagnostic criteria were used by 81.5% physicians. The majority (54.7%) of participants did not use a self-administered rating scale; depression scales were used more than anxiety scales. Among these 433 physicians, 96.8% used selective serotonin reuptake inhibitors for GAD management, and 79.2% used it as the first choice; of 431 physicians who prescribed drug therapy, 54.3% gave antidepressant monotherapy as first choice. The most frequent symptom in patients diagnosed with GAD was excessive anxiety/worry (96.5%); depression was the most commonly reported comorbidity (84.3%) as per physicians aware of GAD (N=508). This study illustrates that although GAD awareness is high among Japanese psychiatric specialists, GAD is not frequently diagnosed using operational diagnostic approaches. Due to a lack of Japanese guidelines for GAD diagnosis and treatment, diverse international guidelines are followed, with similar treatment paradigms as that of depression. This may not be an optimal approach given cultural/geographical differences. These findings highlight the need for uniform diagnosis and treatment recommendations for GAD management in Japan. UMIN-CTR: UMIN000049572.

A Randomized Controlled Trial Comparing Efficacy and Safety of Antidepressant Monotherapy.

The majority of mainstream antidepressants lack the promise of complete amelioration of symptoms. Other pitfalls include the latency period and side effects. These issues prompted investigations concerning thevarious roles of serotonin (5-HT) neurotransmissions in the etiology of depression. In this study, each study participant received vilazodone, vortioxetine, and escitalopram monotherapy for major depressive disorder (MDD)for 16 weeks. After that, the subject's scores on the Hamilton Depression Rating Scale (HDRS)-17 item version and the Montgomery Åsberg Depression Rating Scale (MADRS) were evaluated. In the study population, we kept track of the incidence of adverse events. Ninety-six patients with MDD participated in this open-label, randomized, three-arm study. Participants were allotted into three groups according to a 1:1:1 ratio and given vilazodone (20-40 mg/day), vortioxetine (5-20 mg/day), or escitalopram (10-20 mg/day) for 16 weeks. Vortioxetine and vilazodone are test medications, with escitalopram serving as the control. After the baseline visit, follow-up appointments were scheduled every four weeks. Per-protocol (PP) and intent-to-treat (ITT) populations served as means for efficacy and safety evaluations, respectively. We prospectively registered this research in the Clinical Trial Registry, India (CTRI) (2022/07/043808). Out of the 134 patients we screened, 109 (81.34%) were eligible. Ninety-six (88.07%) of them completed the 16-week trial. In the PP population (n = 96), we analyzed efficacy. They had a mean age of 46.3 ± 6.2 years. At baseline, each group's median HDRS score was 30.0 (p = 0.964). Following 16 weeks of antidepressant therapy, these scores dropped to 15.0, 14.0, and 13.0 (p = 0.002). Baseline MADRS scores for all groups were 36.0 (p = 0.741). They had corresponding values of 20.0, 18.0, and 17.0 at 16 weeks (p < 0.001). Regarding both efficacy endpoints, the post-hoc analysis with the Bonferroni correction demonstrated statistically significant differences (p < 0.001). We performed the safety assessments within our ITT population (n = 109). Ninety-six adverse events were recorded. Nonetheless, none of them seemed serious. Still, five participants opted out because of their side effects. Vomiting and nausea were the most frequent side effects. Compared to escitalopram and vilazodone, vortioxetine demonstrated a statistically significant reduction in HDRS and MADRS scores. It also had fewer and milder side effects. We recommend conducting studies involving a broader population to investigate the antidepressant effects of these medications further.

