Major depressive disorder: hypothesis, mechanism, prevention and treatment.

Worldwide, the incidence of major depressive disorder (MDD) is increasing annually, resulting in greater economic and social burdens. Moreover, the pathological mechanisms of MDD and the mechanisms underlying the effects of pharmacological treatments for MDD are complex and unclear, and additional diagnostic and therapeutic strategies for MDD still are needed. The currently widely accepted theories of MDD pathogenesis include the neurotransmitter and receptor hypothesis, hypothalamic-pituitary-adrenal (HPA) axis hypothesis, cytokine hypothesis, neuroplasticity hypothesis and systemic influence hypothesis, but these hypothesis cannot completely explain the pathological mechanism of MDD. Even it is still hard to adopt only one hypothesis to completely reveal the pathogenesis of MDD, thus in recent years, great progress has been made in elucidating the roles of multiple organ interactions in the pathogenesis MDD and identifying novel therapeutic approaches and multitarget modulatory strategies, further revealing the disease features of MDD. Furthermore, some newly discovered potential pharmacological targets and newly studied antidepressants have attracted widespread attention, some reagents have even been approved for clinical treatment and some novel therapeutic methods such as phototherapy and acupuncture have been discovered to have effective improvement for the depressive symptoms. In this work, we comprehensively summarize the latest research on the pathogenesis and diagnosis of MDD, preventive approaches and therapeutic medicines, as well as the related clinical trials.

Understanding mechanisms of depression prevention: study protocol of a randomized cross-over trial to investigate mechanisms of mindfulness and positive fantasizing as intervention techniques for reducing perseverative cognition in remitted depressed individuals.

BACKGROUND: Major Depressive Disorder (MDD) is one of the most prevalent psychiatric disorders, and involves high relapse rates in which persistent negative thinking and rumination (i.e., perseverative cognition [PC]) play an important role. Positive fantasizing and mindfulness are common evidence-based psychological interventions that have been shown to effectively reduce PC and subsequent depressive relapse. How the interventions cause changes in PC over time, is unknown, but likely differ between the two. Whereas fantasizing may change the valence of thought content, mindfulness may operate through disengaging from automatic thought patterns. Comparing mechanisms of both interventions in a clinical sample and a non-clinical sample can give insight into the effectivity of interventions for different individuals. The current study aims to 1) test whether momentary psychological and psychophysiological indices of PC are differentially affected by positive fantasizing versus mindfulness-based interventions, 2) test whether the mechanisms of change by which fantasizing and mindfulness affect PC differ between remitted MDD versus never-depressed (ND) individuals, and 3) explore potential moderators of the main effects of the two interventions (i.e., what works for whom). METHODS: In this cross-over trial of fantasizing versus mindfulness interventions, we will include 50 remitted MDD and 50 ND individuals. Before the start of the measurements, participants complete several individual characteristics. Daily-life diary measures of thoughts and feelings (using an experience sampling method), behavioural measures of spontaneous thoughts (using the Sustained Attention to Response Task), actigraphy, physiological measures (impedance cardiography, electrocardiography, and electroencephalogram), and measures of depressive mood (self-report questionnaires) are performed during the week before (pre-) the interventions and the week during (peri-) the interventions. After a wash-out of at least one month, pre- and peri-intervention measures for the second intervention are repeated. DISCUSSION: This is the first study integrating self-reports, behavioural-, and physiological measures capturing dynamics at multiple time scales to examine the differential mechanisms of change in PC by psychological interventions in individuals remitted from multiple MDD episodes and ND individuals. Unravelling how therapeutic techniques affect PC in remitted individuals might generate insights that allows development of personalised targeted relapse prevention interventions. TRIAL REGISTRATION: ClinicalTrials.gov: NCT06145984, November 16, 2023.

How fish consumption prevents the development of Major Depressive Disorder? A comprehensive review of the interplay between n-3 PUFAs, LTP and BDNF.

