Personalized relapse prediction in patients with major depressive disorder using digital biomarkers.

Major depressive disorder (MDD) is a chronic illness wherein relapses contribute to significant patient morbidity and mortality. Near-term prediction of relapses in MDD patients has the potential to improve outcomes by helping implement a 'predict and preempt' paradigm in clinical care. In this study, we developed a novel personalized (N-of-1) encoder-decoder anomaly detection-based framework of combining anomalies in multivariate actigraphy features (passive) as triggers to utilize an active concurrent self-reported symptomatology questionnaire (core symptoms of depression and anxiety) to predict near-term relapse in MDD. The framework was evaluated on two independent longitudinal observational trials, characterized by regular bimonthly (every other month) in-person clinical assessments, weekly self-reported symptom assessments, and continuous activity monitoring data with two different wearable sensors for ≥ 1 year or until the first relapse episode. This combined passive-active relapse prediction framework achieved a balanced accuracy of ≥ 71%, false alarm rate of ≤ 2.3 alarm/patient/year with a median relapse detection time of 2-3 weeks in advance of clinical onset in both studies. The study results suggest that the proposed personalized N-of-1 prediction framework is generalizable and can help predict a majority of MDD relapses in an actionable time frame with relatively low patient and provider burden.

Long-term safety and maintenance of response with esketamine nasal spray in participants with treatment-resistant depression: interim results of the SUSTAIN-3 study.

Patients with treatment-resistant depression (TRD) have higher rates of relapse and pronounced decreases in daily functioning and health-related quality of life compared to patients with major depressive disorder who are not treatment-resistant, underscoring the need for treatment choices with sustained efficacy and long-term tolerability. Adults with TRD who participated in ≥1 of 6 phase 3 "parent" studies could continue esketamine treatment, combined with an oral antidepressant, by enrolling in phase 3, open-label, long-term extension study, SUSTAIN-3. Based on their status at parent-study end, eligible participants entered a 4-week induction phase followed by an optimization/maintenance phase, or directly entered the optimization/maintenance phase of SUSTAIN-3. Intranasal esketamine dosing was flexible, twice-weekly during induction and individualized to depression severity during optimization/maintenance. At the interim data cutoff (01 December 2020), 1148 participants were enrolled, 458 at induction and 690 at optimization/maintenance. Mean (median) cumulative duration of maintenance esketamine treatment was 31.5 (37.7) months (totaling 2769 cumulative patient-years). Common treatment-emergent adverse events (≥20%) were headache, dizziness, nausea, dissociation, somnolence, and nasopharyngitis. Mean Montgomery-Åsberg Depression Rating Scale (MADRS) total score decreased during induction, and this reduction persisted during optimization/maintenance (mean [SD] change from the baseline to the endpoint of each phase: induction -12.8 [9.73]; optimization/maintenance +1.1 [9.93]), with 35.6% and 46.1% of participants in remission (MADRS total score ≤12) at induction and optimization/maintenance endpoints, respectively. Improvement in depression ratings generally persisted among participants who remained in maintenance treatment, and no new safety signal was identified during long-term treatment (up to 4.5 years) using intermittent-dosed esketamine in conjunction with daily antidepressant.

Meta-analysis of epigenome-wide association studies of major depressive disorder.