Susceptibility to Treatment-Resistant Depression Within Families

Antidepressant responses and the phenotype of treatment-resistant depression (TRD) are believed to have a genetic basis. Genetic susceptibility between the TRD phenotype and other psychiatric disorders has also been established in previous genetic studies, but population-based cohort studies have not yet provided evidence to support these outcomes. To estimate the TRD susceptibility and the susceptibility between TRD and other psychiatric disorders within families in a nationwide insurance cohort with extremely high coverage and comprehensive health care data. This cohort study assessed data from the Taiwan national health insurance database across entire population (N = 26 554 001) between January 2003 and December 2017. Data analysis was performed from August 2021 to April 2023. TRD was defined as having experienced at least 3 distinct antidepressant treatments in the current episode, each with adequate dose and duration, based on the prescribing records. Then, we identified the first-degree relatives of individuals with TRD (n = 34 467). A 1:4 comparison group (n = 137 868) of first-degree relatives of individuals without TRD was arranged for the comparison group, matched by birth year, sex, and kinship. Modified Poisson regression analyses were performed and adjusted relative risks (aRRs) and 95% CIs were calculated for the risk of TRD, the risk of other major psychiatric disorders, and different causes of mortality. This study included 172 335 participants (88 330 male and 84 005 female; mean [SD] age at beginning of follow-up, 22.9 [18.1] years). First-degree relatives of individuals with TRD had lower incomes, more physical comorbidities, higher suicide mortality, and increased risk of developing TRD (aRR, 9.16; 95% CI, 7.21-11.63) and higher risk of other psychiatric disorders than matched control individuals, including schizophrenia (aRR, 2.36; 95% CI, 2.10-2.65), bipolar disorder (aRR, 3.74; 95% CI, 3.39-4.13), major depressive disorder (aRR, 3.65; 95% CI, 3.44-3.87), attention-deficit/hyperactivity disorders (aRR, 2.38; 95% CI, 2.20-2.58), autism spectrum disorder (aRR, 2.26; 95% CI, 1.86-2.74), anxiety disorder (aRR, 2.71; 95% CI, 2.59-2.84), and obsessive-compulsive disorder (aRR, 3.14; 95% CI, 2.70-3.66). Sensitivity and subgroup analyses validated the robustness of the findings. To our knowledge, this study is the largest and perhaps first nationwide cohort study to demonstrate TRD phenotype transmission across families and coaggregation with other major psychiatric disorders. Patients with a family history of TRD had an increased risk of suicide mortality and tendency toward antidepressant resistance; therefore, more intensive treatments for depressive symptoms might be considered earlier, rather than antidepressant monotherapy.

Optimizing precision medicine for second-step depression treatment: a machine learning approach.

Less than a third of patients with depression achieve successful remission with standard first-step antidepressant monotherapy. The process for determining appropriate second-step care is often based on clinical intuition and involves a protracted course of trial and error, resulting in substantial patient burden and unnecessary delay in the provision of optimal treatment. To address this problem, we adopt an ensemble machine learning approach to improve prediction accuracy of remission in response to second-step treatments. Data were derived from the Level 2 stage of the STAR*D dataset, which included 1439 patients who were randomized into one of seven different second-step treatment strategies after failing to achieve remission during first-step antidepressant treatment. Ensemble machine learning models, comprising several individual algorithms, were evaluated using nested cross-validation on 155 predictor variables including clinical and demographic measures. The ensemble machine learning algorithms exhibited differential classification performance in predicting remission status across the seven second-step treatments. For the full set of predictors, AUC values ranged from 0.51 to 0.82 depending on the second-step treatment type. Predicting remission was most successful for cognitive therapy (AUC = 0.82) and least successful for other medication and combined treatment options (AUCs = 0.51-0.66). Ensemble machine learning has potential to predict second-step treatment. In this study, predictive performance varied by type of treatment, with greater accuracy in predicting remission in response to behavioral treatments than to pharmacotherapy interventions. Future directions include considering more informative predictor modalities to enhance prediction of second-step treatment response.

