Efficacy and Safety of Brolucizumab for Diabetic Macular Edema: The KINGFISHER Randomized Clinical Trial.

Importance: Despite the effectiveness of existing anti-vascular endothelial growth factor (VEGF) therapies, a need remains for further treatment options to improve response rates and/or reduce injection or monitoring frequency in patients with diabetic macular edema (DME). Objective: To evaluate the efficacy and safety of brolucizumab vs aflibercept dosed every 4 weeks in participants with DME. Design, Participants, and Setting: This 52-week, double-masked, phase 3 randomized clinical trial included treatment-naive adults and adults who had previously received anti-VEGF therapy. Data were collected from September 2019 to March 2020, and data were analyzed from April 2020 to February 2021. Intervention: Brolucizumab, 6 mg, intravitreal injection every 4 weeks or aflibercept, 2 mg, intravitreal injection every 4 weeks. Main Outcomes and Measures: Participants were randomized 2:1 to brolucizumab, 6 mg, or aflibercept, 2 mg. The primary end point was change from baseline in best-corrected visual acuity at week 52. Secondary end points were the proportion of participants with a 2-step improvement or greater from baseline in Diabetic Retinopathy Severity Scale score, the proportion of eyes with absence of both subretinal fluid and intraretinal fluid, change from baseline in central subfield thickness, and safety at week 52. Results: A total of 517 participants were randomized to brolucizumab (n = 346) or aflibercept (n = 171); 299 (57.8%) were male, and the mean (SD) age was 60.7 (10.2) years. Brolucizumab was noninferior to aflibercept in best-corrected visual acuity (Early Treatment Diabetic Retinopathy Study letter score) change from baseline at week 52 (brolucizumab, 12.2-letter improvement; aflibercept, 11.0-letter improvement; difference, 1.1; 95% CI, -0.6 to 2.9; noninferiority margin, 4; P < .001). Brolucizumab was superior to aflibercept for the proportion of eyes without subretinal and intraretinal fluid (brolucizumab, 144 of 346 [41.6%]; aflibercept, 38 of 171 [22.2%]; difference, 20.0%; 95% CI, 12.5to 28.6; P < .001) and mean central subfield thickness change from baseline at week 52 (brolucizumab, -237.8 µm; aflibercept, -196.5 µm; difference, -41.4; 95% CI, -58.9 to -23.8; P < .001). Incidence of intraocular inflammation was 4.0% (14 of 346) in the brolucizumab arm and 2.9% (5 of 171) in the aflibercept arm, incidence of retinal vasculitis was 0.9% (3 of 346) and 0.6% (1 of 171), respectively, and incidence of retinal vascular occlusion was 0.3% (1 of 346) and 0.6% (1 of 171). One participant in the brolucizumab arm had retinal artery occlusion. Conclusions and Relevance: In these study participants with DME, no clinically meaningful differences in visual outcomes were noted between the brolucizumab and aflibercept arms; some superior anatomic improvements were noted in the brolucizumab arm. No new safety concerns were identified. Trial Registration: ClinicalTrials.gov Identifier: NCT03917472.

Joint analysis of cognitive and circadian variation in Schizophrenia and Bipolar I Disorder.

BACKGROUND: Impairment in cognitive variables and alterations in circadian function have been documented among patients with schizophrenia (SZ) and bipolar I disorder (BP1), but it is not known whether joint analysis of these variables can define clinically relevant sub-groups in either disorder. OBJECTIVES: To evaluate the pattern and relationship of cognitive and circadian function in SZ and BP1 patients with respect to diagnosis and indices of clinical severity. METHODS: Among patients with SZ and BP1, cognitive function was evaluated using the Penn Computerized Neurocognitive Battery and circadian function was assessed using the Composite Scale of Morningness/ Eveningness (CSM). Clinical severity was estimated using the Global Assessment of Function (GAF) scale, and age at onset of illness (AAO). The patients were compared with community based non-psychotic control individuals and non-psychotic first degree relatives of the SZ patients. The cluster distributions of cognitive function, circadian function and clinical severity were investigated and identified clusters compared across diagnostic groups. RESULTS: Across participants, the cognitive domains could be separated into two clusters. Cluster 1 included the majority of control individuals and non-psychotic relatives, while SZ patients predominated in Cluster 2. BP1 patients were distributed across both clusters. The clusters could be differentiated by GAF scores, but not AAO. CSM scores were not significantly correlated with individual cognitive domains or with the clusters. CONCLUSIONS: Clusters based on levels of cognitive function can discriminate SZ patients from control individuals, but not BP1 patients. CSM scores do not contribute to such discrimination.