MDD (major depressive disorder) is a highly prevalent mental disorder with a complex etiology involving behavioral and neurochemical factors as well as environmental stress. The interindividual variability in response to stress stimuli may be explained by processes such as long-term potentiation (LTP) and long-term depression (LTD). LTP can be described as the strengthening of synaptic transmission, which translates into more efficient cognitive performance and is regulated by brain-derived neurotrophic factor (BDNF), a protein responsible for promoting neural growth. It is found in high concentrations in the hippocampus, a part of the limbic system which is far less active in people with MDD. Omega-3 fatty acids like eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) not only contribute to structural and antioxidative functions but are essential for the maintenance of LTP and stable BDNF levels. This review explores the mechanisms and potential roles of omega-3 fatty acids in the prevention of MDD.

Effects of non-pharmacological interventions on depressive symptoms and risk of major depressive disorder in adults with subthreshold depression: A systematic review and meta-analysis.

Subthreshold depression (StD) is a condition that significantly reduces the quality of life and increases the risk of developing major depressive disorder (MDD). In order to investigate the effectiveness of non-pharmacological interventions (NPIs) in preventing the onset of MDD and improving depressive symptoms in adults with StD (AStDs), we conducted a systematic search of nine databases and included a total of 15 studies. Standardized mean differences (SMDs) were calculated using random effects models. RoB2 tool and GRADEpro software were used to assess the methodological quality and evidence. Funnel plots, Egger's, and Begg's tests were used to analyze publication bias. Sensitivity, subgroup and meta-regression analyses were performed to explore potential sources of heterogeneity. The results showed that NPIs had a significant effect in preventing the onset of MDD and improving depressive symptoms. Subgroup analysis revealed that NPIs were particularly effective in general adult populations, during short-term follow-up (FU) periods, among pregnant women, and in universal prevention programs. The results were found to be robust and credible, as they were less sensitive to changes in the analysis method. Timely detection and treatment of StD is feasible and important, as it can effectively delay or prevent the onset of MDD.

Relation of serum BDNF to major depression and exploration of mechanistic roles of serum BDNF in a study of vitamin D3 and omega-3 supplements for late-life depression prevention.

This study: 1) examined cross-sectional and longitudinal relations of serum brain-derived neurotrophic factor (BDNF) to late-life depression (LLD); 2) tested effects of vitamin D3 and omega-3s on change in BDNF; 3) explored modifying or mediating roles of BDNF on effects of vitamin D3 and omega-3s for LLD. We selected 400 adults from a completed trial of vitamin D3 and omega-3 supplements for LLD prevention. BDNF was measured using an enzyme-linked immunosorbent assay. We administered semi-structured diagnostic interviews and Patient Health Questionnaire [PHQ]-9 to ascertain outcomes at baseline (depression caseness vs. non-caseness; PHQ-9) and at 2-year follow-up among baseline non-depressed individuals (incident vs. no incident MDD; change in PHQ-9). At baseline, while there were no significant differences in mean serum BDNF comparing depression cases and non-cases, being in the lowest vs. highest serum BDNF quartile was significantly associated with worse depressive symptoms. There were no significant longitudinal associations between serum BDNF and LLD. Neither supplement significantly affected change in BDNF; serum BDNF did not appear to modify or mediate treatment effects on LLD. In conclusion, we observed significant cross-sectional but not longitudinal associations between serum BDNF levels and LLD. Vitamin D3 or omega-3s did not alter serum BDNF over 2 years.

Effects of Vitamin D3 and Marine Omega-3 Fatty Acids Supplementation on Indicated and Selective Prevention of Depression in Older Adults: Results From the Clinical Center Sub-Cohort of the VITamin D and OmegA-3 TriaL (VITAL).