A distinctive subcortical functional connectivity pattern linking negative affect and treatment outcome in major depressive disorder

Major depressive disorder (MDD) is associated with functional disturbances in subcortical regions. In this naturalistic prospective study (NCT03294525), we aimed to investigate relationships among subcortical functional connectivity (FC), mood symptom profiles and treatment outcome in MDD using multivariate methods. Medication-free participants with MDD (n = 135) underwent a functional magnetic resonance imaging scan at baseline and completed posttreatment clinical assessment after 8 weeks of antidepressant monotherapy. We used partial least squares (PLS) correlation analysis to explore the association between subcortical FC and mood symptom profiles. FC score, reflecting the weighted representation of each individual in this association, was computed. Replication analysis was undertaken in an independent sample (n = 74). We also investigated the relationship between FC score and treatment outcome in the main sample. A distinctive subcortical connectivity pattern was found to be associated with negative affect. In general, higher FC between the caudate, putamen and thalamus was associated with greater negative affect. This association was partly replicated in the independent sample (similarity between the two samples: r = 0.66 for subcortical connectivity, r = 0.75 for mood symptom profile). Lower FC score predicted both remission and response to treatment after 8 weeks of antidepressant monotherapy. The emphasis here on the role of dorsal striatum and thalamus consolidates prior work of subcortical connectivity in MDD. The findings provide insight into the pathogenesis of MDD, linking subcortical FC with negative affect. However, while the FC score significantly predicted treatment outcome, the low odds ratio suggests that finding predictive biomarkers for depression remains an aspiration.

Longitudinal Influence of Prescribed Antidepressants on Fecal and Oral Microbiomes Among Veterans With Major Depressive Disorder.

The purpose of this study was to evaluate the influence of a new course of antidepressant monotherapy on gut and oral microbiomes and the relationship to depressive symptoms. Longitudinal microbiome samples obtained from 10 U.S. veterans were analyzed. Baseline samples were taken before a new course of antidepressant monotherapy (either switching from a previous treatment or starting a new treatment). Targeted genomic sequencing of the microbiome samples was used to analyze changes in taxonomy and diversity across participants, medications, and medication class. Associations between these changes and Patient Health Questionnaire-9 (PHQ-9) scores were analyzed. Taxonomic variability was observed across participants, with the individual being the main microbial community driver. In terms of the fecal microbiome, antidepressants were associated with shifts toward Bacteroides being less abundant and Blautia, Pseudomonas, or Faecalibacterium being more abundant. Likewise, the composition of the oral microbiome was variable, with individual participants being the primary drivers of community composition. In the oral samples, the relative abundance of Haemophilus decreased after antidepressants were started. Increases in Blautia and decreases in Bacteroides were associated with lower PHQ-9 scores. Antidepressants were found to influence fecal and oral microbiomes such that a new course of antidepressant monotherapy was associated with taxonomic alterations toward healthier states in both fecal and oral microbiomes, which were associated with decreases in depressive symptoms. Additional longitudinal research is required to increase understanding of microbiomes and symptom-based changes, with a particular focus on potential differences between medication classes and underlying mechanisms.

Risk of dementia among antidepressant elderly users: A population-based cohort analysis in Spain

The use of antidepressants with anticholinergic effects has been associated with an increased risk of dementia. However, the results published are contradictory. The aim of the study is to compare the risk of developing dementia in elderly who were prescribed tricyclic antidepressants (TCA) versus those who were prescribed selective serotonin reuptake inhibitors (SSRIs) and other antidepressants (OA). A prospective population-based cohort study was performed using the Spanish Database for Pharmacoepidemiological Research in Primary Care (BIFAP) data (from 2005 to 2018). The cohort study included 62,928 patients age ≥ 60 without dementia and with antidepressant long-term monotherapy. Patients were divided into exposure antidepressant groups based on ATC system [TCA, SSRIs users and OAs users]. The risk of dementia was calculated by Cox regression models, providing hazard ratios (HR) and 95 % confidence intervals. The Kaplan-Meier model was used for survival analysis. Chi2 test was used as association test. The results showed SSRI users had higher dementia risk than TCA users (HR = 1.864; 95%CI = 1.624–2.140). Moreover, OA users had also significant risk of dementia (HR = 2.103; 95%CI = 1.818–2.431). Several limitations are the variation of the trend in the prescription of antidepressants, the small number of patients that use some antidepressants, the lack of information related to the dose, or socioeconomic characteristics, the use of antidepressant drugs for other indications, or the therapeutic compliance.Our findings showed that older users of SSRI and OA have more risk of developing dementia than TCA elderly users. However, additional studies would be needed.

Association between benzodiazepine anxiolytic polypharmacy and concomitant psychotropic medications in Japan: a retrospective cross-sectional study.

