Neurostructural Differences in Adolescents With Treatment-Resistant Depression and Treatment Effects of Transcranial Magnetic Stimulation

BackgroundDespite its morbidity and mortality, the neurobiology of treatment-resistant depression (TRD) in adolescents and the impact of treatment on this neurobiology is poorly understood.MethodsUsing automatic segmentation in FreeSurfer, we examined brain magnetic resonance imaging baseline volumetric differences among healthy adolescents (n = 30), adolescents with major depressive disorder (MDD) (n = 19), and adolescents with TRD (n = 34) based on objective antidepressant treatment rating criteria. A pooled subsample of adolescents with TRD were treated with 6 weeks of active (n = 18) or sham (n = 7) 10-Hz transcranial magnetic stimulation (TMS) applied to the left dorsolateral prefrontal cortex. Ten of the adolescents treated with active TMS were part of an open-label trial. The other adolescents treated with active (n = 8) or sham (n = 7) were participants from a randomized controlled trial.ResultsAdolescents with TRD and adolescents with MDD had decreased total amygdala (TRD and MDD: −5%, P = .032) and caudal anterior cingulate cortex volumes (TRD: −3%, P = .030; MDD: −.03%, P = .041) compared with healthy adolescents. Six weeks of active TMS increased total amygdala volumes (+4%, P < .001) and the volume of the stimulated left dorsolateral prefrontal cortex (+.4%, P = .026) in adolescents with TRD.ConclusionsAmygdala volumes were reduced in this sample of adolescents with MDD and TRD. TMS may normalize this volumetric finding, raising the possibility that TMS has neurostructural frontolimbic effects in adolescents with TRD. TMS also appears to have positive effects proximal to the site of stimulation.     

High S100B Levels Predict Antidepressant Response in Patients With Major Depression Even When Considering Inflammatory and Metabolic Markers

BackgroundThe relationship between antidepressant response and glial, inflammatory, and metabolic markers is poorly understood in depression. This study assessed the ability of biological markers to predict antidepressant response in major depressive disorder (MDD).MethodsWe included 31 MDD outpatients treated with escitalopram or sertraline for 8 consecutive weeks. The Montgomery-Åsberg Depression Rating Scale (MADRS) was administered at baseline and at week 4 and 8 of treatment. Concomitantly, blood samples were collected for the determination of serum S100B, C-reactive protein (CRP), and high-density lipoprotein cholesterol (HDL)-C levels. Treatment response was defined as ≥50% improvement in the MADRS score from baseline to either week 4 or 8. Variables associated with treatment response were included in a linear regression model as predictors of treatment response.ResultsTwenty-seven patients (87%) completed 8 weeks of treatment; 74% and 63% were responders at week 4 and 8, respectively. High S100B and low HDL-C levels at baseline were associated with better treatment response at both time points. Low CRP levels were correlated with better response at week 4. Multivariate analysis showed that high baseline S100B levels and low baseline HDL-C levels were good predictors of treatment response at week 4 (R^2 =0.457, P = .001), while S100B was at week 8 (R² = 0.239, P = .011). Importantly, baseline S100B and HDL-C levels were not associated with depression severity and did not change over time with clinical improvement.ConclusionsSerum S100B levels appear to be a useful biomarker of antidepressant response in MDD even when considering inflammatory and metabolic markers.     

Racemic Ketamine as an Alternative to Electroconvulsive Therapy for Unipolar Depression: A Randomized,Open-Label,Non-Inferiority Trial (KetECT)

BackgroundKetamine has emerged as a fast-acting and powerful antidepressant, but no head to head trial has been performed, Here, ketamine is compared with electroconvulsive therapy (ECT), the most effective therapy for depression.MethodsHospitalized patients with unipolar depression were randomized (1:1) to thrice-weekly racemic ketamine (0.5 mg/kg) infusions or ECT in a parallel, open-label, non-inferiority study. The primary outcome was remission (Montgomery Åsberg Depression Rating Scale score ≤10). Secondary outcomes included adverse events (AEs), time to remission, and relapse. Treatment sessions (maximum of 12) were administered until remission or maximal effect was achieved. Remitters were followed for 12 months after the final treatment session.ResultsIn total 186 inpatients were included and received treatment. Among patients receiving ECT, 63% remitted compared with 46% receiving ketamine infusions (P = .026; difference 95% CI 2%, 30%). Both ketamine and ECT required a median of 6 treatment sessions to induce remission. Distinct AEs were associated with each treatment. Serious and long-lasting AEs, including cases of persisting amnesia, were more common with ECT, while treatment-emergent AEs led to more dropouts in the ketamine group. Among remitters, 70% and 63%, with 57 and 61 median days in remission, relapsed within 12 months in the ketamine and ECT groups, respectively (P = .52).ConclusionRemission and cumulative symptom reduction following multiple racemic ketamine infusions in severely ill patients (age 18–85 years) in an authentic clinical setting suggest that ketamine, despite being inferior to ECT, can be a safe and valuable tool in treating unipolar depression.     

