Application Of Depression Research Articles

Adjunctive use of mindfulness-based mobile application in depression: randomized controlled study.

Mindfulness-based interventions (MBI) are effective in relapse prevention in Major Depressive Disorder (MDD). Internet-based interventions have been demonstrated to be effective in the treatment of MDD. Consequently, the integration of MBI through mobile applications emerges as a promising supplementary intervention for MDD, contributing to the augmentation of mental health services, particularly within ambulatory care contexts. The current randomized controlled study is designed to evaluate the efficacy of adjunctive MBI delivered via a mobile app in mitigating symptom severity and stress levels. This assessment involves a comparison with standard treatment practices in an ambulatory setting among individuals diagnosed with MDD. A total of 83 patients diagnosed with MDD (depressive episode, recurrent depression or depressive phase of bipolar disorder) were randomly allocated to the intervention (41 patients) or control condition (42 patients). The intervention consisted of the daily use of the mindfulness mobile application "Headspace" for thirty days. The control condition was treatment as usual (TAU) only. The symptom severity has been assessed by the Beck Depression Inventory (BDI-II) as well as the Hamilton Depression Rating Scale (HDRS-17). Blood pressure and resting heart rate have been assessed as secondary outcome. Upon hospital discharge, the mean scores on the Beck Depression Inventory (BDI) and Hamilton Depression Rating Scale (HDRS) signaled partial remission of MDD in both treatment arms. In both groups, a subsequent decrease in both self-reported and expert-rated scores was evident after a 30-day period. However, the decrease in depression severity as measured by HDRS was significantly higher in the MBI group compared to the control group after 30days. For secondary outcomes, systolic blood pressure was lower in the intervention group compared to control group. The total drop-out rate was 29%. Short term mindfulness intervention via mobile application (30days) can be beneficial as adjunctive therapy to treatment as usual in patients with MDD.

Probiotics and Fecal Microbiota Transplantation in Major Depression: Doxa or Episteme?

In the human body, eukaryotic somatic cells and prokaryotic microorganisms live together. In this state, the body can be viewed as a "superorganism." Symbiotic life with commensal microorganisms can be observed in almost every part of the body. Intestinal microbiota plays an important role in health and disease, and in shaping and regulating neuronal functions from the intrauterine period to the end of life. Microbiota-based treatment opportunities are becoming more evident in both understanding the etiopathogenesis and treatment of neuropsychiatric disorders, especially depression. Antidepressant drugs, which are the first choice in the treatment of depression, also have antimicrobial and immunomodulatory mechanisms of action. From these perspectives, direct probiotics and fecal microbiota transplantation are treatment options to modulate microbiota composition. There are few preclinical and clinical studies on the effectiveness and safety of these applications in depression. The information obtained from these studies may still be at a doxa level. However, the probability that this information will become episteme in the future seems to be increasing.

Potential Plausible Role of Stem Cell for Treating Depressive Disorder: a Retrospective Review.

Depression poses a significant threat to global physical and mental health, impacting around 3.8% of the population with a rising incidence. Current treatment options primarily involve medication and psychological support, yet their effectiveness remains limited, contributing to high relapse rates. There is an urgent need for innovative and more efficacious treatment modalities. Stem cell therapy, a promising avenue in regenerative medicine for a spectrum of neurodegenerative conditions, has recently garnered attention for its potential application in depression. While much of this work remains preclinical, it has demonstrated considerable promise. Identified mechanisms underlying the antidepressant effects of stem cell therapy encompass the stimulation of neurotrophic factors, immune function modulation, and augmented monoamine levels. Nonetheless, these pathways and other undiscovered mechanisms necessitate further investigation. Depression fundamentally manifests as a neurodegenerative disorder. Given stem cell therapy's success in addressing a range of neurodegenerative pathologies, it opens the door to explore its application in depression treatment. This exploration may include repairing damaged nerves directly or indirectly and inhibiting neurotoxicity. Nevertheless, significant challenges must be overcome before stem cell therapies can be applied clinically. Successful resolution of these issues will ultimately determine the feasibility of incorporating stem cell therapies into the clinical landscape. This narrative review provides insights into the progress of research, potential avenues for exploration, and the prevailing challenges in the implementation of stem cell therapy for treatment of depression.

Antidepressant pharmacological mechanisms: focusing on the regulation of autophagy.