Guidelines for various psychiatric disorders recommend short-term use of benzodiazepine anxiolytic monotherapy in few cases. Contrarily, benzodiazepine anxiolytic polypharmacy (BAP) is not recommended in any case. However, BAP is often used in real world. Therefore, this study aimed to determine the association between BAP and concomitant use of psychotropic medications. This retrospective cross-sectional study used claims data from the Japan Medical Data Center. Medical information of health insurance subscribers treated with benzodiazepine anxiolytics in June 2019 was extracted. Prescription of two or more benzodiazepine anxiolytics was defined as BAP. Binary logistic regression analysis was performed to investigate the factors associated with BAP, using age group, sex, type of subscriber, and number of concomitant hypnotics, antidepressants, and antipsychotics (none, one, and two or more) as covariates. The eligible participants were 104,796 adults who were prescribed benzodiazepine anxiolytics. Among them, 12.6% were prescribed two or more drugs. Logistic regression analysis revealed that BAP was significantly associated with those who received hypnotic monotherapy (adjusted odds ratio [aOR]: 1.04, 95% confidence interval [CI]: 1.001-1.09, p=0.04), antidepressant monotherapy and polypharmacy (aOR: 1.57, 95% CI: 1.51-1.63, p<0.001 and aOR: 1.98, 95% CI: 1.88-2.09, p<0.001, respectively), and antipsychotic monotherapy and polypharmacy (aOR: 1.12, 95% CI: 1.07-1.19, p<0.001 and aOR: 1.41, 95% CI: 1.30-1.54, p<0.001, respectively). Conversely, lower BAP was associated with those who received hypnotic polypharmacy (aOR: 0.86, 95% CI: 0.81-0.91, p<0.001). This study showed that the greater the number of concomitant antidepressants and antipsychotics, the greater the association with BAP. Since combination therapy with antidepressants or antipsychotics is generally not recommended, patients receiving combination therapy with these medications may be resistant to pharmacotherapy. Therefore, implementing the recommended non-pharmacological treatments may reduce BAP.

Antipsychotics in the maintenance phase for psychotic depression.

This study aimed to associate antidepressants with versus without antipsychotics with readmission and suicide in patients with psychotic unipolar depression. Swedish national registers were used to identify inpatients with psychotic unipolar depression, treated 2007-2016. The participants collected antidepressants with or without antipsychotics from a pharmacy within 14 days after discharge and were followed up for 2 years. The primary outcome was hospital readmission due to any psychiatric disorder, suicide attempt, or completed suicide. Cox regression was used to analyze the data, which were adjusted for sex, age, prior admissions, comorbidity, electroconvulsive therapy, and other pharmacological treatments. We identified 4391 patients, of which 2972 were in the antidepressant + antipsychotic combination therapy group, and 1419 were in the antidepressant monotherapy group. After 2 years, 42.3% and 36.6% of patients were readmitted or committed suicide in the combination therapy and monotherapy group, respectively. Monotherapy was significantly associated with a lower risk of reaching the outcome in the main analysis (hazard ratio = 0.86; 95% confidence interval: 0.77-0.95). The results went in the same direction in all sensitivity analyses. Our findings do not indicate any advantage of adding antipsychotics as adjunctive to antidepressants as maintenance treatment. Considering the wide use, known side effects, and the current lack of evidence supporting the benefit, further studies on the effect of antipsychotics in the maintenance phase of psychotic unipolar depression are urgently warranted.