Objective: To test vitamin D3 and omega-3 fatty acids (omega-3s) for late-life depression prevention under the National Academy of Medicine framework for indicated (targeting subthreshold depression) and selective (targeting presence of high-risk factors) prevention.Methods: The VITamin D and OmegA-3 TriaL (VITAL) is a 2 × 2 factorial trial of vitamin D3 (2,000 IU/d) and/or omega-3s (1 g/d) for cardiovascular and cancer prevention (enrollment: November 2011-March 2014; end date: December 31, 2017). In this targeted prevention study, we included 720 VITAL clinical sub-cohort participants who completed neurobehavioral assessments at baseline and 2 years (91.9% retention). High-risk factors were subthreshold or clinical anxiety, impaired activities of daily living, physical/functional limitation, medical comorbidity, cognitive impairment, caregiving burden, problem drinking, and low psychosocial support. Coprimary outcomes were incident major depressive disorder (MDD), adjudicated using DSM-IV (Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition), and change in mood (Patient Health Questionnaire-9 [PHQ-9]). We used exact tests to determine treatment effects on MDD incidence and repeated-measures models to determine treatment effects on PHQ-9.Results: A total of 11.1% had subthreshold depression, 60.8% had ≥ 1 high-risk factor, MDD incidence was 4.7% (5.1% among completers), and mean PHQ-9 score change was 0.02 points. Among those with subthreshold depression, the MDD risk ratio (95% confidence interval) was 0.36 (0.06 to 1.28) for vitamin D3 and 0.85 (0.25 to 2.92) for omega-3s, compared to placebo; results were also null among those with ≥ 1 high-risk factor (vitamin D3 vs placebo: 0.63 [0.25 to 1.53]; omega-3s vs placebo: 1.08 [0.46 to 2.71]). There were no significant differences in PHQ-9 score change comparing either supplement with placebo.Conclusions: Neither vitamin D3 nor omega-3s showed benefits for indicated and selective prevention of late-life depression; statistical power was limited.Trial Registration: ClinicalTrials.gov identifier: NCT01696435.

Resting-state functional connectivity disruption between the left and right pallidum as a biomarker for subthreshold depression.

Although the identification of late adolescents with subthreshold depression (StD) may provide a basis for developing effective interventions that could lead to a reduction in the prevalence of StD and prevent the development of major depressive disorder, knowledge about the neural basis of StD remains limited. The purpose of this study was to develop a generalizable classifier for StD and to shed light on the underlying neural mechanisms of StD in late adolescents. Resting-state functional magnetic resonance imaging data of 91 individuals (30 StD subjects, 61 healthy controls) were included to build an StD classifier, and eight functional connections were selected by using the combination of two machine learning algorithms. We applied this biomarker to an independent cohort (n = 43) and confirmed that it showed generalization performance (area under the curve = 0.84/0.75 for the training/test datasets). Moreover, the most important functional connection was between the left and right pallidum, which may be related to clinically important dysfunctions in subjects with StD such as anhedonia and hyposensitivity to rewards. Investigation of whether modulation of the identified functional connections can be an effective treatment for StD may be an important topic of future research.

A multiple health behaviour change intervention to prevent depression: A randomized controlled trial.

OBJECTIVE: To examine the effectiveness of a 12-month MHBC intervention in the prevention of onset depression in primary health care (PHC). METHODS: Twenty-two PHC centres took part in the cluster-randomized controlled trial. Patients were randomized to receive either usual care or an MHBC intervention. The endpoints were onset of major depression and reduction of depressive symptoms in participants without baseline depression at a 12-month follow-up. RESULTS: 2531 patients agreed and were eligible to participate. At baseline, around 43% were smokers, 82% were non-adherent to the Mediterranean diet and 55% did not perform enough physical activity. The intervention group exhibited a greater positive change in two or more behaviours (OR 1.75 [95%CI: 1.17 to 2.62]; p = 0.006); any behaviour (OR 1.58 [95%CI: 1.13 to 2.20]; p = 0.007); and adherence to the Mediterranean diet (OR 1.94 [95%CI: 1.29 to 2.94]; p = 0.002), while this increase was not statistically significant for smoking and physical activity. The intervention was not effective in preventing major depression (OR 1.17; [95% CI 0.53 to 2.59)]; p = 0.690) or reducing depressive symptoms (Mean difference: 0.30; [95% CI -0.77 to 1.36]; p = 0.726) during follow-up. CONCLUSIONS: As compared to usual care, the MHBC intervention provided a non-significant reduction in the incidence of major depression. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03136211.

Developmental Pathways of the Family Bereavement Program to Prevent Major Depression 15 Years Later.