A randomised controlled trial of adjunctive yoga and adjunctive physical exercise training for cognitive dysfunction in schizophrenia.

BACKGROUND: Yoga and physical exercise have been used as adjunctive intervention for cognitive dysfunction in schizophrenia (SZ), but controlled comparisons are lacking. Aims A single-blind randomised controlled trial was designed to evaluate whether yoga training or physical exercise training enhance cognitive functions in SZ, based on a prior pilot study. METHODS: Consenting, clinically stable, adult outpatients with SZ (n=286) completed baseline assessments and were randomised to treatment as usual (TAU), supervised yoga training with TAU (YT) or supervised physical exercise training with TAU (PE). Based on the pilot study, the primary outcome measure was speed index for the cognitive domain of 'attention' in the Penn computerised neurocognitive battery. Using mixed models and contrasts, cognitive functions at baseline, 21 days (end of training), 3 and 6 months post-training were evaluated with intention-to-treat paradigm. RESULTS: Speed index of attention domain in the YT group showed greater improvement than PE at 6 months follow-up (p<0.036, effect size 0.51). In the PE group, 'accuracy index of attention domain showed greater improvement than TAU alone at 6-month follow-up (p<0.025, effect size 0.61). For several other cognitive domains, significant improvements were observed with YT or PE compared with TAU alone (p<0.05, effect sizes 0.30-1.97). CONCLUSIONS: Both YT and PE improved attention and additional cognitive domains well past the training period, supporting our prior reported beneficial effect of YT on speed index of attention domain. As adjuncts, YT or PE can benefit individuals with SZ.

NONPARAMETRIC MANOVA APPROACHES FOR NON-NORMAL MULTIVARIATE OUTCOMES WITH MISSING VALUES.

Between-group comparisons often entail many correlated response variables. The multivariate linear model, with its assumption of multivariate normality, is the accepted standard tool for these tests. When this assumption is violated, the nonparametric multivariate Kruskal-Wallis (MKW) test is frequently used. However, this test requires complete cases with no missing values in response variables. Deletion of cases with missing values likely leads to inefficient statistical inference. Here we extend the MKW test to retain information from partially-observed cases. Results of simulated studies and analysis of real data show that the proposed method provides adequate coverage and superior power to complete-case analyses.

Electronic protocol for suicide risk management in research participants.

OBJECTIVE: To describe an electronic, telephone-delivered, suicide risk management protocol (SRMP) that is designed to guide research staff and safely triage study participants who are at risk for self-harm. METHODS: We tested the SRMP in the context of the NIH-funded randomized clinical trial "Bypassing the Blues" in which 302 patients who had undergone coronary artery bypass graft surgery (CABG) were screened for depression and assessed by telephone 2-weeks following hospital discharge and at 2-, 4-, and 8-month follow-up. We programmed the SRMP to assign different risk levels based on patients' answers from none to imminent with action items for research staff keyed to each of them. We describe frequency of suicidal thinking, SRMP use, and completion of specific steps in the SRMP management process over the 8-month follow-up period. RESULTS: Suicidal ideation was expressed by 74 (25%) of the 302 study participants in 139 (13%) of the 1069 blinded telephone assessments performed by research staff. The SRMP was launched in 103 (10%) of assessments, and the suicidal risk level was classified as moderate or high in 10 (1%) of these assessments, thereby necessitating an immediate evaluation by a study psychiatrist. However, no hospitalizations, emergency room visits, or deaths ascribed to suicidal ideation were discovered during the study period. CONCLUSION: The SRMP was successful in systematically and safely guiding research staff lacking specialty mental health training through the standardized risk assessment and triaging research participants at risk for self-harm. TRIAL REGISTRATION: Clinicaltrials.gov Identifier: NCT00091962 (http://clinicaltrials.gov/ct2/show/NCT00091962?term=rollman+cabg&rank=1).