Epigenetic mechanisms have been hypothesized to play a role in the etiology of major depressive disorder (MDD). In this study, we performed a meta-analysis between two case-control MDD cohorts to identify differentially methylated positions (DMPs) and differentially methylated regions (DMRs) in MDD. Using samples from two Cohorts (a total of 298 MDD cases and 63 controls with repeated samples, on average ~ 1.8 samples/subject), we performed an EWAS meta-analysis. Multiple cytosine-phosphate-guanine sites annotated to TNNT3 were associated with MDD reaching study-wide significance, including cg08337959 (p = 2.3 × 10-11). Among DMPs with association p values less than 0.0001, pathways from REACTOME such as Ras activation upon Ca2+ influx through the NMDA receptor (p = 0.0001, p-adjusted = 0.05) and long-term potentiation (p = 0.0002, p-adjusted = 0.05) were enriched in this study. A total of 127 DMRs with Sidak-corrected p value < 0.05 were identified from the meta-analysis, including DMRs annotated to TNNT3 (chr11: 1948933 to 1949130 [6 probes], Sidak corrected P value = 4.32 × 10-41), S100A13 (chr1: 153599479 to 153600972 [22 probes], Sidak corrected P value = 5.32 × 10-18), NRXN1 (chr2: 50201413 to 50201505 [4 probes], Sidak corrected P value = 1.19 × 10-11), IL17RA (chr22: 17564750 to 17565149, Sidak corrected P value = 9.31 × 10-8), and NPFFR2 (chr4: 72897565 to 72898212, Sidak corrected P value = 8.19 × 10-7). Using 2 Cohorts of depression case-control samples, we identified DMPs and DMRs associated with MDD. The molecular pathways implicated by these data include mechanisms involved in neuronal synaptic plasticity, calcium signaling, and inflammation, consistent with reports from previous genetic and protein biomarker studies indicating that these mechanisms are involved in the neurobiology of depression.

Circulating microRNA associated with future relapse status in major depressive disorder.

Major depressive disorder (MDD) is an episodic condition with relapsing and remitting disease course. Elucidating biomarkers that can predict future relapse in individuals responding to an antidepressant treatment holds the potential to identify those patients who are prone to illness recurrence. The current study explored relationships between relapse risk in recurrent MDD and circulating microRNAs (miRNAs) that participate in RNA silencing and post-transcriptional regulation of gene expression. Serum samples were acquired from individuals with a history of recurrent MDD who were followed longitudinally in the observational study, OBSERVEMDD0001 (ClinicalTrials.gov Identifier: NCT02489305). Circulating miRNA data were obtained in 63 participants who relapsed ("relapsers") and 154 participants who did not relapse ("non-relapsers") during follow-up. The miRNA was quantified using the ID3EAL™ miRNA Discovery Platform from MiRXES measuring 575 circulating miRNAs using a patented qPCR technology and normalized with a standard curve from spike-in controls in each plate. The association between miRNAs and subsequent relapse was tested using a linear model, adjusting for age, gender, and plate. Four miRNAs were nominally associated with relapse status during the observational follow-up phase with a false discover rate adjusted p-value < 0.1. Enrichment analysis of experimentally validated targets revealed 112 significantly enriched pathways, including neurogenesis, response to cytokine, neurotrophin signaling, vascular endothelial growth factor signaling, relaxin signaling, and cellular senescence pathways. These data suggest these miRNAs putatively associated with relapse status may have the potential to regulate genes involved in multiple signaling pathways that have previously been associated with MDD. If shown to be significant in a larger, independent sample, these data may hold potential for developing a miRNA signature to identify patients likely to relapse, allowing for earlier intervention.

A randomized, multicenter, crossover psychometric evaluation study of an iPad-administered cognitive test battery in participants with major depressive disorder who responded to treatment with oral antidepressants.

BACKGROUND: Performance validity and test-retest reliability of ReVeRe.D, an iPad-administered cognitive test battery in major depressive disorder (MDD) were analyzed. METHODS: Participants aged 18-59 years had DSM-5 diagnosis of MDD with adequate visual and hearing acuity. All had responded to oral antidepressant treatment for a major depressive episode within the most recent 24-months and were stable with no greater than mild depressive symptoms as evidenced by Montgomery Asberg Depression Rating Scale total score <17. Participants were randomly assigned to 1 of 2 test sequences (AABB or BBAA; A=ReVeRe.D; B=examiner-administered tests) in a crossover design. RESULTS: 244 randomized participants (AABB: n=123; BBAA: n=121) had mean age of 38.3 years; 54.9% had a college, baccalaureate, or higher education. At first administration, Pearson correlation coefficients (PCC) for 6/10 pairs of corresponding ReVeRe.D vs examiner-administered tests exceeded the pre-specified acceptance criterion (PCC=0.53) for the primary analysis; 8 test score pairs had PCC exceeding 0.40. At second administration, PCC for 9/10 test scores pairs exceeded PCC=0.53. Together, the series of PCCs supports the concurrent validity for ReVeRe.D. Test-retest reliability for ReVeRe.D test scores was generally moderate to high. LIMITATIONS: The study included stable participants with MDD who had responded to oral antidepressant treatment, with most in at least partial remission. The sample was limited to English-speaking participants, and skewed towards white, college-educated women. Further studies in acutely ill MDD patients who represent a broader demographic, are warranted. CONCLUSIONS: iPad-administered ReVeRe.D is a valid and reliable computerized test battery for assessment of cognitive performance in MDD.

