The consequences of heatwaves for the reproductive success and physiology of the wingless sub-Antarctic fly Anatalanta aptera.

Sub-lethal effects of warming temperatures are an important, yet sometimes overlooked impact of climate change that may threaten the long-term survival of numerous species. This, like many other effects of climate change, is especially concerning for cold-adapted ectotherms living in rapidly warming polar regions. This study examines the effects of warmer temperatures on cold-adapted Diptera, using the long-lived sub-Antarctic sphaerocerid fly, Anatalanta aptera, as a focal species. We conducted two experiments to assess heat stress in adult flies, one varying the intensity of the heat stress (daily heating from 4 °C to 8 °C, 20 °C, or 24 °C) and one varying the frequency of heat stress exposure (heating from 4 °C to 12 °C every one, two, or three days) and examined consequences for reproductive success and metabolic responses. We found that more heat stress reduced reproductive output, but not timing of reproduction. Surprisingly, individuals sampled at different times during heat stress exposure were undifferentiable when all metabolite concentrations were analysed with redundancy analysis, however some individual metabolites did exhibit significant differences. Overall, our findings suggest that warmer temperatures in the sub-Antarctic may put this species at greater risk, especially when combined with other concurrent threats from biological invasions.

Assessment of health-related quality of life and health status in patients with treatment-resistant depression treated with esketamine nasal spray plus an oral antidepressant.

BACKGROUND: Patients with treatment-resistant depression (TRD) report significant deficits in physical and mental health, as well as severely impaired health-related quality of life (HRQoL) and functioning. Esketamine effectively enhances the daily functioning in these patients while also improving their depressive symptoms. This study assessed HRQoL and health status of patients with TRD, who were treated with esketamine nasal spray and an oral antidepressant (ESK + AD) vs. placebo nasal spray and an AD (AD + PBO). METHODS: Data from TRANSFORM-2, a phase 3, randomized, double-blind, short-term flexibly dosed study, were analyzed. Patients (aged 18-64 years) with TRD were included. The outcome assessments included the European Quality of Life Group, Five Dimension, Five Level (EQ-5D-5L), EQ-Visual Analogue Scale (EQ-VAS), and Sheehan Disability Scale (SDS). The health status index (HSI) was calculated using EQ-5D-5L scores. RESULTS: The full analysis set included 223 patients (ESK + AD: 114; AD + PBO: 109; mean [SD] age: 45.7 [11.89]). At Day 28, a lower percentage of patients reported impairment in the ESK + AD vs. AD + PBO group in all five EQ-5D-5L dimensions: mobility (10.6% vs. 25.0%), self-care (13.5% vs. 32.0%), usual activities (51.9% vs. 72.0%), pain/discomfort (35.6% vs. 54.0%), and anxiety/depression (69.2% vs. 78.0%). The mean (SD) change from baseline in HSI at Day 28 was 0.310 (0.219) for ESK + AD and 0.235 (0.252) for AD + PBO, with a higher score reflecting better levels of health. The mean (SD) change from baseline in EQ-VAS score at Day 28 was greater in ESK + AD (31.1 [25.67]) vs. AD + PBO (22.1 [26.43]). The mean (SD) change in the SDS total score from baseline to Day 28 also favored ESK + AD (-13.6 [8.31]) vs. AD + PBO (-9.4 [8.43]). CONCLUSIONS: Greater improvements in HRQoL and health status were observed among patients with TRD treated with ESK + AD vs. AD + PBO. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02418585.

Relationship Between Dissociation and Antidepressant Effects of Esketamine Nasal Spray in Patients With Treatment-Resistant Depression.