Serotonin Transporter Gene Promoter Hypomethylation as a Predictor of Antidepressant Treatment Response in Major Depression: A Replication Study

BackgroundThe serotonin transporter gene (SLC6A4; 5-HTT; SERT) is considered a prime candidate in pharmacogenetic research in major depressive disorder (MDD). Besides genetic variation, recent advances have spotlighted the involvement of epigenetic mechanisms such as DNA methylation in predicting antidepressant treatment response in “pharmaco-epigenetic” approaches. In MDD, lower SLC6A4 promoter methylation has been suggested to predict impaired response to serotonergic antidepressants. The present study sought to replicate and extend this finding in a large, independent sample of MDD patients.MethodsThe sample comprised n = 236 Caucasian patients with MDD receiving antidepressant medication in a naturalistic treatment setting. Functional DNA methylation of 9 CpG sites located in the SLC6A4 promoter region was analyzed via direct sequencing of sodium bisulfite– treated DNA extracted from blood cells. Patients were assessed over the course of a 6-week in-patient treatment using the Hamilton Depression Scale (HAM-D).ResultsResults confirm relative SLC6A4 hypomethylation to predict impaired antidepressant response both dimensionally and categorically (HAM-D reductions < 50%) and to furthermore be indicative of nonremission (HAM-D > 7). This also held true in a homogenous subgroup of patients continuously treated with selective serotonin reuptake inhibitors or serotonin/noradrenaline reuptake inhibitors (n = 110).ConclusionsImpaired response to serotonergic antidepressants via SLC6A4 hypomethylation may be conveyed by increased gene expression and consequently decreased serotonin availability, which may counteract the effects of serotonergic antidepressants. The present results could in the future inform clinical decision-making towards a more personalized treatment of MDD.     

Serotonin 1A Receptor Binding of [11C]CUMI-101 in Bipolar Depression Quantified Using Positron Emission Tomography: Relationship to Psychopathology and Antidepressant Response

BackgroundThe pathophysiology of bipolar disorder (BD) remains largely unknown despite it causing significant disability and suicide risk. Serotonin signaling may play a role in the pathophysiology, but direct evidence for this is lacking. Treatment of the depressed phase of the disorder is limited. Previous studies have indicated that positron emission tomography (PET) imaging of the serotonin 1A receptor (5HT1AR) may predict antidepressant response.MethodsA total of 20 participants with BD in a current major depressive episode and 16 healthy volunteers had PET imaging with [¹¹C]CUMI-101, employing a metabolite-corrected input function for quantification of binding potential to the 5HT1AR. Bipolar participants then received an open-labeled, 6-week clinical trial with a selective serotonin reuptake inhibitor (SSRI) in addition to their mood stabilizer. Clinical ratings were obtained at baseline and during SSRI treatment.ResultsPretreatment binding potential (BP_F) of [¹¹C]CUMI-101 was associated with a number of pretreatment clinical variables within BD participants. Within the raphe nucleus, it was inversely associated with the baseline Montgomery Åsberg Rating Scale (P = .026), the Beck Depression Inventory score (P = .0023), and the Buss Durkee Hostility Index (P = .0058), a measure of lifetime aggression. A secondary analysis found [¹¹C]CUMI-101 BP_F was higher in bipolar participants compared with healthy volunteers (P = .00275). [¹¹C]CUMI-101 BP_F did not differ between SSRI responders and non-responders (P = .907) to treatment and did not predict antidepressant response (P = .580). Voxel-wise analyses confirmed the results obtained in regions of interest analyses.ConclusionsA disturbance of serotonin system function is associated with both the diagnosis of BD and its severity of depression. Pretreatment 5HT1AR binding did not predict SSRI antidepressant outcome.The study was listed on clinicaltrials.gov with identifier {"type":"clinical-trial","attrs":{"text":"NCT02473250","term_id":"NCT02473250"}}NCT02473250.     