Esketamine Nasal Spray Plus Oral Antidepressant in Patients With Treatment-Resistant Depression: Assessment of Long-Term Safety in a Phase 3, Open-Label Study (SUSTAIN-2).

OBJECTIVE: To evaluate long-term safety and efficacy of esketamine nasal spray plus a new oral antidepressant (OAD) in patients with treatment-resistant depression (TRD). METHODS: This phase 3, open-label, multicenter, long-term (up to 1 year) study was conducted between October 2015 and October 2017. Patients (≥ 18 years) with TRD (DSM-5 diagnosis of major depressive disorder and nonresponse to ≥ 2 OAD treatments) were enrolled directly or transferred from a short-term study (patients aged ≥ 65 years). Esketamine nasal spray (28-mg, 56-mg, or 84-mg) plus new OAD was administered twice a week in a 4-week induction (IND) phase and weekly or every-other-week for patients who were responders and entered a 48-week optimization/maintenance (OP/MAINT) phase. RESULTS: Of 802 enrolled patients, 86.2% were direct-entry and 13.8% were transferred-entry; 580 (74.5%) of 779 patients who entered the IND phase completed the phase, and 150 (24.9%) of 603 who entered the OP/MAINT phase completed the phase. Common treatment-emergent adverse events (TEAEs) were dizziness (32.9%), dissociation (27.6%), nausea (25.1%), and headache (24.9%). Seventy-six patients (9.5%) discontinued esketamine due to TEAEs. Fifty-five patients (6.9%) experienced serious TEAEs. Most TEAEs occurred on dosing days, were mild or moderate in severity, and resolved on the same day. Two deaths were reported; neither was considered related to esketamine. Cognitive performance generally either improved or remained stable postbaseline. There was no case of interstitial cystitis or respiratory depression. Treatment-emergent dissociative symptoms were transient and generally resolved within 1.5 hours postdose. Montgomery-Åsberg Depression Rating Scale total score decreased during the IND phase, and this reduction persisted during the OP/MAINT phase (mean [SD] change from baseline of respective phase to endpoint: IND, -16.4 [8.76]; OP/MAINT, 0.3 [8.12]). CONCLUSIONS: Long-term esketamine nasal spray plus new OAD therapy had a manageable safety profile, and improvements in depression appeared to be sustained in patients with TRD. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02497287.

Efficacy and Safety of Esketamine Nasal Spray Plus an Oral Antidepressant in Elderly Patients With Treatment-Resistant Depression-TRANSFORM-3.

BACKGROUND: Elderly patients with major depression have a poorer prognosis, are less responsive to treatment, and show greater functional decline compared with younger patients, highlighting the need for effective treatment. METHODS: This phase 3 double-blind study randomized patients with treatment-resistant depression (TRD) ≥65 years (1:1) to flexibly dosed esketamine nasal spray and new oral antidepressant (esketamine/antidepressant) or new oral antidepressant and placebo nasal spray (antidepressant/placebo). The primary endpoint was change in the Montgomery-Åsberg Depression Rating Scale (MADRS) from baseline to day 28. Analyses included a preplanned analysis by age (65-74 versus ≥75 years) and post-hoc analyses including age at depression onset. RESULTS: For the primary endpoint, the median-unbiased estimate of the treatment difference (95% CI) was -3.6 (-7.20, 0.07); weighted combination test using MMRM analyses z = 1.89, two-sided p = 0.059. Adjusted mean (95% CI) difference for change in MADRS score between treatment groups was -4.9 (-8.96, -0.89; t = -2.4, df = 127; two-sided nominal p = 0.017) for patients 65 to 74 years versus -0.4 (-10.38, 9.50; t = -0.09, two-sided nominal p = 0.930) for those ≥75 years, and -6.1 (-10.33, -1.81; t = -2.8, df = 127; two-sided nominal p = 0.006) for patients with depression onset <55 years and 3.1 (-4.51, 10.80; t = 0.8, two-sided nominal p = 0.407) for those ≥55 years. Patients who rolled over into the long-term open-label study showed continued improvement with esketamine following 4 additional treatment weeks. CONCLUSIONS: Esketamine/antidepressant did not achieve statistical significance for the primary endpoint. Greater differences between treatment arms were seen for younger patients (65-74 years) and patients with earlier onset of depression (<55 years).