BACKGROUND: In this post-hoc analysis, data from 2 positive, pivotal, phase 3 trials of esketamine nasal spray (ESK) in treatment-resistant depression (TRD)-short-term study (TRANSFORM-2) and maintenance study (SUSTAIN-1)-were analyzed to evaluate the relationship between dissociation and antidepressant effects of ESK. METHODS: Analysis by responder status, correlation analysis, and mediation analysis were performed to assess the relationships between peak Clinician Administered Dissociative States Scale (CADSS) scores after first (day 1) and last (day 25) ESK dose and change in Montgomery-Åsberg Depression Rating Scale (MADRS) total scores at the first (day 2) and last assessments (day 28) in TRANSFORM-2 and peak CADSS after first maintenance ESK dose and time to relapse in SUSTAIN-1 (only for mediation analysis). RESULTS: In TRANSFORM-2, the percentage of responders (>50% reduction in MADRS) at day 2 and day 28 did not significantly differ between patients who did vs did not manifest significant dissociation (peak CADSS scores >4 or ≤4, respectively) following the first ESK dose. Spearman correlation coefficients between dissociation and depression improvement were nonsignificant and close to zero. CADSS scores did not significantly mediate the reduction in MADRS at day 2 or 28 in TRANSFORM-2 or the time to depression relapse in SUSTAIN-1. The mean difference in MADRS between ESK and active-control arms persisted beyond day 2 without significant change across time, although the mean peak CADSS scores significantly decreased across consecutive doses and fewer patients experienced significant dissociation after the last ESK dose compared with the first. CONCLUSION: Within the dose range tested, the dissociative and antidepressant effects of ESK were not significantly correlated. TRIAL REGISTRATION: NCT02417064 (TRANSFORM-1); NCT02418585(TRANSFORM-2); NCT02493868 (SUSTAIN-1).

Comparison of Long-Term Efficacy and Safety of Esketamine Nasal Spray Plus Oral Antidepressant in Younger Versus Older Patients With Treatment-Resistant Depression: Post-Hoc Analysis of SUSTAIN-2, a Long-Term Open-Label Phase 3 Safety and Efficacy Study.

BACKGROUND: Older, compared with younger, patients with treatment-resistant depression (TRD) typically have lower response and remission rates with poorer tolerability to antidepressant treatment. This post-hoc analysis compared outcomes following treatment with esketamine nasal spray (ESK) between younger (18-64 years) and older (≥65 years) patients with TRD. METHODS: SUSTAIN-2, an up to 1-year open-label safety and efficacy study of ESK plus an oral antidepressant, included patients with TRD either directly enrolled (≥18-year) or transferred from a phase 3 double-blind study, TRANSFORM-3 (≥65-year). Patients were treated in two phases: 4-week induction and 48-week optimization/maintenance. RESULTS: Younger (n = 624) and older (n = 178) patients had similar baseline characteristics except for hypertension history (21.5% versus 48.3%, respectively). Patients (younger versus older) had similar mean baseline Montgomery-Åsberg Depression Rating Scale (MADRS) total scores and mean (SD) reductions in MADRS total scores for induction (-18.0 [7.19] versus -18.1 [9.37]; p = 0.492 [t = 0.69, df = 701]) and optimization/maintenance (week 12) (-19.9 [7.03] versus -22.2 [9.50]; p = 0.265 [t = -1.12, df = 3470]) phases. Treatment-emergent adverse events (TEAEs) reported in younger versus older patients, respectively, were: induction, 86.1% versus 74.8%; optimization/maintenance, 86.8% versus 81.0%; serious TEAEs: induction, 2.2% versus 1.9%; optimization/maintenance, 6.7% versus 4.8%; TEAEs of increased blood pressure: induction, 6.9% versus 6.5%; optimization/maintenance, 7.1% versus 9.5%; and falls: induction, 0.3% versus 0.6%; optimization/maintenance, 0.2% versus 0.8%. Cognitive tests did not show clinically meaningful differences between the age groups. CONCLUSIONS: Although limited by the open-label design of SUSTAIN-2, this post-hoc analysis showed generally comparable improvement in depression between ESK-treated younger and older adult patients with TRD, with consistent safety outcomes.

Efficacy and safety of esketamine nasal spray by sex in patients with treatment-resistant depression: findings from short-term randomized, controlled trials.