Intrinsic reward circuit connectivity profiles underlying symptom and quality of life outcomes following antidepressant medication: a report from the iSPOT-D trial

There is a critical need to better understand the neural basis of antidepressant medication (ADM) response with respect to both symptom alleviation and quality of life (QoL) in major depressive disorder (MDD). Reward neurocircuitry has been implicated in QoL, the neural basis of MDD, and the mechanisms of ADM response. Yet, we do not know whether change in reward neurocircuitry as a function of ADM is associated with change in symptoms and QoL. To address this gap in knowledge, we analyzed data from 128 patients with MDD who participated in the iSPOT-D trial and were assessed with functional neuroimaging pre- and post-ADM treatment (randomized to sertraline, venlafaxine-XR, or escitalopram). 58 matched healthy controls were scanned at the same time points. We quantified functional connectivity (FC) of reward neurocircuitry using nucleus accumbens (NAc) seed regions of interest, and then characterized how changes in FC relate to symptom response (primary outcome) and QoL response (secondary outcome). Symptom responders showed an increase in NAc-dorsal anterior cingulate cortex (ACC) FC relative to non-responders (p < 0.001) which was associated with improvement in physical QoL (p < 0.0003), and a decrease in NAc-inferior parietal lobule FC relative to controls (p < 0.001). QoL response was characterized by increases in FC between NAc-ventral ACC for environmental, NAc-thalamus for physical, and NAc-paracingulate gyrus for social domains (p < 0.001). Symptom responders to sertraline were distinguished by a decrease in NAc-insula FC (p < 0.001) and to venlafaxine-XR by an increase in NAc-inferior temporal gyrus FC (p < 0.005). Findings suggest that change in reward neurocircuitry may underlie differential ADM response profiles with respect to symptoms and QoL in depression.Subject terms: Predictive markers, Depression     

Efficacy,Safety, and Tolerability of Ansofaxine (LY03005) Extended-Release Tablet for Major Depressive Disorder: A Randomized,Double-Blind,Placebo-Controlled,Dose-Finding,Phase 2 Clinical Trial

BackgroundAnsofaxine (LY03005) extended-release tablet is a potential triple reuptake inhibitor of serotonin, norepinephrine, and dopamine. This study assessed the efficacy, safety, and appropriate dosage of ansofaxine for the treatment of major depressive disorder (MDD).MethodsA multicenter, randomized, double-blind, placebo-controlled, dose-finding, Phase 2 clinical trial was conducted in China. Eligible patients with MDD (18–65 years) were randomly assigned to receive fixed-dose ansofaxine extended-release tablets (40, 80, 120, or 160 mg/d) or placebo for 6 weeks. The primary outcome measure was a change in the total score on the 17-item Hamilton Depression Rating Scale from baseline to week 6.ResultsA total of 260 patients were recruited from October 2015 to September 2017, and 255 patients received the study drug as follows: 40 mg (n = 52), 80 mg (n = 52), 120 mg (n = 51), and 160 mg (n = 51) ansofaxine and placebo (n = 49). Significant differences were found in mean changes in 17-item Hamilton Depression Rating Scale total scores at week 6 in the 4 ansofaxine groups vs placebo (−12.46; χ²=−9.71, P = .0447). All doses of ansofaxine were generally well-tolerated. Treatment-related adverse events occurred in 141 patients (303 cases), yielding incidence rates of 51.92%, 65.38%, 56.86%, and 62.75% in the 40-, 80-, 120-, and 160-mg ansofaxine groups and 38.78% in the placebo group.ConclusionActive doses (40, 80, 120, and 160 mg/d) of ansofaxine in a controlled setting were safe, tolerated, and effective in improving depression symptoms in MDD patients.     