The core symptoms of depression are anhedonia and persistent hopelessness. Selective serotonin reuptake inhibitors (SSRIs) and their related medications are commonly used for clinical treatment, despite their significant adverse effects. Traditional Chinese medicine with its multiple targets, channels, and compounds, exhibit immense potential in treating depression. Autophagy, a vital process in depression pathology, has emerged as a promising target for intervention. This review summarized the pharmacological mechanisms of antidepressants by regulating autophagy. We presented insights from recent studies, discussed current research limitations, and proposed new strategies for basic research and their clinical application in depression.

The Endocannabinoid System as a Biomarker for Diagnostic and Therapeutic Applications in Depression and Anxiety.

Depression and anxiety belong to a family of mental disturbances that have increased significantly in recent years. The etiology of both disorders comprises multiple and complex factors, from genetic background to environmental influence. Since depression and anxiety present severe symptoms, they represent a greater clinical burden and greater therapeutic difficulty. Currently, standardized diagnostic procedures for depression and anxiety allow for the addition of further treatments, including psychotherapy and/or pharmacological intervention, with effective outcomes. However, further steps should be considered with regard to consideration of the endocannabinoid system's role in depression and anxiety. This study aimed to review the evidence from animal research and clinical studies on the role of cannabinoid receptors, the major endocannabinoids -anandamide (AEA) and 2-arachidonoylglycerol (2-AG)- and the enzymes related to the synthesis and degradation of these chemicals as putative biomarkers for diagnostic and therapeutic elements of depression and anxiety. This review included the online search, identification, and analysis of articles (basic and clinical trials) published in English in PubMed linked to the role of cannabinoid receptors, AEA, 2- AG, and the enzymes associated with the synthesis and degradation of these endocannabinoids in depression and anxiety. The neurobiological relevance of the endocannabinoid system offers genetic or pharmacological manipulation of this system as a potential strategy for the diagnostic and clinical management of mood disorders, including depression and anxiety. Although the described approach in this review is promising, no solid evidence is yet available, and along with additional experiments using animal models that mimic human depression and anxiety, clinical trials are needed to explore the role of the endocannabinoid system's elements as well as the anandamide membrane transporter, none of which have been adequately studied in depression and anxiety.

The 100 most-cited articles on bibliotherapy: a bibliometric analysis

ABSTRACT Bibliotherapy is an important part of art therapy and many publications regarding bibliotherapy have been published in the past. However, there has none about the scientometric study to systematically analyze the development and emerging research trends on bibliotherapy. Therefore, we performed a scientometric investigation to describe trends of this theme. All publications related to bibliotherapy published from 1980 to 2020 were identified and selected from Science Citation Index Expanded, Social Sciences Citation Index, and Arts & Humanities Citation Index of Web of Science Core Collection. VOSviewer was used to create collaborative network plots of countries, institutions, and authors and to perform cluster analysis of keywords. A total of 703 articles were searched, and we retrieved the 100 most cited articles published by 146 institutions from 15 countries in 57 academic journals. The United States occupied a leading position in the field of bibliotherapy and Linköping University was the most productive institution. Journal of Consulting and Clinical Psychology was the most productive journal. Andersson G, Carlbring P, and Cuijpers P may have an important influence on bibliotherapy research. The applications in depression, anxiety, panic disorder, insomnia, and aphasia are the hot themes. This scientometric review provided a comprehensive understanding of the bibliotherapy research using quantitative and qualitative methods, which can provide references for researchers in the bibliotherapy field. As investigators continue to work, we look forward to the development of bibliotherapy efficacy and the implementation form and steps.

The Use of Safflower (Carthamus tinctorius) in Treating Depression and Anxiety.