OBJECTIVE: To examine the developmental pathways through which the Family Bereavement Program (FBP) reduces major depression and generalized anxiety disorder 15 years later. METHOD: A randomized trial of the FBP included 5 assessments, at pretest, posttest (98% retention), and follow-ups at 11 months (90% retention), 6 years (89% retention), and 15 years (80% retention) following the program. Participants included 244 children and adolescents (from 156 families) 8 to 16 years of age who were randomly assigned to the FBP (135 children/adolescents, 90 families), a 12-session program that included a caregiver component and a child/adolescent component or a literature comparison condition (109 children/adolescents, 66 families). In-home interviews assessed mediators directly targeted for change at post-test and 11 months (eg, parenting and coping); 6-year theoretical mediators (ie, internalizing problems, aversive views of the self) and 15-year children's/adolescents' major depression and generalized anxiety disorder. Data analysis tested 3 path mediation models in which FBP effects at post-test and 11 months led to effects on 6-year theoretical mediators, which in turn lad to reductions in major depression and generalized anxiety disorder at 15 years. RESULTS: The FBP had a significant effect on reducing the prevalence of major depression (odds ratio = 0.332, p < .01) at 15 years. Significant 3-path mediation models found that multiple variables that were targeted by the caregiver and child components of the FBP at post-test and 11 months mediated FBP effects on depression at 15 years through their impact on aversive self-views and internalizing problems at 6 years. CONCLUSION: The findings support the 15-year impact of the Family Bereavement Program on major depression and for maintaining components of the FBP that affect aspects of parenting and children's coping, grief, and self-regulation as the program is disseminated. CLINICAL TRIAL REGISTRATION INFORMATION: 6-Year Follow-up of a Prevention Program for Bereaved Families; https://clinicaltrials.gov/; NCT01008189. DIVERSITY & INCLUSION STATEMENT: We worked to ensure race, ethnic, and/or other types of diversity in the recruitment of human participants. We actively worked to promote sex and gender balance in our author group. One or more of the authors of this paper self-identifies as a member of one or more historically underrepresented racial and/or ethnic groups in science. We actively worked to promote inclusion of historically underrepresented racial and/or ethnic groups in science in our author group.

Effects up to 20-Year Follow-Up of Preventive Cognitive Therapy in Adults Remitted from Recurrent Depression: The DELTA Study.

INTRODUCTION: Major depressive disorder (MDD) is common, and recurrence rates are high. Preventive Cognitive Therapy (PCT), has been shown to prolong time to recurrence and reduce risk of recurrence(s) over 2-10 years in patients with recurrent depression. OBJECTIVE: The aim of the study was to examine the effectiveness of PCT over 20 years on time to first recurrence, cumulative proportion of first recurrences, percentage of depression-free time, mean severity of recurrences, and the number of recurrences within a patient. METHODS: Adults remitted from recurrent MDD were randomized to PCT or Treatment As Usual (TAU). Clinical outcomes were assessed using the SCID over 20 years. We used Cox regression analyses, Kaplan-Meier analyses, ANOVA, and negative binomial regression and tested for interaction with the number of previous episodes. RESULTS: There was a significant interaction effect for number of previous episodes with treatment condition on time to first recurrence (Wald[1, n = 172] = 8.840, p = 0.003). For participants with more than 3 previous episodes, the mean time to recurrence was 4.8 years for PCT versus 1.6 years for TAU; the cumulative proportion of first recurrences was 87.5% for PCT and 100% for TAU. For participants with more than 3 previous episodes, exploratory analyses suggest that PCT had 53% less recurrences and percentage of depression-free time was significantly higher compared to TAU. There were no significant effects on mean severity. CONCLUSIONS: Up to 20 years, for MDD patients with more than 3 previous episodes, those who received PCT had significantly longer time to a first recurrence and lower recurrence risk and may have less recurrences and more depression-free time compared to TAU. This suggests long term protective effects of PCT up to 20-years.

Sleep to Reduce Incident Depression Effectively (STRIDE): study protocol for a randomized controlled trial comparing stepped-care cognitive-behavioral therapy for insomnia versus sleep education control to prevent major depression.