The objective of this analysis was to determine if there are sex differences with esketamine for treatment-resistant depression (TRD). Post hoc analyses of three randomized, controlled studies of esketamine in patients with TRD (TRANSFORM-1, TRANSFORM-2 [18-64 years], TRANSFORM-3 [≥ 65 years]) were performed. In each 4-week study, adults with TRD were randomized to esketamine or placebo nasal spray, each with a newly initiated oral antidepressant. Change from baseline to day 28 in Montgomery-Åsberg Depression Rating Scale (MADRS) total score was assessed by sex in pooled data from TRANSFORM-1/TRANSFORM-2 and separately in data from TRANSFORM-3 using a mixed-effects model for repeated measures. Use of hormonal therapy was assessed in all women, and menopausal status was assessed in women in TRANSFORM-1/TRANSFORM-2. Altogether, 702 adults (464 women) received ≥ 1 dose of intranasal study drug and antidepressant. Mean MADRS total score (SD) decreased from baseline to day 28, more so among patients treated with esketamine/antidepressant vs. antidepressant/placebo in both women and men: TRANSFORM-1/TRANSFORM-2 women-esketamine/antidepressant -20.3 (13.19) vs. antidepressant/placebo -15.8 (14.67), men-esketamine/antidepressant -18.3 (14.08) vs. antidepressant/placebo -16.0 (14.30); TRANSFORM-3 women-esketamine/antidepressant -9.9 (13.34) vs. antidepressant/placebo -6.9 (9.65), men-esketamine/antidepressant -10.3 (11.96) vs. antidepressant/placebo -5.5 (7.64). There was no significant sex effect or treatment-by-sex interaction (p > 0.35). The most common adverse events in esketamine-treated patients were nausea, dissociation, dizziness, and vertigo, each reported at a rate higher in women than men. The analyses support antidepressant efficacy and overall safety of esketamine nasal spray are similar between women and men with TRD. The TRANSFORM studies are registered at clinicaltrials.gov (identifiers: NCT02417064 (first posted 15 April 2015; last updated 4 May 2020), NCT02418585 (first posted 16 April 2015; last updated 2 June 2020), and NCT02422186 (first posted 21 April 2015; last updated 29 September 2021)).

A Choice-Based Conjoint Analysis of the Psychiatrist Decision-Making Process Used in Determining When to Discharge Adults With Major Depressive Disorder Hospitalized for Active Suicidal Ideation With Intent.

ABSTRACT: To ascertain the relative importance of attributes considered when deciding to discharge patients hospitalized with major depressive disorder (MDD) and active suicidal ideation with intent, a choice-based conjoint analysis was conducted via online survey among US-based psychiatrists actively managing such patients. Potential attributes and attribute levels were identified. Attribute importance in decision to discharge and the discharge time frame were assessed. One hundred psychiatrists completed the survey. The relative importance of attributes were current MDD severity (relative importance weight [out of 100] 24.8 [95% confidence interval, 23.3-26.3]), clinician assessment of current suicidal ideation (20.8 [18.5-23.0]), previous history of suicide attempts (16.7 [15.9-17.6]), psychosocial support at discharge (13.0 [11.7-14.4]), postdischarge outpatient follow-up (9.8 [8.8-10.8]), current length of hospital stay (9.2 [8.1-10.3]), and suicidal ideation at admission (5.7 [4.8-6.6]). Thus, current clinical symptoms were considered the most important attributes by psychiatrists when discharging patients initially hospitalized with MDD and active suicidal ideation with intent.

Clinically meaningful changes on depressive symptom measures and patient-reported outcomes in patients with treatment-resistant depression.

OBJECTIVE: To use the Clinical Global Impression-Severity (CGI-S) scale to estimate clinically meaningful and clinically substantial changes as measured using the Montgomery-Åsberg Depression Rating Scale (MADRS), the Sheehan Disability Scale (SDS), and the Patient Health Questionnaire-9 (PHQ-9) in patients with treatment-resistant depression (TRD). METHODS: Pooled data were derived from two 4-week, randomized, active-controlled studies evaluating esketamine nasal spray (ESK) plus oral antidepressant (OAD) or OAD plus placebo nasal spray (PBO) in adults with TRD (N = 565). CGI-S, MADRS, SDS, and PHQ-9 scores were obtained at baseline and over 4 weeks of treatment. In this post hoc analysis, change scores on the MADRS, SDS, and PHQ-9 that corresponded to a clinically meaningful (1-point) or clinically substantial (2-point) change on the CGI-S scale were identified. RESULTS: Clinically meaningful changes in CGI-S scores after 28 days corresponded to 6-, 4-, and 3-point changes from baseline on the MADRS, SDS, and PHQ-9, respectively. Similarly, a 2-point CGI-S score change (clinically substantial change) corresponded to a 12-, 8-, and 6-point change on the MADRS, SDS, and PHQ-9, respectively. The proportion of patients showing substantial clinical improvement in the ESK plus OAD group versus the OAD plus PBO group after 28 days of treatment favored ESK plus OAD: 69.0% vs 55.3% (MADRS), 64.5% vs 48.9% (SDS), and 77.1% vs 64.7% (PHQ-9). CONCLUSION: We provide a basis for identifying clinically meaningful and clinically substantial changes as assessed with commonly used outcome measures for depression to facilitate the translation of clinical trial results into clinical practice.