Bipolar Disorder and Antidepressant Associated Hypomania

The impact of antidepressant associated hypomania on monomanic depression and its relationship to bipolar disorder. This review attempts to investigate and review current research on bipolar disorder diagnosis, the neurobiological mechanisms of antidepressant-associated hypomania, risk factors, and how to manage the occurrence of this condition. Bipolar disorder is a widespread, debilitating, recurrent, variable-severity mental health condition in which the patient exhibits two different states and unpredictable mood switching. Mania, hypomania, mixed states, depression, and depression interspersed with moments of relative health are the stages of the disorder. Early identification of bipolar disorder can improve prognosis. Patients with monophasic episodes are uncommon, as the clinical manifestation of bipolar illness is unpredictable. Throughout their lives, individuals with bipolar disorder alternate between episodes of mania or hypomania and depression. Depressive episodes in bipolar disorder are referred to as bipolar depression, and the underlying core symptom is depressed mood, which are essentially identical to the diagnostic criteria and clinical symptoms of uniphasic depression, so there is a high risk of misdiagnosis during the initial visit. Patients often choose to seek specialist help during depressive episodes, and this can lead to a tendency to overlook whether a patient has bipolar disorder. Antidepressant monotherapy is contraindicated for hypomanic episodes. Antidepressants tend to induce hypomanic and manic episodes, a phenomenon known as antidepressant-associated hypomania (AAH). All antidepressant drugs may cause mania. One is drug induced mania; The other is considered a potential bipolar disorder. There is a high co-occurrence of psychiatric disorders, but only bipolar disorder, monophasic depression, and antidepressant-induced hypomanic episodes are discussed here.

Antidepressant and antipsychotic side-effects and personalised prescribing: a systematic review and digital tool development

Side-effects of psychiatric medication impair quality of life and functioning. Furthermore, they contribute to morbidity, mortality, stigma, and poor treatment concordance resulting in relapse of psychiatric illness. Guidelines recommend discussing side-effects with patients when making treatment decisions, but a synthesis of antidepressant and antipsychotic side-effects to guide this process is missing, and considering all side-effects is a complex, multidimensional process. We aimed to create comprehensive databases of antipsychotic and antidepressant side-effects, and a digital tool to support database navigation. To create the databases, we did an umbrella review of Embase, PsycINFO, and MEDLINE from database inception to June 26, 2023. We included meta-analyses of randomised controlled trials examining antipsychotic monotherapy in the treatment of schizophrenia or antidepressant monotherapy in the treatment of major depressive disorder. We included meta-analyses in adults (aged ≥18 years) that assessed drugs with a common comparator. The search was complemented by a review of national and international guidelines and consensus statements for the treatment of major depressive disorder and schizophrenia in adults. Effect sizes for antipsychotic and antidepressant side-effects were extracted from meta-analyses examining the largest number of drugs. In cases of incomplete meta-analytic coverage, data were imputed on the basis of guideline-derived ordinal rankings or, if imputation was not possible, ordinal scores were extracted. Both meta-analytic and ordinal outcomes were normalised to provide values between 0 and 1. We then constructed a digital tool, the Psymatik Treatment Optimizer, to combine the side-effect databases with side-effect concerns of an individual user, to enable users to select side-effects of concern and the relative degree of concern for each side-effect. Concern weightings and the side-effect databases are synthesised via a multicriteria decision analysis method (technique for order of preference by similarity to ideal situation, or TOPSIS). Of 3724 citations, 14 articles containing 68 meta-analyses of individual side-effects met inclusion criteria. After review of 19 guidelines, seven provided ordinal data. Antipsychotic data were extracted from five studies (11 meta-analyses, n=65 594 patients) and four guidelines, and antidepressant data were extracted from three guidelines. The resultant databases included data on 32 antipsychotics (14 side-effects) and 37 antidepressants (nine side-effects). The databases highlighted the clinical dilemma associated with balancing side-effects, with avoidance of one side-effect (eg, weight gain for antipsychotics) increasing the risk of others (eg, akathisia). To aid with this dilemma, the Psymatik Treatment Optimizer synthesises the side-effect databases with individual user-defined concern weights. After computing up to 5851 pairwise comparisons for antidepressants and 5142 pairwise comparisons for antipsychotics, Psymatik ranks treatments in order of preference for the individual user, with the output presented in a heatmap. By facilitating collaborative, personalised, and evidence-based prescribing decisions, the side-effect databases and digital application supports care delivery that is consistent with international regulatory guidance for the treatment of schizophrenia and depression, and it therefore has promise for informing psychiatric practice and improving outcomes. National Institute for Health and Care Research, Maudsley Charity, Wellcome Trust, Medical Research Council.