Sex Differences in the Association of Cigarette Craving With Insula Structure

BackgroundCigarette craving, which can negatively impact smoking cessation, is reportedly stronger in women than in men when they initiate abstinence from smoking. Identifying approaches to counteract craving in people of different sexes may facilitate the development of personalized treatments for Tobacco Use Disorder, which disproportionately affects women. Because cigarette craving is associated with nicotine dependence and structure of the insula, this study addressed whether a person’s sex influences these associations.MethodsThe research participants (n = 99, 48 women) reported daily cigarette smoking and provided self-reports of nicotine dependence. After overnight abstinence from smoking, they underwent structural magnetic resonance imaging scanning to determine cortical thickness of the left and right anterior circular insular sulcus, and self-rated their cigarette craving before and after their first cigarette of the day.ResultsWomen reported stronger craving than men irrespective of smoking condition (i.e., pre- and post-smoking) (P = .048), and smoking reduced craving irrespective of sex (P < .001). A 3-way interaction of sex, smoking condition, and right anterior circular insular sulcus thickness on craving (P = .033) reflected a negative association of cortical thickness with pre-smoking craving in women only (P = .012). No effects of cortical thickness in the left anterior circular insular sulcus were detected. Nicotine dependence was positively associated with craving (P < .001) across groups and sessions, with no sex differences in this association.ConclusionsA negative association of right anterior insula thickness with craving in women only suggests that this region may be a relevant therapeutic target for brain-based smoking cessation interventions in women.     

Course of Improvement in Depressive Symptoms to a Single Intravenous Infusion of Ketamine vs Add-on Riluzole: Results from a 4-Week,Double-Blind,Placebo-Controlled Study

The N-methyl--aspartate antagonist ketamine has rapid antidepressant effects in patients with treatment-resistant major depression (TRD); these effects have been reported to last for 1 week in some patients. However, the extent and duration of this antidepressant effect over longer periods has not been well characterized under controlled conditions. Riluzole, a glutamatergic modulator with antidepressant and synaptic plasticity-enhancing effects, could conceivably be used to promote the antidepressant effects of ketamine. This study sought to determine the extent and time course of antidepressant improvement to a single-ketamine infusion over 4 weeks, comparing the addition of riluzole vs placebo after the infusion. Forty-two subjects (18–65) with TRD and a Montgomery–Asberg Depression Rating Scale (MADRS) score of ⩾22 received a single intravenous infusion of ketamine (0.5 mg/kg). Four to six hours post-infusion, subjects were randomized to double-blind treatment with either riluzole (100–200 mg/day; n=21) or placebo (n=21) for 4 weeks. Depressive symptoms were rated daily. A significant improvement (P<0.001) in MADRS scores from baseline was found. The effect size of improvement with ketamine was initially large and remained moderate throughout the 28-day trial. Overall, 27% of ketamine responders had not relapsed by 4 weeks following a single ketamine infusion. The average time to relapse was 13.2 days (SE=2.2). However, the difference between the riluzole and placebo treatment groups was not significant, suggesting that the combination of riluzole with ketamine treatment did not significantly alter the course of antidepressant response to ketamine alone.     

Differences in Executive Function Among Patients With Schizophrenia,Their Unaffected First-Degree Relatives,and Healthy Participants

BackgroundPatients with schizophrenia (SCZ) display impaired executive functions compared with healthy controls (HCs). Furthermore, unaffected first-degree relatives (FRs) of patients with SCZ independently perform worse executive functions than do HCs. However, few studies have investigated the differences in executive functions assessed among patients with SCZ, FRs, and HCs, and the findings are inconsistent.MethodsWe investigated diagnostic differences in executive functions, namely (1) numbers of categories achieved (CA), (2) total errors (TE), and (3) percentage of perseverative errors of Nelson types (%PEN), using the Wisconsin card sorting test among patients with SCZ (n = 116), unaffected FRs (n = 62), and HCs (n = 146) at a single institute. Correlations between these executive functions and clinical variables were investigated.ResultsSignificant differences existed in all executive functions among diagnostic groups (CA, F_2,319 = 15.5, P = 3.71 × 10^–7; TE, F_2,319 = 16.2, P = 2.06 × 10^–7; and %PEN, F_2,319 = 21.3, P = 2.15 × 10^–9). Patients with SCZ had fewer CA and more TE and %PEN than those of HCs (CA, Cohen’s d = −0.70, P = 5.49 × 10^–8; TE, d = 0.70, P = 5.62 × 10^–8; and %PEN, d = 0.82, P = 2.85 × 10⁻¹⁰) and FRs (TE, d = 0.46, P = 3.73 × 10^–3 and %PEN, d = 0.38, P = .017). Of the 3 executive functions, CA and %PEN of FRs were intermediately impaired between patients with SCZ and HCs (CA, d = −0.41, P = .011 and %PEN, d = 0.41, P = .012). In contrast, no significant difference in TE existed between FRs and HCs (d = 0.22, P = .18). Although CA and TE were affected by the duration of illness (P < .017), %PEN was not affected by any clinical variable in patients with SCZ (P > .017).ConclusionsExecutive function, particularly %PEN, could be a useful intermediate phenotype for understanding the genetic mechanisms implicated in SCZ pathophysiology.     