The effect of esketamine in patients with treatment-resistant depression with and without comorbid anxiety symptoms or disorder.

BACKGROUND: Comorbid anxiety is generally associated with poorer response to antidepressant treatment. This post hoc analysis explored the efficacy of esketamine plus an antidepressant in patients with treatment-resistant depression (TRD) with or without comorbid anxiety. METHODS: TRANSFORM-2, a double-blind, flexible-dose, 4-week study (NCT02418585), randomized adults with TRD to placebo or esketamine nasal spray, each with a newly-initiated oral antidepressant. Comorbid anxiety was defined as clinically noteworthy anxiety symptoms (7-item Generalized Anxiety Disorder scale [GAD-7] score ≥10) at screening and baseline or comorbid anxiety disorder diagnosis at screening. Treatment effect based on change in Montgomery-Åsberg Depression Rating Scale (MADRS) total score, and response and remission were examined by presence/absence of comorbid anxiety using analysis of covariance and logistic regression models. RESULTS: Approximately 72% (162/223) of patients had baseline comorbid anxiety. Esketamine-treated patients with and without anxiety demonstrated significant reductions in MADRS (mean [SD] change from baseline at day 28: -21.0 [12.51] and -22.7 [11.98], respectively). Higher rates of response and remission, and a significantly greater decrease in MADRS score at day 28 were observed compared to antidepressant/placebo, regardless of comorbid anxiety (with anxiety: difference in LS means [95% CI] -4.2 [-8.1, -0.3]; without anxiety: -7.5 [-13.7, -1.3]). There was no significant interaction of treatment and comorbid anxiety (p = .371). Notably, in the antidepressant/placebo group improvement was similar in those with and without comorbid anxiety. CONCLUSION: Post hoc data support efficacy of esketamine plus an oral antidepressant in patients with TRD, regardless of comorbid anxiety.

Association of depression symptom severity with short-term risk of an initial hospital encounter in adults with major depressive disorder.

BACKGROUND: Despite the availability of pharmacologic and nonpharmacologic treatment options, depression continues to be one of the leading causes of disability worldwide. This study evaluated whether depression symptom severity, as measured by PHQ-9 score, of patients diagnosed with MDD is associated with short-term risk of a hospital encounter (ER visit or inpatient stay). METHODS: Adults with ≥1 PHQ-9 assessment in an outpatient setting (index date) and ≥ 1 MDD diagnosis within 6 months prior were included from the de-identified Optum Electronic Health Record database (April 2016-June 2019). Patients were categorized by depression symptom severity based on PHQ-9 scores obtained by natural language processing. Crude rates, adjusted absolute risks, and adjusted relative risks of all-cause and MDD-related hospital encounters within 30 days following assessment of depression severity were determined. RESULTS: The study population consisted of 280,145 patients with MDD and ≥ 1 PHQ-9 assessment in an outpatient setting. Based on PHQ-9 scores, 26.9% of patients were categorized as having none/minimal depression symptom severity, 16.4% as mild, 24.7% as moderate, 19.6% as moderately severe, and 12.5% as severe. Among patients with none/minimal, mild, moderate, moderately severe, and severe depression, the adjusted absolute short-term risks of an initial all-cause hospital encounter were 4.1, 4.4, 4.8, 5.6, and 6.5%, respectively; MDD-related hospital encounter adjusted absolute risks were 0.8, 1.0, 1.3, 1.6, and 2.1%, respectively. Compared to patients with none/minimal depression symptom severity, the adjusted relative risks of an all-cause hospital encounter were 1.60 (95% CI 1.50-1.70) for those with severe, 1.36 (1.29-1.44) for those with moderately severe, 1.18 (1.12-1.25) for those with moderate, and 1.07 (1.00-1.13) for those with mild depression symptom severity. CONCLUSIONS: These study findings indicate that depression symptom severity is a key driver of short-term risk of hospital encounters, emphasizing the need for timely interventions that can ameliorate depression symptom severity.

Managing Esketamine Treatment Frequency Toward Successful Outcomes: Analysis of Phase 3 Data.