BACKGROUND: Prevention of major depressive disorder (MDD) is a public health priority. Strategies targeting individuals at elevated risk for MDD may guide effective preventive care. Insomnia is a reliable precursor to depression, preceding half of all incident and relapse cases. Thus, insomnia may serve as a useful entry point for preventing MDD. Cognitive-behavioral therapy for insomnia (CBT-I) is recommended as the first-line treatment for insomnia, but widespread implementation is limited by a shortage of trained specialists. Innovative stepped-care approaches rooted in primary care can increase access to CBT-I and reduce rates of MDD. METHODS/DESIGN: We propose a large-scale stepped-care clinical trial in the primary care setting that utilizes a sequential, multiple assignment, randomized trial (SMART) design to determine the effectiveness of dCBT-I alone and in combination with clinician-led CBT-I for insomnia and the prevention of MDD incidence and relapse. Specifically, our care model uses digital CBT-I (dCBT-I) as a first-line intervention to increase care access and reduce the need for specialist resources. Our proposal also adds clinician-led CBT-I for patients who do not remit with first-line intervention and need a more personalized approach from specialty care. We will evaluate negative repetitive thinking as a potential treatment mechanism by which dCBT-I and CBT-I benefit insomnia and depression outcomes. DISCUSSION: This project will test a highly scalable model of sleep care in a large primary care system to determine the potential for wide dissemination and implementation to address the high volume of population need for safe and effective insomnia treatment and associated prevention of depression. TRIAL REGISTRATION: ClinicalTrials.gov NCT03322774. Registered on October 26, 2017.

The preventive effect of internet-based cognitive behavioral therapy for prevention of depression during pregnancy and in the postpartum period (iPDP): a large scale randomized controlled trial.

BACKGROUND: Prevention of perinatal depression beginning from the antenatal period is essential. Therefore, this study aimed to investigate the effectiveness of recently developed internet-delivered cognitive behavioral therapy (iCBT) for preventing the onset of a major depressive episode (MDE) in the third trimester and at 3 months postpartum. METHODS: This is a two-arm, parallel-group, general-information controlled, randomized controlled trial. Participants were 5017 pregnant women at 16-20 weeks' gestation without MDE at baseline. They were randomly assigned to an iCBT (intervention; n = 2509) or general-information (control; n = 2508) group, stratified by psychological distress at baseline. The primary outcomes were the numbers of new MDE onsets, measured using the World Health Organization Composite International Diagnostic Interview 3.0, at 32 weeks' gestation and at 3 months postpartum. RESULTS: New MDE onset was reported by 59 participants (2.35%) in the intervention group and 73 (2.91%) in the control group during follow-up. Compared with the control group, the hazard ratio (HR) of MDE in the intervention group was 0.85 (95% CI 0.61-1.20), which was not significantly different. Among participants who scored between 5 and 8 on K6 at baseline, 10 (1.37%) in the intervention group reported new onset of MDE, compared with 28 (3.81%) in the control group, and the HR of MDE was 0.38 (95%CI 0.19-0.79). CONCLUSIONS: No intervention effect was found for iCBT in preventing new onset of perinatal MDE. iCBT might prevent perinatal depression only among pregnant women with subthreshold depressive symptoms. TRIAL REGISTRATION: UMIN000038190.

Biological Role of Nutrients, Food and Dietary Patterns in the Prevention and Clinical Management of Major Depressive Disorder.

Major Depressive Disorder (MDD) is a growing disabling condition affecting around 280 million people worldwide. This complex entity is the result of the interplay between biological, psychological, and sociocultural factors, and compelling evidence suggests that MDD can be considered a disease that occurs as a consequence of an evolutionary mismatch and unhealthy lifestyle habits. In this context, diet is one of the core pillars of health, influencing multiple biological processes in the brain and the entire body. It seems that there is a bidirectional relationship between MDD and malnutrition, and depressed individuals often lack certain critical nutrients along with an aberrant dietary pattern. Thus, dietary interventions are one of the most promising tools to explore in the field of MDD, as there are a specific group of nutrients (i.e., omega 3, vitamins, polyphenols, and caffeine), foods (fish, nuts, seeds fruits, vegetables, coffee/tea, and fermented products) or dietary supplements (such as S-adenosylmethionine, acetyl carnitine, creatine, amino acids, etc.), which are being currently studied. Likewise, the entire nutritional context and the dietary pattern seem to be another potential area of study, and some strategies such as the Mediterranean diet have demonstrated some relevant benefits in patients with MDD; although, further efforts are still needed. In the present work, we will explore the state-of-the-art diet in the prevention and clinical support of MDD, focusing on the biological properties of its main nutrients, foods, and dietary patterns and their possible implications for these patients.