ObjectiveIn the era of evidence-based medicine, research in the area of herbal psychopharmacology has increased dramatically in recent decades. To date, however, there is no comprehensive review of safflower as an herbal antidepressant and anxiolytic with details on its psychopharmacology and applications in depression and anxiety.MethodsThis research is a review and qualitative research through an electronic survey among the Saudi population, thus assessing their knowledge about using safflower in treating depression and anxiety. The survey was distributed in Saudi Arabia in December 2021 and the results were finalized in January 2022.ResultsA total of 1074 Saudi participants were included in the study; 1002 (93.3%) participants reported knowing safflower very well while 72 (6.7%) had never heard of it. Some participants had used safflower infusions to treat anxiety and depression; 446 (44.4%) participants had never used it, but the remaining 558 (55.6%) had used it to varying degrees to treat anxiety and depression. Among the 752 participants who previously tried safflower, 279 (37.1%) reported that safflower was very effective, 389 (51.73%) reported some improvement, and 93 (12.36%) reported no improvement.ConclusionEmerging medical evidence is guiding herbal treatments. This research illustrates that more than 75% of the Saudi population are using Safflower to treat psychological stress. It elaborates that more than half of the population are already using safflower off the label to treat depression and anxiety and that they find it useful. A well-constructed clinical trial is thus critical to prove the evidence-based benefits of safflower in treating depression and anxiety. More studies on possible side effects are required to guarantee its safety. Nature has previously provided remarkable remedies, and more work will illustrate the value of safflower.

Development of depression intervention software and its effectiveness on depressive symptoms

Background and purpose: Web-based treatments are expanding rapidly. The aim of the present study was to compile a web-based treatment package and evaluate its effectiveness on the severity of depression symptoms. Methods: in the first stage, based on the themes extracted around the treatment of depression, four main themes (behavioral, cognitive, emotional and communication) and eighteen secondary themes (behavior modification and adjustment, reward, behavioral activation and promotion of health and sleep quality, problem-solving skills problem, correcting ineffective schemas, reducing rumination, correcting negative beliefs, decision-making skills, reducing self-criticism, challenging cognitive errors and mindfulness skills, strengthening internal motivation, self-compassion and emotion regulation skills, empathy skills, effective communication skills and Dare skill) to develop an intervention application in depression. This 13-session application consists of 46 educational videos and their related exercises, which have been approved by experts with an agreement coefficient of 0.89. This research is of a quantitative type and to achieve the objective of the sample research, 40 people between twenty-five and forty years of age with moderate depression were randomly divided into two experimental and control groups. Results: The research results indicate the effectiveness of the researcher's software on the severity of depression symptoms (F=44.66, P<0.001). Also, the results of the follow-up after two months indicated the stability of the effectiveness of the researcher's software on the severity of depression symptoms (F=56.82, P<0.001). Besides, the evaluation indicated that the changes were not significant according to gender (F=0.57, P=0.46). Conclusion: It can be concluded that the researcher's software was effective on the severity of depression symptoms and these results were permanent until the follow-up period

Evaluation of antidepressant activity of ondansetron in rodent models of depression

Background: At present, there is an escalating concern regarding possible role of 5-HT3 receptor in psychopharmacology and the therapeutic potential of their antagonists. Moreover, inclusion of 5-HT3 receptor antagonist may curtail the antidepressant-induced LTP decrease causing memory deficits, thereby improving efficacy of current antidepressants. Aim and Objective: This study aims to evaluate the antidepressant activity of 5-HT3 antagonist, that is, ondansetron (OND) in rodent models of depression. Materials and Methods: Male Swiss albino mice (20–30 g bw) and Wistar rats (100–200 g bw) were divided into five groups. Animals received either OND p.o. (0.1, 0.5 and 1 mg/kg), venlafaxine (10 mg/kg), or vehicle (1 ml distilled water p.o.) in control. Tail suspension and forced swim test were used to evaluate the effects of drugs and control after 60 min of their administration. Furthermore, assessment of locomotor activity (LA) was done by photoactometer after 24 h of drug administration. Results: Ondansetron exhibited significant antidepressants activity (P < 0.05) in rodent models. However, LA was not significantly altered by OND. Conclusion: Ondansetron exhibited significant antidepressant activity in rodent models hence paving the way for exploration of 5-HT3 receptor antagonist in future researches and its therapeutic application in depression.

Clinical Application of Real-Time fMRI-Based Neurofeedback for Depression.

Real-time functional magnetic resonance imaging-based neurofeedback (rt-fMRI NF) is a recent technique used to train self-regulation of circumscribed brain areas or networks. For clinical applications in depression, NF training targets brain areas with disturbed activation patterns, such as heightened reactivity of amygdala in response to negative stimuli, in order to normalize the neurophysiology and their behavioral correlates. Recent studies have targeted emotion processing areas such as the amygdala, the salience network, and top-down control areas such as the lateral prefrontal cortex. Different methods of rt-fMRI-based NF in depression, their potential for clinical improvement, and most recent advancements of this technology are discussed considering their role for future clinical applications. Initial findings of randomized controlled trials show promising results. However, for lasting treatment effects, clinical efficiency and optimal target regions, tasks, control conditions, and duration of training need to be established.