Twelve-month cost-effectiveness of telephone-delivered collaborative care for treating depression following CABG surgery: a randomized controlled trial.

OBJECTIVE: To determine the 12-month cost-effectiveness of a collaborative care (CC) program for treating depression following coronary artery bypass graft (CABG) surgery versus physicians' usual care (UC). METHODS: We obtained 12 continuous months of Medicare and private medical insurance claims data on 189 patients who screened positive for depression following CABG surgery, met criteria for depression when reassessed by telephone 2 weeks following hospitalization (nine-item Patient Health Questionnaire ≥10) and were randomized to either an 8-month centralized, nurse-provided and telephone-delivered CC intervention for depression or to their physicians' UC. RESULTS: At 12 months following randomization, CC patients had $2068 lower but statistically similar estimated median costs compared to UC (P=.30) and a variety of sensitivity analyses produced no significant changes. The incremental cost-effectiveness ratio of CC was -$9889 (-$11,940 to -$7838) per additional quality-adjusted life-year (QALY), and there was 90% probability it would be cost-effective at the willingness to pay threshold of $20,000 per additional QALY. A bootstrapped cost-effectiveness plane also demonstrated a 68% probability of CC "dominating" UC (more QALYs at lower cost). CONCLUSIONS: Centralized, nurse-provided and telephone-delivered CC for post-CABG depression is a quality-improving and cost-effective treatment that meets generally accepted criteria for high-value care.

Benefits of collaborative care for post-CABG depression are not related to adjustments in antidepressant pharmacotherapy.

OBJECTIVE: To determine whether the use and adjustment of antidepressant pharmacotherapy accounted for the beneficial effects of collaborative care treatment on the improvement of mood symptoms and health-related quality of life (HRQoL) after coronary artery bypass graft (CABG) surgery. METHODS: In a post-hoc analysis of data from the Bypassing the Blues (BtB) trial we tested the impact of antidepressant medication on changes in depression and HRQoL from the early postoperative period to 8-month follow-up. Two hundred fifty-nine depressed post-CABG patients scoring ≥10 on the Patient Health Questionnaire-9 were classified in four groups according to whether or not they received antidepressants at baseline and 8-months following randomization. RESULTS: Patients using antidepressant pharmacotherapy at baseline and follow-up tended to be younger and female (p≤0.01), but were similar in various clinical characteristics. Just 24% (63/259) of patients were on an antidepressant at baseline which increased to 36% at follow-up (94/259). Compared to other groups, patients on antidepressants at both baseline and follow-up assessment showed the smallest improvement in mood symptoms and HRQoL. While multivariate analyses confirmed that randomization to collaborative care was associated with greater improvement in mood symptoms (odds ratio [OR]=3.1; 95%-confidence interval [CI]=1.8-5.4, p<0.0001) and mental HRQoL (OR=3.6, CI=1.4-9.3, p=0.01), use of antidepressant medication had no differential impact on either measure (p=0.06 and p=0.92, respectively). CONCLUSION: The beneficial effects of collaborative care for post-CABG depression were not generated by adjustments in antidepressant medication. TRIAL REGISTRATION: Clinicaltrials.gov Identifier: NCT00091962. (http://clinicaltrials.gov/ct2/show/NCT00091962?term=rollman+cabg&rank=1).

Pain adversely affects outcomes to a collaborative care intervention for anxiety in primary care.