Stage models for major depression: Cognitive behavior therapy, mechanistic treatment targets, and the prevention of stage transition.

Stage models encourage a longitudinal perspective on the care of those with major depression: supporting vigilance to the risk for stage progression and the selection of interventions to address that risk. A central goal for this article is to evaluate the role of cognitive-behavior therapy (CBT) in addressing stage progression in the treatment of major depression. We summarize the evidence supporting depression-focused CBT for: (1) preventing depression onset, (2) treating syndromal depression, (3) treating residual symptoms, (4) preventing relapse, and (5) addressing pharmacologic treatment resistance. In addition, consistent with the goal of aiding prevention and intervention development by refining mechanistic treatment targets, we evaluate the role of two specific risk-factors for stage progression: insomnia and rumination. These risk factors have a feed-forward relationship with stress, both being amplified by stress and amplifying the negative consequences of stress. Moreover, each of these risk factors predict depression stage transmissions across multiple stages, and both are modifiable with treatment. Accordingly, insomnia and rumination appear to serve as excellent mechanistic targets for the prevention of depression stage progression. These findings are discussed in relation to current limitations and future research directions for targeting these risk factors and furthering the effective treatment of depression.

Augmenting neurocognitive remediation therapy to Preventive Cognitive Therapy for partially remitted depressed patients: protocol of a pragmatic multicentre randomised controlled trial.

INTRODUCTION: Major depressive disorder (MDD) affects 163 million people globally every year. Individuals who experience subsyndromal depressive symptoms during remission (ie, partial remission of MDD) are especially at risk for a return to a depressive episode within an average of 4 months. Simultaneously, partial remission of MDD is associated with work and (psycho)social impairment and a lower quality of life. Brief psychological interventions such as preventive cognitive therapy (PCT) can reduce depressive symptoms or relapse for patients in partial remission, although achieving full remission with treatment is still a clinical challenge. Treatment might be more effective if cognitive functioning of patients is targeted as well since cognitive problems are the most persisting symptom in partial remission and predict poor treatment response and worse functioning. Studies show that cognitive functioning of patients with (remitted) MDD can be improved by online neurocognitive remediation therapy (oNCRT). Augmenting oNCRT to PCT might improve treatment effects for these patients by strengthening their cognitive functioning alongside a psychological intervention. METHODS AND ANALYSIS: This study will examine the effectiveness of augmenting oNCRT to PCT in a pragmatic national multicentre superiority randomised controlled trial. We will include 115 adults partially remitted from MDD with subsyndromal depressive symptoms defined as a Hamilton Depression Rating Scale score between 8 and 15. Participants will be randomly allocated to PCT with oNCRT, or PCT only. Primary outcome measure is the effect on depressive symptomatology over 1 year. Secondary outcomes include time to relapse, cognitive functioning, quality of life and healthcare costs. This first dual approach study of augmenting oNCRT to PCT might facilitate full remission in partially remitted individuals as well as prevent relapse over time. ETHICS AND DISSEMINATION: Ethical approval was obtained by Academic Medical Center, Amsterdam. Outcomes will be made publicly available. TRIAL REGISTRATION NUMBER: NL9582.

Menopausal Hormone Therapy and the Mind: The Role of Hormone Replacement in the Prevention and Treatment of Cognitive Decline, Dementia, and Cognitive Dysfunction of Depression.