The Effects of Probiotics and Prebiotics on Mental Disorders: A Review on Depression, Anxiety, Alzheimer, and Autism Spectrum Disorders.

Probiotics and their nutrient sources (prebiotics) have been shown to have positive effects on different organs of the host. The idea of their potential benefits on Central Nervous Systems (CNS) and the incidence of Anxiety, Schizophrenia, Alzheimer, Depression, Autism, and other mental disorders has proposed a new category of medicines called "psychobiotic" which is hoped to be of low-side effect anti-inflammatory, antidepressant, and anti-anxiety constitutes. In the current review, we present valuable insights into the complicated interactions between the GI microbiota (especially in the colon), brain, immune and central nervous systems and provide a summary of the main findings of the effects of pro- and prebiotics on important mental disorders from the potential mechanisms of action to their application in clinical practice. Google Scholar, Pub Med, Scopus, and Science Direct databases were searched using following key words: "probiotics", "prebiotics", "mental disorders", "psychological disorders", "depression", "anxiety", "stress", "Alzheimer" and "autism spectrum". The full text of potentially eligible studies was retrieved and assessed in detail by the reviewers. Data were extracted and then summarized from the selected papers. The results of the provided evidence suggest that probiotic and prebiotics might improve mental function via several mechanisms. The beneficial effects of their application in Depression, Anxiety, Alzheimer and autism spectrum diseases have also been supported in clinical studies. Pro and prebiotics can improve mental health and psychological function and can be offered as new medicines for common mental disorders, however, more clinical studies are necessary to conduct regarding the clinical significance of the effects and their bioequivalence or superiority against current treatments.

计算精神病学：抑郁症研究和临床应用的新视角

计算精神病学：抑郁症研究和临床应用的新视角

Anxiolytic and antidepressant effects of ACPA and harmaline co-treatment.

Depression and anxiety disorders are among the most common illnesses and a close relationship between them has been found. Because the psychotropic effects and abuse liability of cannabis prevent its therapeutic application in depression and anxiety states, we decided to investigate the effects of the combination of ineffective doses of cannabinoid CB1 receptor agonist arachidonylcyclopropylamide (ACPA) and β-carbolines on anxiety- and depression-related behaviors in male NMRI mice. Anxiety- and depression-related behaviors were assesses using elevated plus maze (EPM) and forced swim test (FST), respectively. Intraperitoneal administration of ACPA (1 mg/kg) decreased the percentage of time spent in the open-arms (%OAT) and the number of entries to the open-arms (OAE) in the EPM, indicating an anxiogenic-like effect. ACPA also decreased immobility time in the FST compared to the control group, suggesting an antidepressant-like effect. β-carbolines including harmane (5 and 10 mg/kg), norharmane (5 mg/kg) and harmaline (2.5 and 5 mg/kg) produced an anxiogenic-like response, while the highest dose of harmane or harmaline and the middle dose of norharmane induced an antidepressant-like behavior. Furthermore, co-administration of a subthreshold dose of ACPA (0.5 mg/kg) and harmaline (1.25 mg/kg), but not harmane or norharmane (both at the dose of 2.5 mg/kg), caused anxiolytic- and antidepressant-like behaviors and decreased locomotor activity. Our findings suggest a therapeutic potential for combined ineffective doses of ACPA and harmaline on anxiety- and depression-related processes.

STUDIES ON SCHIZOPHRENIA AND DEPRESSIVE DISEASES BASED ON FUNCTIONAL NEAR-INFRARED SPECTROSCOPY

Many investigations have been carried out on functional near infrared spectroscopy (fNIRS) applications in depression and schizophrenia patients that are most mysterious and costliest mental disorders in current society. fNIRS is a new optical method which assesses brain cortex hemodynamic and nervous activities non-invasively and it has been used in medicine as a study tool. Most of the researches of this approach have assessed the homodynamic response of frontal and temporal regions by means of various cognitive tasks. In this research, first, the cognitive task execution techniques have been explained concisely, and then some findings of fNIRS-based researches about depression and schizophrenia have been summarized and assessed. In fNIRS studies that have used various devices with different number of channels, the brain cortex functionality in schizophrenia and depressive patients has been investigated. The results demonstrate that a decrease in prefrontal regions activities can be observed in schizophrenia and depressive patients. Also more detailed studies illustrate ventrolateral, prefrontal and frontopolar region disorders. In severe depressive patients, a decrease in activities of prefrontal and temporal regions has been detected. Therefore, by paying attention to the deficiencies in these regions’ functions, it is possible to treat these diseases.