BACKGROUND: Primary care patients with Panic Disorder (PD) and Generalized Anxiety Disorder (GAD) experience poorer than expected clinical outcomes, despite the availability of efficacious pharmacologic and non-pharmacologic treatments. A barrier to recovery from PD/GAD may be the co-occurrence of pain. OBJECTIVE: To evaluate whether pain intensity interfered with treatment response for PD and/or GAD in primary care patients who had received collaborative care for anxiety disorders. DESIGN: A secondary data analysis of a randomized, controlled effectiveness trial comparing a telephone-delivered collaborative care intervention for primary care patients with severe PD and/or GAD to their doctor's "usual" care. PARTICIPANTS: Patients had to have a diagnosis of PD and/or GAD and a severe level of anxiety symptoms. The 124 patients randomized at baseline to the collaborative care intervention were analyzed. Participants were divided into two pain intensity groups based on their response to the SF-36 Bodily Pain scale (none or mild pain vs. at least moderate pain). MAIN MEASURES: Pain was assessed using the Bodily Pain scale of the SF-36. Anxiety symptoms were measured with the Hamilton Anxiety Rating Scale (HRS-A), Panic Disorder Severity Scale (PDSS) and Generalized Anxiety Disorder Severity Scale (GADSS). Measures were collected over 12 months. KEY RESULTS: At baseline, patients with at least moderate pain were significantly more likely to endorse more anxiety symptoms on the HRS-A than patients with no pain or mild pain (P < .001). Among patients with severe anxiety symptoms, 65 % (80/124) endorsed experiencing at least moderate pain in the previous month. A significantly lesser number of patients achieved a 50 % improvement at 12 months on the HRS-A and GADSS if they had at least moderate pain as compared to patients with little or no pain (P = 0.01 and P = 0.04, respectively). CONCLUSIONS: Coexisting pain was common in a sample of primary care patients with severe PD/GAD, and appeared to negatively affect response to anxiety treatment.

A positive 2-item Patient Health Questionnaire depression screen among hospitalized heart failure patients is associated with elevated 12-month mortality.

BACKGROUND: Given the association of depression with poorer cardiac outcomes, an American Heart Association Science Advisory has advocated routine screening of cardiac patients for depression using the 2-item Patient Health Questionnaire (PHQ-2) "at a minimum." However, the prognostic value of the PHQ-2 among HF patients is unknown. METHODS AND RESULTS: We screened hospitalized HF patients (ejection fraction [EF] <40%) that staff suspected may be depressed with the PHQ-2, and then determined vital status at up to 12-months follow-up. At baseline, PHQ-2 depression screen-positive patients (PHQ-2+; n = 371), compared with PHQ-2 screen-negative patients (PHQ-2-; n = 100), were younger (65 vs 70 years) and more likely to report New York Heart Association (NYHA) functional class III/IV than class II symptoms (67% vs. 39%) and lower levels of physical and mental health-related quality of life (all P ≤ .002); they were similar in other characteristics (65% male, 26% mean EF). At 12 months, 20% of PHQ-2+ versus 8% of PHQ-2- patients had died (P = .007) and PHQ-2 status remained associated with both all-cause (hazard ratio [HR] 3.1, 95% confidence interval [CI] 1.4-6.7; P = .003) and cardiovascular (HR 2.7, 95% CI 1.1-6.6; P = .03) mortality even after adjustment for age, gender, EF, NYHA functional class, and a variety of other covariates. CONCLUSIONS: Among hospitalized HF patients, a positive PHQ-2 depression screen is associated with an elevated 12-month mortality risk.

Prevalence and correlates of complicated grief in adults who have undergone a coronary artery bypass graft.

BACKGROUND: Complicated grief (CG) is a recently described mental health condition that follows bereavement. CG is often comorbid with depression and may also be associated with poor health outcomes. However, CG has not been studied in depressed medically ill populations. This study examined the prevalence, correlates, and impact of CG in depressed post-coronary artery bypass graft surgery (CABG) patients. METHODS: A 5-item CG screen was administered to 302 depressed post-CABG patients participating in a comparative effectiveness intervention trial at 7 Pittsburgh-area hospitals from March 2004 to September 2007. Eligible patients were randomly assigned to either a telephone-delivered collaborative care intervention for depression or their primary care physicians' usual care. Measures examined depression, physical and mental health-related quality of life, and physical functioning over 8 months. RESULTS: Compared to CG screen-negative patients, CG screen-positive patients were younger, more likely to: be female, non-White, have lost a partner or child, and to have used tobacco or antidepressants. At baseline, they had significantly higher depression and lower mental health scores. At 8 months, screen-positives had poorer physical functioning and marginally higher depression scores. LIMITATIONS: The study lacked a definitive measure of CG. Moreover, the CG-positive group was relatively small, reducing the power to detect differences between groups or control for the possible influence of other variables on identified results. CONCLUSIONS: CG in depressed post-CABG patients is associated with negative health and mental health outcomes. These results underscore the importance of identifying and treating CG in depressed medically ill populations.