LEARNING OBJECTIVES: After participating in this activity, learners should be better able to:• Outline the clinical recommendations for menopausal hormone treatment related to cognitive concerns• Debate and discuss the various research pieces on the use of menopausal hormone therapy cognitive decline, dysfunction, and dementia. ABSTRACT: Menopause has been associated with subjective cognitive dysfunction and elevated rates of depression. While menopausal hormone therapy (MHT) is Food and Drug Administration-approved for the treatment of vasomotor symptoms related to menopause, a potential role for MHT in treating and preventing cognitive decline, dysfunction, and dementia has remained unclear and a topic of continued interest and debate across decades of research. Increasing numbers of patients are seeking help for subjective cognitive decline, and those with poorer mental health are substantially more likely to perceive themselves to be at high risk of developing dementia; thus, mental health professionals are likely to encounter such patients and may be asked to provide advice concerning MHT, cognition, and indications for MHT use. Here, we synthesize the neurobiological effects of MHT, make recommendations for its use in current clinical practice in the contexts of cognitive dysfunction associated with major depressive disorder, cognitive decline, and Alzheimer's disease, and discuss the frontiers being explored by ongoing research on this topic. We conclude that MHT to improve cognitive functioning has only a few scenarios where it would be recommended and that particular caution may be warranted for carriers of the APOE ε4 allele.

PATH 2 Purpose: Design of a comparative effectiveness study of prevention programs for adolescents at-risk for depression in the primary care setting.

The majority of mental, emotional, and behavioral (MEB) disorders have an initial onset before age 24, with 20% annual incidence, and with major depressive disorder (MDD) being the most common MEB. Health systems may be able to reduce costs by transitioning from the current treatment-focused model for MDD to a prevention model. However, evidence is needed for (1) the comparative effectiveness of a "scalable intervention" and (2) an implementation model for such a scalable intervention in the primary care setting. This paper describes a comparative effectiveness trial evaluating the efficacy of two evidence-based cognitive-behavioral prevention (CBP) programs: Teens Achieving Mastery over Stress (TEAMS), the "gold standard," group therapy model, and Competent Adulthood Transition with Cognitive Behavioral, Humanistic and Interpersonal Training (CATCH-IT), a scalable, self-directed, technology-based model. Eligible adolescents, age 13-19, are offered one of these two depression prevention programs across five health systems (30 clinics) in urban and suburban Chicago, IL, rural Western IL, and Louisville, KY. We are comprehensively evaluating patient-centered outcomes and stakeholder-valued moderators of effect versus baseline at two, six, 12, and 18-month assessment points. Using a hybrid clinical trial design that simultaneously examines the implementation process, the study is also assessing adolescents', parents', and providers' experiences (e.g., efficacy, time commitment, cultural acceptability) within each intervention approach.

Treating Insomnia with High Risk of Depression Using Therapist-Guided Digital Cognitive, Behavioral, and Circadian Rhythm Support Interventions to Prevent Worsening of Depressive Symptoms: A Randomized Controlled Trial.

INTRODUCTION: The global disease burden of major depressive disorder urgently requires prevention in high-risk individuals, such as recently discovered insomnia subtypes. Previous studies targeting insomnia with fully automated eHealth interventions to prevent depression are inconclusive: dropout was high and likely biased, and depressive symptoms in untreated participants on average improved rather than worsened. OBJECTIVE: This randomized controlled trial aimed to efficiently prevent the worsening of depressive symptoms by selecting insomnia subtypes at high risk of depression for internet-based circadian rhythm support (CRS), cognitive behavioral therapy for insomnia (CBT-I), or their combination (CBT-I+CRS), with online therapist guidance to promote adherence. METHODS: Participants with an insomnia disorder subtype conveying an increased risk of depression (n = 132) were randomized to no treatment (NT), CRS, CBT-I, or CBT-I+CRS. The Inventory of Depressive Symptomatology - Self Report (IDS-SR) was self-administered at baseline and at four follow-ups spanning 1 year. RESULTS: Without treatment, depressive symptoms indeed worsened (d = 0.28, p = 0.041) in high-risk insomnia, but not in a reference group with low-risk insomnia. Therapist-guided CBT-I and CBT-I+CRS reduced IDS-SR ratings across all follow-up assessments (respectively, d = -0.80, p = 0.001; d = -0.95, p < 0.001). Only CBT-I+CRS reduced the 1-year incidence of clinically meaningful worsening (p = 0.002). Dropout during therapist-guided interventions was very low (8%) compared to previous automated interventions (57-62%). CONCLUSIONS: The findings tentatively suggest that the efficiency of population-wide preventive strategies could benefit from the possibility to select insomnia subtypes at high risk of developing depression for therapist-guided digital CBT-I+CRS. This treatment may provide effective long-term prevention of worsening of depressive symptoms. TRIAL REGISTRATION: the Netherlands Trial Register (NL7359).