Smart phone technologies and ecological momentary data: is this the way forward on depression management and research?

Depression is a complex and burdensome condition; it often leads to personal, societal and economic costs. Despite advances in treatments, its management over time remains a challenge; many treated for depression do not achieve full recovery or remain well for long. Novel ways to monitor patients are warranted, as well as better understanding of contributors to relapse or sustained wellness. Mobile health technologies (m-Health) are emerging as useful tools for real-time assessments of moods, behaviours and activities in a more convenient and less burdensome manner. Yet, there are numerous questions around privacy, reliability and accuracy of data collected via mobile apps. This review provides a critical overview of advances in m-Health and evaluate the future potential of smartphone technology in the assessment and treatment of depression. There is an abundance of apps in the market that claim to exert beneficial effects on the management of depression; to date, only a small fraction has been validated in clinical trials or has had the support of academic centers. Although promising, the use of mobile health applications in depression warrants further investigation and incorporation into mainstream research to facilitate greater adoption and validation of its clinical utility.

A sensitive and practical RP-HPLC-FLD for determination of the low neuroactive amino acid levels in body fluids and its application in depression

Ion-exchange high performance liquid chromatography (HPLC) generally fails as a method to determine low levels of free amino acids (AAs) in body fluids. Here we present a modified reversed-phase HPLC (RP-HPLC) protocol for the determination of AAs in body fluids and its application in mood disorder patients. We improved a previous research protocol by modifying i) sample preparation, including deproteination, ii) derivitization, including derivating agent and condition, and iii) sample separation, which is mainly determined by the pH value, the components and the additives of the mobile phases. The combination of these modifications, together with fluorescence detection (FLD), allows sensitive and practical determination of free AA levels in body fluids of depressive patients. This protocol was validated by determining the postmortem cerebrospinal fluid (CSF) glutamic acid (Glu) and γ-aminobutyric acid (GABA) levels of 8 major depressive disorder (MDD) patients, 9 bipolar disorder (BD) patients, and 19 well-matched controls, while also testing the plasma and CSF AA levels of living MDD patients. CSF Glu and GABA levels were both significantly decreased in MDD but not in BD patients. The data indicate that this RP-HPLC-FLD protocol is applicable for detection of low levels of neuroactive AAs in body fluids, as well as for routine clinical applications.

Pathogenetic and Therapeutic Applications of Tumor Necrosis Factor-α (TNF-α) in Major Depressive Disorder: A Systematic Review.

Major depressive disorder (MDD) is characterized by mood, vegetative, cognitive, and even psychotic symptoms and signs that can cause substantial impairments in quality of life and functioning. Up to now, the exact pathogenesis of MDD remains poorly understood. Recent research has begun to reveal that the pro-inflammatory cytokines, particularly, tumor necrosis factor-α (TNF-α), play an integral role in the pathophysiology of depressive disorders and the mechanism of antidepressant treatment. On the base of several observations: it is found that subsets of MDD patients have enhanced plasma levels TNF-α; antidepressant treatments had linked with the decline of TNF-α; central administration of TNF-α gives rise to sickness behavior which shares features with depression; and a blockade of it can ameliorate depressive symptomatology in animal models and clinical trials. In this review article, we focus on recent evidence linking TNF-α and MDD looking at data from animal and clinical studies, illustrating the pathophysiological role, susceptibility and its therapeutic application in depression. We conclude by discussing future directions for research, in particular the opportunities for the development of novel therapeutics that target TNF-α. This will be very important for designing preventative strategies and for the identification of new drug targets and preventative strategies.