A computerized, self-administered test of verbal episodic memory in elderly patients with mild cognitive impairment and healthy participants: A randomized, crossover, validation study.

INTRODUCTION: Performance of "Revere", a novel iPad-administered word-list recall (WLR) test, in quantifying deficits in verbal episodic memory, was evaluated versus examiner-administered Rey Auditory Verbal Learning Test (RAVLT) in patients with mild cognitive impairment and cognitively normal participants. METHODS: Elderly patients with clinically diagnosed mild cognitive impairment (Montreal Cognitive Assessment score 24-27) and cognitively normal (Montreal Cognitive Assessment score ≥28) were administered RAVLT or Revere in a randomized crossover design. RESULTS: A total of 153/161 participants (Revere/RAVLT n = 75; RAVLT/Revere n = 78) were randomized; 148 (97%) completed study; 121 patients (mean [standard deviation] age: 70.4 [7.84] years) were included for analysis. Word-list recall scores (8 trials) were comparable between Revere and RAVLT (Pearson's correlation coefficients: 0.12-0.70; least square mean difference [Revere-RAVLT]: -0.84 [90% CI, -1.15; -0.54]). Model factor estimates indicated trial (P < .001), period (P < .001) and evaluation sequence (P = .038) as significant factors. Learning over trials index and serial position effects were comparable. DISCUSSION: Participants' verbal recall performance on Revere and RAVLT were equivalent.

Effect of intranasal esketamine on cognitive functioning in healthy participants: a randomized, double-blind, placebo-controlled study.

BACKGROUND: The effect of intranasal esketamine on cognitive functioning in healthy participants is assessed in this study. METHODS: Twenty-four participants (19-49 years) were randomized to one of two treatment sequences in which either esketamine 84 mg or placebo was intranasally administered in a double-blind, two-period crossover design. Primary measures included five tests of Cogstate® computerized test battery assessed at 1 h predose and 40 min, 2, 4, and 6 h postdose. Secondary measures included the Mental Effort Scale, Karolinska Sleepiness Scale (KSS), and safety. RESULTS: Esketamine was associated with significant cognitive performance impairment at 40 min postdose for all five Cogstate® tests (Detection p = 0.0011, Identification p = 0.0006, One-Card Learning p = 0.0040, One Back p = 0.0017, and Groton Maze Learning Test p < 0.0001) versus placebo. In contrast, performance on these tests did not differ significantly between esketamine and placebo at 2, 4, or 6 h postdose. Secondary outcomes indicated a significant, transient increase from baseline under esketamine versus placebo at 40 min postdose on the Mental Effort Scale and at 40 min and 2 h postdose on KSS (p < 0.0001 for both); however, no significant difference was observed on these outcomes between esketamine and placebo at later timepoints. The most commonly reported adverse events were dizziness (67%), nausea (37.5%), disturbance in attention (29.2%), and fatigue (29.2%); the majority were considered mild in severity. CONCLUSIONS: Esketamine was associated with cognitive performance decline, and greater effort was required to complete the test battery versus placebo at 40 min postdose, which returned to placebo-comparable levels by 2 h postdose. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02094378.

Paliperidone suppresses the development of the aggressive phenotype in a developmentally sensitive animal model of escalated aggression.