Optimism, response to treatment of depression, and rehospitalization after coronary artery bypass graft surgery.

OBJECTIVE: Optimism has been associated with a lower risk of rehospitalization after coronary artery bypass graft (CABG) surgery, but little is known about how optimism affects treatment of depression in post-CABG patients. METHODS: Using data from a collaborative care intervention trial for post-CABG depression, we conducted exploratory post hoc analyses of 284 depressed post-CABG patients (2-week posthospitalization score in the 9-item Patient Health Questionnaire ≥ 10) and 146 controls without depression who completed the Life Orientation Test - Revised (full scale and subscale) to assess dispositional optimism. We classified patients as optimists and pessimists based on the sample-specific Life Orientation Test - Revised distributions in each cohort (full sample, depressed, nondepressed). For 8 months, we assessed health-related quality of life (using the 36-item Short-Form Health Survey) and mood symptoms (using the Hamilton Rating Scale for Depression [HRS-D]) and adjudicated all-cause rehospitalization. We defined treatment response as a 50% or higher decline in HRS-D score from baseline. RESULTS: Compared with pessimists, optimists had lower baseline mean HRS-D scores (8 versus 15, p = .001). Among depressed patients, optimists were more likely to respond to treatment at 8 months (58% versus 27%, odds ratio = 3.02, 95% confidence interval = 1.28-7.13, p = .01), a finding that was not sustained in the intervention group. The optimism subscale, but not the pessimism subscale, predicted treatment response. By 8 months, optimists were less likely to be rehospitalized (odds ratio = 0.54, 95% confidence interval = 0.32-0.93, p = .03). CONCLUSIONS: Among depressed post-CABG patients, optimists responded to depression treatment at higher rates. Independent of depression, optimists were less likely to be rehospitalized by 8 months after CABG. Further research should explore the impact of optimism on these and other important long-term post-CABG outcomes.

The impact of pain and depression on recovery after coronary artery bypass grafting.

OBJECTIVE: To describe the relationship between pain and depression on recovery after coronary artery bypass grafting (CABG). METHODS: A secondary data analysis on 453 depressed and nondepressed post-CABG patients enrolled in a randomized, controlled, effectiveness trial of telephone-delivered collaborative care for depression. Outcome measures were collected from March 2004 to September 2007 and included pain, physical function, and mood symptoms. RESULTS: Depressed patients (baseline Patient Health Questionnaire-9 score ≥10) versus those without depression reported significantly worse pain scores on the 36-Item Short Form Health Survey Bodily Pain Scale at baseline and up to 12 months post-CABG, p < .05. Among patients with depression, those who received collaborative care reported significantly better pain scores at each time point between 2 and 12 months post-CABG versus depressed patients randomized to the usual care control group, p < .05. Regardless of intervention status, depressed participants with at least moderate pain at baseline reported significantly lower functional status (measured by the Duke Activity Status Index) at 8 and 12 months versus depressed patients with none or mild pain, p < .05. Depressed patients with at least moderate pain at baseline were also significantly less likely to show improvement of depressive symptoms throughout the course of follow-up versus depressed patients with little or no pain, p < .05. These findings controlled for age, gender, education, race, comorbid conditions, and baseline pain diagnosis. CONCLUSIONS: Depression and pain seem to influence functional recovery post-CABG. The relationship between these two conditions and 12-month outcomes should be considered by clinicians when planning treatment.