Genetic evidence for a potential causal relationship between insomnia symptoms and suicidal behavior: a Mendelian randomization study

Insomnia and restless leg syndrome (RLS) are associated with increased risk for suicidal behavior (SB), which is often comorbid with mood or thought disorders; however, it is unclear whether these relationships are causal. We performed a two-sample Mendelian randomization study using summary-level genetic associations with insomnia symptoms and RLS against the outcomes of risk of major depressive disorder (MDD), bipolar disorder (BP), schizophrenia (SCZ), and SB. The inverse-variance weighted method was used in the main analysis. We performed replication and sensitivity analyses to examine the robustness of the results. We identified outcome cohorts for MDD (n = 170,756 cases/329,443 controls), BP (n = 20,352/31,358), SCZ (n = 69,369/236,642), SB-Cohort-2019 (n = 6569/14,996 all with MDD, BP or SCZ; and SB within individual disease categories), and SB-Cohort-2020 (n = 29,782/519,961). Genetically proxied liability to insomnia symptoms significantly associated with increased risk of MDD (odds ratio (OR) = 1.23, 95% confidence interval (CI) = 1.2–1.26, P = 1.37 × 10^–61), BP (OR = 1.15, 95% CI = 1.07–1.23, P = 5.11 × 10^–5), SB-Cohort-2019 (OR = 1.17, 95% CI = 1.07–1.27, P = 2.30 × 10^–4), SB-Cohort-2019 in depressed patients (OR = 1.34, 95% CI = 1.16–1.54, P = 5.97 × 10^–5), and SB-Cohort-2020 (OR = 1.24, 95% CI = 1.18–1.3, P = 1.47 × 10^–18). Genetically proxied liability to RLS did not significantly influence the risk of any of the outcomes (all corrected P > 0.05). Results were replicated for insomnia with MDD and SB in Mass General Brigham Biobank and were consistent in multiple lines of sensitivity analyses. In conclusion, human genetic evidence supports for the first time a potentially independent and causal effect of insomnia on SB and encourages further clinical investigation of treatment of insomnia for prevention or treatment of SB.Subject terms: Genetic markers, Risk factors, Psychiatric disorders     

Exploring the Effects of Pharmacological,Psychosocial, and Alternative/Complementary Interventions in Children and Adolescents With Attention-Deficit/Hyperactivity Disorder: Meta-Regression Approach

BackgroundThere have been various therapies for attention-deficit/hyperactivity disorder (ADHD), but the previous meta-analysis of ADHD efficacy remains unclear. This study aims to systemically meta-regress the effect sizes (ES) of psychostimulant pharmacotherapy (methylphenidate and lisdexamfetamine), non-stimulant pharmacotherapy (atomoxetine and alpha-2 agonists), psychosocial therapy (parental behavioral therapy [PBT]), combination therapy (psychostimulant plus PBT), and alternative/complementary interventions to determine the right treatment for ADHD.MethodsWe searched various ADHD interventions from the MEDLINE and PubMed databases (National Center for Biotechnology Information) between January 1, 1980, and July 30, 2018. Following the meta-analysis of random effects, the meta-regression analyses were used to explore factors potentially influencing treatment efficacy. The confounding variables included type of treatment, type of study, age, type of symptom scale used, and year of publication.ResultsA total of 107 trials (n = 9883 participants) were included. After adjustment, compared with the psychostimulant therapy (28 trial, 2134 participants), non-stimulant pharmacotherapy (28 trials, 4991 participants) and alternative/complement intervention (25 trials, 1195 participants) were less effective by the ES of −0.384 (P = .004) and −0.419 (P = .028), respectively. However, compared with psychostimulant, PBT (19 trials, 1122 participants; ES = −0.308, P = .095) and the combination of psychostimulant and PBT (7 trials, 441participants; ES = −0.196, P = .209) did not differ significantly.ConclusionsPsychostimulant therapy surpassed non-stimulant pharmacotherapy and alternative/complement intervention. Psychostimulant therapy, PBT, and the combination of psychostimulant therapy and PBT appear to be similar in efficacy according to this meta-regression.     