RATIONALE: Atypical antipsychotics are commonly prescribed to clinically referred youngsters for treatment of heightened aggressive behavior associated with various psychiatric disorders. Previously, we demonstrated risperidone's anti-aggressive effects using a well-validated animal model of offensive aggression. Paliperidone, the main active metabolite of risperidone, is a potent serotonin-2A and dopamine-2 receptor antagonist with slightly different pharmacodynamic properties compared to risperidone. Given that much of risperidone's therapeutic efficacy is due to its active metabolite, paliperidone may effectively suppress aggression with fewer adverse side effects. OBJECTIVES: Investigate whether paliperidone administration would reduce heightened aggressive behavior induced by low-dose cocaine exposure in a developmentally sensitive model of offensive aggression. MATERIALS AND METHODS: Male Syrian hamsters (n = 12/group) were administered an acute dose of paliperidone (0.05, 0.1, 0.2, and 0.3 mg/kg) and then tested for aggressive behavior using the resident-intruder paradigm. To investigate the effects of chronic paliperidone administration, a separate set of animals (n = 12/group) was exposed to repeated paliperidone administration (0.1 mg kg(-1) day(-1)) during different developmental periods and varying lengths of time (1-4 weeks). RESULTS: Experiment 1 results revealed a dose-dependent decrease in bite and attack behaviors with an effective dose observed at 0.1 mg/kg. In Experiment 2, the maximal reduction in aggressive behavior in response to chronic paliperidone treatment was observed in animals treated during the third week of adolescence, and this reduction occurred without concomitant alterations in non-aggressive behaviors. CONCLUSIONS: These results support the specific aggression-suppressing properties of paliperidone and the potential use of this compound in the treatment of maladaptive aggression in clinical settings.

Repeated risperidone administration during puberty prevents the generation of the aggressive phenotype in a developmentally immature animal model of escalated aggression.

Risperidone has been shown to be clinically effective for the treatment of aggressive behavior in children, yet until recently no information was available regarding whether risperidone exhibits aggression-specific suppression in preclinical studies employing validated developmentally immature animal models of escalated aggression. Recently, using a pharmacologic animal model of escalated offensive aggression, we reported that acute risperidone treatment selectively and dose-dependently reduces the expression of the adult aggressive phenotype, with a significant reduction in aggressive responses observed at 0.1 mg/kg, i.e., a dose within the range administered to children and adolescents in the clinical setting. This study examined whether repeated exposure to risperidone during puberty would prevent the generation of the highly escalated aggressive phenotype in this animal model. To test this hypothesis, the aggression-eliciting stimulus (i.e., cocaine hydrochloride, 0.5 mg/kg/dayx28 days) was co-administered with an aggression-suppressing dose of risperidone (i.e., 0.1 mg/kg/day) during different time frames of puberty and for varied lengths of time (i.e., 1-4 weeks), and then animals were scored for targeted measures of offensive aggression during late puberty. Risperidone administration prevented the generation of the adult aggressive phenotype, with a complete blockade of matured offensive responses (i.e., lateral attacks and flank/rump bites) seen only after prolonged periods of exposure to risperidone (i.e., 3-4 weeks). The selective prevention of these aggressive responses, while leaving other measures of aggression intact (e.g., upright offensive postures), suggest that risperidone is acting in a highly discriminatory anti-aggressive fashion, targeting neurobehavioral elements important for the mature aggressive response pattern.

Structural color production by constructive reflection from ordered collagen arrays in a bird (Philepitta castanea: Eurylaimidae).

Ordered hexagonal arrays of parallel collagen fibers produce the brilliant green structural color of the fleshy, supraorbital caruncles of male Velvet Asity (Philepitta castanea; Aves: Eurylaimidae). The collagen arrays are organized in larger macrofibrils that are packed irregularly within cone-shaped papillae that cover the surface of the caruncle. The color of the caruncle conforms closely to the wavelengths predicted by applying Bragg's Law of constructive reflection to measurements of the size and spatial organization of the collagen arrays. These observations constitute a novel mechanism of structural color production in animals. These collagen arrays are convergently similar to the smaller, highly structured collagen arrays in the mammalian cornea, which exploit the same physical mechanism to produce optical transparency. © 1994 Wiley-Liss, Inc.