Prevention of Incident and Recurrent Major Depression in Older Adults With Insomnia: A Randomized Clinical Trial.

Importance: Older adults with insomnia have a high risk of incident and recurrent depression. Depression prevention is urgently needed, and such efforts have been neglected for older adults. Objective: To examine whether treatment of insomnia disorder with cognitive behavioral therapy for insomnia (CBT-I) compared with an active comparator condition, sleep education therapy (SET), prevents major depressive disorder in older adults. Design, Setting, and Participants: This assessor-blinded, parallel-group, single-site randomized clinical trial assessed a community-based sample of 431 people and enrolled 291 adults 60 years or older with insomnia disorder who had no major depression or major health events in past year. Study recruitment was performed from July 1, 2012, to April 30, 2015. The trial protocol was modified to extend follow-up from 24 to 36 months, with follow-up completion in July 2018. Data analysis was performed from March 1, 2019, to March 30, 2020. Interventions: Participants were randomized to 2 months of CBT-I (n = 156) or SET (n = 135). Main Outcomes and Measures: The primary outcome was time to incident major depressive disorder as diagnosed by interview and Diagnostic and Statistical Manual of Mental Disorders (Fifth Edition) criteria. Secondary outcome was sustained remission of insomnia disorder before depression event or duration of follow-up. Results: Among 291 randomized participants (mean [SD] age, 70.1 [6.7] years; 168 [57.7%] female; 7 [2.4%] Asian, 32 [11.0%] Black, 3 [1.0%] Pacific Islander, 241 [82.8%] White, 6 [2.1%] multiracial, and 2 [0.7%] unknown), 156 were randomized to CBT-I and 135 to SET. A total of 140 participants (89.7%) completed CBT-I and 130 (96.3%) participants completed SET (χ2 = 4.9, P = .03), with 114 (73.1%) completing 24 months of follow-up in the CBT-I group and 117 (86.7%) in the SET group (χ2 = 8.4, P = .004). After protocol modification, 92 (59.0%) of the CBT-I participants and 86 (63.7%) of the SET participants agreed to extended follow-up (χ2 = 0.7, P = .41), with 81 (51.9%) of the CBT-I participants and 77 (57.0%) of the SET group completing 36 months of follow-up (χ2 = 0.8; P = .39). Incident or recurrent major depression occurred in 19 participants (12.2%) in the CBT-I group and in 35 participants (25.9%) in the SET group, with an overall benefit (hazard ratio, 0.51; 95%, CI 0.29-0.88; P = .02) consistent across subgroups. Remission of insomnia disorder continuously sustained before depression event or during follow-up was more likely in CBT-I participants (41 [26.3%]) compared with the SET participants (26 [19.3%], P = .03). Those in the CBT-I group with sustained remission of insomnia disorder had an 82.6% decreased likelihood of depression (hazard ratio, 0.17; 95%, CI 0.04-0.73; P = .02) compared with those in the SET group without sustained remission of insomnia disorder. Conclusions and Relevance: The findings of this randomized clinical trial indicate that treatment of insomnia with CBT-I has an overall benefit in the prevention of incident and recurrent major depression in older adults with insomnia disorder. Community-level screening for insomnia concerns in older adults and wide delivery of CBT-I-based treatment for insomnia could substantially advance public health efforts to treat insomnia and prevent depression in this vulnerable older adult population. Trial Registration: ClinicalTrials.gov Identifier: NCT01641263.