A sensitive and practical RP-HPLC-FLD for determination of the low neuroactive amino acid levels in body fluids and its application in depression

Ion-exchange high performance liquid chromatography (HPLC) generally fails as a method to determine low levels of free amino acids (AAs) in body fluids. Here we present a modified reversed-phase HPLC (RP-HPLC) protocol for the determination of AAs in body fluids and its application in mood disorder patients. We improved a previous research protocol by modifying i) sample preparation, including deproteination, ii) derivitization, including derivating agent and condition, and iii) sample separation, which is mainly determined by the pH value, the components and the additives of the mobile phases. The combination of these modifications, together with fluorescence detection (FLD), allows sensitive and practical determination of free AA levels in body fluids of depressive patients. This protocol was validated by determining the postmortem cerebrospinal fluid (CSF) glutamic acid (Glu) and γ-aminobutyric acid (GABA) levels of 8 major depressive disorder (MDD) patients, 9 bipolar disorder (BD) patients, and 19 well-matched controls, while also testing the plasma and CSF AA levels of living MDD patients. CSF Glu and GABA levels were both significantly decreased in MDD but not in BD patients. The data indicate that this RP-HPLC-FLD protocol is applicable for detection of low levels of neuroactive AAs in body fluids, as well as for routine clinical applications.

Characterization and in vitro and in vivo evaluation of cross-linked chitosan films as implant for controlled release of citalopram

The aim of the present study is to develop cross-linked chitosan (CH) films that can release drug over an extended period of time and that too in a controlled manner. A solution of different percentages of CH, is prepared in 1% lactic acid, followed by addition of citalopram (CTP) and then reacted with increasing amounts of glutaraldehyde (GL) to obtain films with different cross-linking densities. Prepared films are characterized for their physical and mechanical properties. The films are then subjected to in vitro drug release studies using pH 7·4 phosphate buffer saline (PBS) as dissolution medium and cumulative amount of drug released is calculated. Kinetic analysis of drug release is performed using Power law model and Higuchi’s model. With increase in concentration of CH, water absorption capacity and mechanical strength are increased; whereas, water vapour permeability and elasticity of the films are decreased. The effect of cross-linking agent, GL, is such that with an increase in the amount of GL, water vapour permeability, water absorption capacity and elasticity of the films are decreased; whereas, mechanical strength increased to some extent and then decreased. In vitro release studies indicate that films containing 3% CH, cross-linked with 2–3% GL and films containing 4% CH, cross-linked 1% GL are able to sustain the drug release for a prolonged time along with releasing almost complete drug in a desired period. Out of these batches, films containing 3% CH, cross-linked with 2–3% GL are having sufficient strength, water vapour permeation, water absorption capacity and elongation at break for implantation purpose. The in vitro degradation studies and histopathological studies were carried out with a sample film (batch C3 as in table 1) in rabbit model. In vitro degradation study indicates that the films maintained their integrity for desired implantation. The histopathological studies under optical microscope indicates that on implanting, there is no evidence of any inflammation, any foreign body granuloma or any necrosis or hemorrhage. Tissue configuration remains unaltered after 30 days of implantation. So, it can be suggested that cross-linked CH films of above said composition can be used as implant for long term application in depression and related disorders.

A structured approach to choosing estimands and estimators in longitudinal clinical trials

An important evolution in the missing data arena has been the recognition of need for clarity in objectives. The objectives of primary focus in clinical trials can often be categorized as assessing efficacy or effectiveness. The present investigation illustrated a structured framework for choosing estimands and estimators when testing investigational drugs to treat the symptoms of chronic illnesses. Key issues were discussed and illustrated using a reanalysis of the confirmatory trials from a new drug application in depression. The primary analysis used a likelihood-based approach to assess efficacy: mean change to the planned endpoint of the trial assuming patients stayed on drug. Secondarily, effectiveness was assessed using a multiple imputation approach. The imputation model-derived solely from the placebo group-was used to impute missing values for both the drug and placebo groups. Therefore, this so-called placebo multiple imputation (a.k.a. controlled imputation) approach assumed patients had reduced benefit from the drug after discontinuing it. Results from the example data provided clear evidence of efficacy for the experimental drug and characterized its effectiveness. Data after discontinuation of study medication were not required for these analyses. Given the idiosyncratic nature of drug development, no estimand or approach is universally appropriate. However, the general practice of pairing efficacy and effectiveness estimands may often be useful in understanding the overall risks and benefits of a drug. Controlled imputation approaches, such as placebo multiple imputation, can be a flexible and transparent framework for formulating primary analyses of effectiveness estimands and sensitivity analyses for efficacy estimands.