BACKGROUND: Esketamine nasal spray was recently approved for treatment-resistant depression. The current analysis evaluated the impact of symptom-based treatment frequency changes during esketamine treatment on clinical outcomes. METHODS: This is a post-hoc analysis of an open-label, long-term (up to 1 year) study of esketamine in patients with treatment-resistant depression (SUSTAIN 2). During a 4-week induction phase, 778 patients self-administered esketamine twice weekly plus a new oral antidepressant daily. In responders (≥50% reduction in Montgomery-Åsberg Depression Rating Scale total score from baseline), esketamine treatment frequency was thereafter decreased during an optimization/maintenance phase to weekly for 4 weeks and then adjusted to the lowest frequency (weekly or every other week) that maintained remission (Montgomery-Åsberg Depression Rating Scale ≤ 12) based on a study-defined algorithm. The relationship between treatment frequency and symptom response, based on clinically meaningful change in Clinical Global Impression-Severity score, was subsequently evaluated 4 weeks after treatment frequency adjustments in the optimization/maintenance phase. RESULTS: Among 580 responders treated with weekly esketamine for the first 4 weeks in the optimization/maintenance phase (per protocol), 26% continued to improve, 50% maintained clinical benefit, and 24% worsened. Thereafter, when treatment frequency could be reduced from weekly to every other week, 19% further improved, 49% maintained benefit, and 32% worsened. For patients no longer in remission after treatment frequency reduction, an increase (every other week to weekly) resulted in 47% improved, 43% remained unchanged, and 10% worsened. CONCLUSIONS: These findings support individualization of esketamine nasal spray treatment frequency to optimize treatment response in real-world clinical practice. 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).

Efficacy and Safety of Fixed-Dose Esketamine Nasal Spray Combined With a New Oral Antidepressant in Treatment-Resistant Depression: Results of a Randomized, Double-Blind, Active-Controlled Study (TRANSFORM-1).

BACKGROUND: About one-third of patients with depression fail to achieve remission despite treatment with multiple antidepressants and are considered to have treatment-resistant depression. METHODS: This Phase 3, double-blind, multicenter study enrolled adults with moderate-to-severe depression and nonresponse to ≥2 antidepressants in the current depression episode. Eligible patients (N = 346) were randomized (1:1:1) to twice-weekly nasal spray treatment (esketamine [56 or 84 mg] or placebo) plus a newly initiated, open-label, oral antidepressant taken daily for 4 weeks. The primary efficacy endpoint was change from baseline to day 28 in the Montgomery-Asberg Depression Rating Scale total score, performed by blinded, remote raters. Based on the predefined statistical testing sequence, esketamine 84 mg/antidepressant had to be significant for esketamine 56 mg/antidepressant to be formally tested. RESULTS: Statistical significance was not achieved with esketamine 84 mg/antidepressant compared with antidepressant/placebo (least squares [LS] means difference [95% CI]: -3.2 [-6.88, 0.45]; 2-sided P value = .088). Although esketamine 56 mg/antidepressant could not be formally tested, the LS means difference was -4.1 [-7.67, -0.49] (nominal 2-sided P value = .027). The most common (>20%) adverse events reported for esketamine/antidepressant were nausea, dissociation, dizziness, vertigo, and headache. CONCLUSIONS: Statistical significance was not achieved for the primary endpoint; nevertheless, the treatment effect (Montgomery-Asberg Depression Rating Scale) for both esketamine/antidepressant groups exceeded what has been considered clinically meaningful for approved antidepressants vs placebo. Safety was similar between esketamine/antidepressant groups and no new dose-related safety concerns were identified. This study provides supportive evidence for the safety and efficacy of esketamine nasal spray as a new, rapid-acting antidepressant for patients with treatment-resistant depression. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02417064.

Metabolic and body mass parameters after treatment with JNJ-37822681, a novel fast-dissociating D2 receptor antagonist, vs olanzapine in patients with schizophrenia.