Dose-related effects of ketamine for antidepressant-resistant symptoms of posttraumatic stress disorder in veterans and active duty military: a double-blind,randomized, placebo-controlled multi-center clinical trial

This study tested the efficacy of repeated intravenous ketamine doses to reduce symptoms of posttraumatic stress disorder (PTSD). Veterans and service members with PTSD (n = 158) who failed previous antidepressant treatment were randomized to 8 infusions administered twice weekly of intravenous placebo (n = 54), low dose (0.2 mg/kg; n = 53) or standard dose (0.5 mg/kg; n = 51) ketamine. Participants were assessed at baseline, during treatment, and for 4 weeks after their last infusion. Primary analyses used mixed effects models. The primary outcome measure was the self-report PTSD Checklist for DSM-5 (PCL-5), and secondary outcome measures were the Clinician-Administered PTSD Scale for DSM-5 (CAPS-5) and the Montgomery Åsberg Depression Rating Scale (MADRS). There were no significant group-by-time interactions for PTSD symptoms measured by the PCL-5 or CAPS-5. The standard ketamine dose ameliorated depression measured by the MADRS significantly more than placebo. Ketamine produced dose-related dissociative and psychotomimetic effects, which returned to baseline within 2 h and were less pronounced with repeated administration. There was no evidence of differential treatment discontinuation by ketamine dose, consistent with good tolerability. This clinical trial failed to find a significant dose-related effect of ketamine on PTSD symptoms. Secondary analyses suggested that the standard dose exerted rapid antidepressant effects. Further studies are needed to determine the role of ketamine in PTSD treatment. ClinicalTrials.gov identifier: {"type":"clinical-trial","attrs":{"text":"NCT02655692","term_id":"NCT02655692"}}NCT02655692.Subject terms: Drug development, Trauma     

Apathy and Anhedonia in Adult and Adolescent Cannabis Users and Controls Before and During the COVID-19 Pandemic Lockdown

BackgroundCOVID-19 lockdown measures have caused severe disruptions to work and education and prevented people from engaging in many rewarding activities. Cannabis users may be especially vulnerable, having been previously shown to have higher levels of apathy and anhedonia than non-users.MethodsIn this survey study, we measured apathy and anhedonia, before and after lockdown measures were implemented, in n = 256 adult and n = 200 adolescent cannabis users and n = 170 adult and n = 172 adolescent controls. Scores on the Apathy Evaluation Scale (AES) and Snaith-Hamilton Pleasure Scale (SHAPS) were investigated with mixed-measures ANCOVA, with factors user group, age group, and time, controlling for depression, anxiety, and other drug use.ResultsAdolescent cannabis users had significantly higher SHAPS scores before lockdown, indicative of greater anhedonia, compared with adolescent controls (P = .03, η _p² = .013). Contrastingly, adult users had significantly lower scores on both the SHAPS (P < .001, η _p² = .030) and AES (P < .001, η _p² = .048) after lockdown compared with adult controls. Scores on both scales increased during lockdown across groups, and this increase was significantly smaller for cannabis users (AES: P = .001, η _p² = .014; SHAPS: P = .01, η _p² = .008). Exploratory analyses revealed that dependent cannabis users had significantly higher scores overall (AES: P < .001, η _p² = .037; SHAPS: P < .001, η _p² = .029) and a larger increase in scores (AES: P = .04, η _p² =.010; SHAPS: P = .04, η _p² = .010), compared with non-dependent users.ConclusionsOur results suggest that adolescents and adults have differential associations between cannabis use as well as apathy and anhedonia. Within users, dependence may be associated with higher levels of apathy and anhedonia regardless of age and a greater increase in levels during the COVID-19 lockdown.     