BACKGROUND: The highly selective and fast dissociating D2 receptor antagonist JNJ-37822681 may be associated with lower risk for weight gain and undesirable metabolic effects compared with available antipsychotics. METHODS: In this double-blind, randomized study, patients were randomly assigned (1:1:1:1:1) to 12 weeks of JNJ-37822681 (10 mg, 20 mg, or 30 mg, twice daily) or olanzapine (10 mg/d during week 1; 15 mg/d after week 1), or 6 weeks of placebo (followed by 6 weeks of olanzapine, 15 mg/d). Metabolic and body mass parameters were assessed at weeks 6 and 12. RESULTS: For metabolic parameters, at week 6 none of the JNJ-37822681 groups demonstrated significant change vs placebo; however, significant changes (P < .05) were observed in the olanzapine vs placebo group in triglycerides, low-density lipoprotein (LDL) and very-LDL cholesterol, and free fatty acids. For all JNJ-37822681 groups, mean weight changes at week 12 (-0.3 [10 mg], + 0.3 [20 mg], + 0.8 kg [30 mg]) were significantly less (P < .001) than for the olanzapine group (+ 2.7 kg). A higher percentage of overweight or obese patients (baseline body mass index: ≥25 kg/m2) receiving olanzapine had ≥7% increase in weight than those receiving JNJ-37822681 (9.8% vs 2.3%, respectively). CONCLUSIONS: JNJ-37822681 treatment was associated with a more favorable outcome on weight and metabolic adverse effects vs olanzapine for treating schizophrenia; the 10 mg twice-daily dose demonstrated minimal to no weight gain.

Post-Approval Research in Drug Development: Priorities and Practices.

A prescriber might ask if a new medication is a good option for use in the patients he or she sees in clinic, with their particular blends of demographic and comorbid clinical characteristics. Is this medicine more effective, safe, tolerable, or affordable than the options used in the past? A payer may ask if the new medication offers a more effective, cost-efficient, or convenient alternative to those treatments already being covered. These are the types of questions that are often difficult to answer on the basis of the clinical trials used to support a medication's initial approval, which are generally designed to evaluate a medication's efficacy, safety, and tolerability in narrowly defined patient populations. Consequently, in order to answer the questions most relevant to key stakeholders (i.e., regulators, patients, and clinicians), it is important to continue to examine a medication's impact and characteristics after it has received regulatory approval. Such studies vary in their purpose, scope, and methodology. In this chapter, we review the types of questions most likely to be investigated after regulatory approval, the methods generally used to investigate them, and the characteristics typically considered when prioritizing the allocation of resources.

Intranasal esketamine effectively treats treatment-resistant depression in adults regardless of baseline irritability.

OBJECTIVE: To evaluate the impact of baseline irritability on clinical outcomes in adults with treatment-resistant depression (TRD) treated with fixed or flexible doses of esketamine nasal spray plus a newly initiated oral antidepressant (ESK+AD) and to explore whether treatment with ESK affects irritability symptoms over time. METHODS: This was a post hoc analysis of pooled data from two 4-week, double-blind, phase 3 studies: TRANSFORM-1 (NCT02417064) and TRANSFORM-2 (NCT02418585). Adults with TRD (n = 560) were randomly assigned to ESK+AD or placebo nasal spray plus oral antidepressant (AD+PBO). Irritability was assessed with Item 6 of the 7-item Generalized Anxiety Disorder scale at screening and baseline. Changes in depression severity (Montgomery-Åsberg Depression Rating Scale [MADRS] total score) were evaluated by analysis of covariance (ANCOVA) models. Rates of MADRS response (≥50 % decrease from baseline total score) and remission (total score ≤ 12) were examined using multiple logistic regression models. RESULTS: Of 560 participants with TRD, 52.9 %, 23.2 %, and 23.9 % had high, low, and varying levels of irritability, respectively. No significant interaction between baseline irritability and treatment group was observed for change in MADRS total score, treatment response, or remission at day 28; numerically greater improvement was observed on all outcomes with ESK+AD versus AD+PBO at day 28 regardless of baseline irritability level. Percentages of patients reporting adverse events were similar across the three baseline irritability groups. LIMITATIONS: TRANSFORM-1 and TRANSFORM-2 were not designed to prospectively evaluate predetermined irritability outcomes. CONCLUSIONS: These post hoc results support efficacy of ESK+AD in patients with TRD, regardless of baseline irritability. TRIAL REGISTRATION: ClinicalTrials.gov identifiers: NCT02417064 (TRANSFORM-1), NCT02418585 (TRANSFORM-2).

Climate Change Helps Polar Invasives Establish and Flourish: Evidence from Long-Term Monitoring of the Blowfly Calliphora vicina.