Efficacy and Safety of Seltorexant as Adjunctive Therapy in Major Depressive Disorder: A Phase 2b,Randomized, Placebo-Controlled,Adaptive Dose-Finding Study

BackgroundSeltorexant, a selective antagonist of human orexin-2 receptors, demonstrated antidepressant effects in a previous exploratory study in patients with major depressive disorder (MDD).MethodsTo replicate and extend this observation, a double-blind, adaptive dose-finding study was performed in patients with MDD who had an inadequate response to 1–3 selective serotonin/serotonin-norepinephrine reuptake inhibitors in the current episode. Patients were randomized (2:1:1) to placebo or seltorexant (20 mg or 40 mg) once-daily, administered adjunctively to the antidepressant the patient had been receiving at screening. After an interim analysis (6 weeks post-randomization of 160th patient), newly recruited patients randomly received (3:3:1) placebo or seltorexant 10 mg or 20 mg; the 40-mg dose was no longer assigned. Patients were stratified by baseline Insomnia Severity Index (ISI) scores (ISI ≥ 15 vs < 15). The primary endpoint was change from baseline Montgomery-Åsberg Depression Rating Scale (MADRS) total score at week 6.ResultsMixed-Model for Repeated Measures analysis showed a greater improvement in MADRS total score in the seltorexant 20-mg group vs placebo at weeks 3 and 6; least-square means difference (90% CI): −4.5 (−6.96; −2.07), P = .003; and −3.1 (−6.13; −0.16), P = .083, respectively. The improvement in MADRS score at week 6 for seltorexant 20 mg was greater in patients with baseline ISI ≥ 15 vs those with ISI < 15; least-square means difference (90% CI) vs placebo: −4.9 (−8.98; −0.80) and −0.7 (−5.16; 3.76), respectively. The most common (≥5%) adverse events with seltorexant were somnolence, headache, and nausea.ConclusionsA clinically meaningful reduction of depressive symptoms was observed for seltorexant 20 mg. In the subset of patients with sleep disturbance (ISI ≥ 15), a larger treatment difference between seltorexant 20 mg and placebo was observed, warranting further investigation. No new safety signal was identified.RegistrationClinicalTrials.gov Identifier: {"type":"clinical-trial","attrs":{"text":"NCT03227224","term_id":"NCT03227224"}}NCT03227224Previous presentationPoster presented at 58th Annual Meeting of American College of Neuropsychopharmacology (ACNP), December 8–11, 2019, Orlando, FL.     

Antidepressive Effect of Antipsychotics in the Treatment of Schizophrenia: Meta-Regression Analysis of Randomized Placebo-Controlled Trials

BackgroundAntipsychotics improve the positive symptoms of schizophrenia. However, little is known about the extent of antidepressive effects of antipsychotics and their correlation with effects on other symptom domains in schizophrenia. The aim was to investigate whether antidepressive effects of antipsychotics have a significant correlation with the effects on specific symptom domains of schizophrenia.MethodsElectronic databases were searched to identify eligible studies that reported antidepressive effects of antipsychotics for the treatment of adult patients with schizophrenia in double-blind, randomized placebo-controlled trials (RCTs). Mean change from baseline in depressive symptoms was meta-analyzed, and the correlation with the effects on other symptom domains was examined through meta-regression analysis.ResultsThirty-five RCTs (13 890 patients) were included in this meta-analysis. Overall, antipsychotics showed greater efficacy than placebo in reducing depressive symptoms, with small to medium effect sizes (standardized mean difference = −0.27, 95% confidence interval −0.32 to −0.22, P < .001). All the antipsychotics, except for chlorpromazine, haloperidol, and ziprasidone, were associated with significantly greater decreases in depressive symptoms compared with placebo (standardized mean difference = −0.19 to −0.40). A higher antidepressive effect was significantly correlated with a higher improvement in Positive and Negative Syndrome Scale/Brief Psychiatric Rating Scale total, positive, and negative, and Positive and Negative Syndrome Scale-general psychopathology symptoms (β = .618, P < .001; β = .476, P < .001; β = .689, P < .001; β = .603, P < .001, respectively).ConclusionsSecond-generation antipsychotics (except for ziprasidone) were associated with small to medium effects sizes on improvement in depressive symptoms among adult patients with schizophrenia. The antidepressive effect of antipsychotics was significantly correlated with improvement in other symptom domains, with the highest correlation observed for improvement in negative symptoms.PROSPERO registration numberCRD42019133015     

Neurofilament Light Chain Is a Novel Biomarker for Major Depression and Related Executive Dysfunction

BackgroundEvidence suggests that major depressive disorder is related to neuroaxonal injury and that neurofilament light chain (NfL) is a biomarker of neuroaxonal injury. In addition, proinflammatory cytokines have been reported to be associated with major depression and neuroaxonal injury.MethodsForty patients with major depression and 40 age- and sex-matched healthy control participants were enrolled for the measurement of NfL and proinflammatory cytokines and assessment of executive function. General linear models were used to examine the association between NfL levels, proinflammatory cytokine levels, and executive function.ResultsPatients with major depressive disorder exhibited significantly higher NfL levels (P = .007) than the control participants. NfL levels were positively related to log-transformed levels of tumor necrosis factor-α (P = .004). Higher levels of NfL (P = .002) and tumor necrosis factor-α (P = .013) were associated with greater deficits in executive function.DiscussionNfL was a novel biomarker for major depressive disorder and related executive dysfunction. Further studies are necessary to elucidate the role of NfL in the pathophysiology of major depression and related cognitive impairment.     

A Study in First-Episode Psychosis Patients: Does Angiotensin I-Converting Enzyme Activity Associated With Genotype Predict Symptom Severity Reductions After Treatment With Atypical Antipsychotic Risperidone?

BackgroundOur previous studies showed increased angiotensin I-converting enzyme (ACE) activity in chronic schizophrenia patients compared with healthy control (HC) volunteers, and the relevance of combining ACE genotype and activity for predicting schizophrenia was suggested.MethodsACE activity was measured in plasma of ACE insertion/deletion (I/D) genotyped HC volunteers (n = 53) and antipsychotic-naïve first-episode psychosis (FEP) patients (n = 45) assessed at baseline (FEB-B) and also after 2 months (FEP-2M) of treatment with the atypical antipsychotic risperidone.ResultsACE activity measurements showed significant differences among HC, FEP-B, and FEP-2M groups (F = 5.356, df = 2, P = .005) as well as between HC and FEP-2M (post-hoc Tukey’s multiple comparisons test, P = .004). No correlation was observed for ACE activity increases and symptom severity reductions in FEP as assessed by total Positive and Negative Syndrome Scale (r = −0.131, P = .434). FEP subgrouped by ACE I/D genotype showed significant ACE activity increases, mainly in the DD genotype subgroup. No correlation between ACE activity and age was observed in FEP or HC groups separately (r = 0.210, P = .392), but ACE activity level differences observed between these groups were influenced by age.ConclusionsThe importance of measuring the ACE activity in blood plasma, associated with ACE I/D genotyping to support the follow-up of FEP patients, did not show correlation with general symptom amelioration in the present study. However, new insights into the influence of age and I/D genotype for ACE activity changes in FEP individuals upon treatment was demonstrated.     

A large-scale genome-wide gene expression analysis in peripheral blood identifies very few differentially expressed genes related to antidepressant treatment and response in patients with major depressive disorder

A better understanding of the biological factors underlying antidepressant treatment in patients with major depressive disorder (MDD) is needed. We perform gene expression analyses and explore sources of variability in peripheral blood related to antidepressant treatment and treatment response in patients suffering from recurrent MDD at baseline and after 8 weeks of treatment. The study includes 281 patients, which were randomized to 8 weeks of treatment with vortioxetine (N = 184) or placebo (N = 97). To our knowledge, this is the largest dataset including both gene expression in blood and placebo-controlled treatment response measured by a clinical scale in a randomized clinical trial. We identified three novel genes whose RNA expression levels at baseline and week 8 are significantly (FDR < 0.05) associated with treatment response after 8 weeks of treatment. Among these genes were SOCS3 (FDR = 0.0039) and PROK2 (FDR = 0.0028), which have previously both been linked to depression. Downregulation of these genes was associated with poorer treatment response. We did not identify any genes that were differentially expressed between placebo and vortioxetine groups at week 8 or between baseline and week 8 of treatment. Nor did we replicate any genes identified in previous peripheral blood gene expression studies examining treatment response. Analysis of genome-wide expression variability showed that type of treatment and treatment response explains very little of the variance, a median of <0.0001% and 0.05% in gene expression across all genes, respectively. Given the relatively large size of the study, the limited findings suggest that peripheral blood gene expression might not be the best approach to explore the biological factors underlying antidepressant treatment.Subject terms: Predictive markers, Depression