The isolated sub-Antarctic islands are of major ecological interest because of their unique species diversity and long history of limited human disturbance. However, since the presence of Europeans, these islands and their sensitive biota have been under increasing pressure due to human activity and associated biological invasions. In such delicate ecosystems, biological invasions are an exceptional threat that may be further amplified by climate change. We examined the invasion trajectory of the blowfly Calliphora vicina (Robineau-Desvoidy 1830). First introduced in the sub-Antarctic Kerguelen Islands in the 1970s, it is thought to have persisted only in sheltered microclimates for several decades. Here, we show that, in recent decades, C. vicina has been able to establish itself more widely. We combine experimental thermal developmental data with long-term ecological and meteorological monitoring to address whether warming conditions help explain its current success and dynamics in the eastern Kerguelen Islands. We found that warming temperatures and accumulated degree days could explain the species' phenological and long-term invasion dynamics, indicating that climate change has likely assisted its establishment. This study represents a unique long-term view of a polar invader and stresses the rapidly increasing susceptibility of cold regions to invasion under climate change.

Suicide-specific mortality among patients with treatment-resistant major depressive disorder, major depressive disorder with prior suicidal ideation or suicide attempts, or major depressive disorder alone.

BACKGROUND: The impact of treatment-resistant depression (TRD) or prior suicidal ideation/suicide attempt (SI/SA) on mortality by suicide among patients with major depressive disorder (MDD) is not well known. This retrospective, observational, descriptive cohort study characterized real-world rates of suicide-specific mortality among patients with MDD with or without TRD or SI/SA. METHODS: Adult patients with MDD among commercially insured and Medicare enrollees in Optum Research Database were included and assigned to three cohorts: those with treatment-resistant MDD (TRD), those with MDD and SI/SA (MDD+SI/SA), and those with MDD without TRD or SI/SA (MDD alone). Suicide-specific mortality was obtained from the National Death Index. The effects of demographic characteristics and SI/SA in the year prior to the end of observation on suicide-specific mortality were assessed. RESULTS: For the 139,753 TRD, 85,602 MDD+SI/SA, and 572,098 MDD alone cohort patients, mean age ranged from 55 to 59 years and the majority were female. At baseline, anxiety disorders were present in 53.92%, 44.11%, and 21.72% of patients with TRD, MDD+SI/SA, and MDD alone, respectively. Suicide-mortality rates in the three cohorts were 0.14/100 person-years for TRD, 0.27/100 person-years for MDD+SI/SA, and 0.04/100 person-years for MDD alone. SI/SA during the year prior to the end of observation, younger age, and male sex were associated with increased suicide risk. CONCLUSIONS: Patients with TRD and MDD+SI/SA have a heightened risk of mortality by suicide compared with patients with MDD alone. Suicide rates were higher in patients with recent history versus older or no history of SI/SA, men versus women, and those of young age versus older age.

Predictors of response and remission in patients with treatment-resistant depression: A post hoc pooled analysis of two acute trials of esketamine nasal spray.

This exploratory post hoc analysis of two pooled 4-week, phase 3, double-blind, placebo- and active-controlled studies that compared esketamine nasal spray plus a newly initiated oral antidepressant (ESK+AD; n = 310) with a newly initiated oral AD plus placebo nasal spray (AD+PBO; n = 208) in patients with treatment-resistant depression (TRD) examined baseline patient demographic and psychiatric characteristics as potential predictors of response (≥50% reduction from baseline in Montgomery-Åsberg Depression Rating Scale [MADRS] total score) and remission (MADRS total score ≤12) at day 28. Overall, younger age, any employment, fewer failed ADs in the current depressive episode, and reduction in Clinical Global Impression-Severity (CGI-S) score at day 8 were significant positive predictors of response and remission at day 28. Treatment assignment was an important predictor of both response and remission. Patients treated with ESK+AD had 68% and 55% increased odds of achieving response and remission, respectively, versus those treated with AD+PBO. In the ESK+AD group, attainment of response and remission was more likely in patients who were employed, without significant anxiety at baseline, and who experienced a reduction in CGI-S score at day 8. Identification of predictors of response and remission may facilitate identification of those patients with TRD most likely to benefit from ESK+AD. Trial Registration: ClinicalTrials.gov: NCT02417064 (clinicaltrials.gov/ct2/show/NCT02417064) and NCT02418585 (clinicaltrials.gov/ct2/show/NCT02418585).