Clinical Trials

Depression (major depressive disorder).

Displaying 61 studies

The purpose of this study is to evaluate the effectiveness of adjunctive lithium in the acute (2 weeks) and continuation phase (4 weeks) for maintenance of ketamine-associated remission.

The purpose of this study is to learn if measures of brain activity are different in children and adolescents with depression who are in different stages of treatment. This is important because it may identify a biological marker for depression that could one day be used to identify depressed children who would benefit from certain treatments (medications for example), or to monitor how well treatments are working. Brain activity measures(known as cortical excitability and inhibition) will be collected by Transcranial Magnetic Stimulation (TMS). TMS is a noninvasive (no surgery or implants) brain stimulation technology which can make parts of the ...

The purpose of this study is to ascertain the effects of the Authentic Connections intervention among nurse leaders who are mothers at Mayo Clinic Rochester in comparison to a control group. Outcomes that will be measured include: psychological distress, depression, self-compassion, parenting stress, burnout, and feasibility measures.

This is a double-blind, sham controlled, multi-center study to confirm the safety and efficacy of synchronized transcranial magnetic stimulation (sTMS) for the treatment of patients currently experiencing an episode of depression who have failed to respond to at least one (1) antidepressant medication. Patients will be randomly assigned to either active or sham therapy and will undergo daily treatments for a period of time. Following completion of blinded treatments, patients may be eligible for a course of open label treatments.

The purpose of this study is to evaluate the feasibility of developing a microbiome probe of depression and to evaluate the microbiome change in a preliminary analysis of treatment response (n=20) vs. non response (n=20) to the antidepressant citalopram. This study is a 12 week open trial that will enroll approximately 80 participants (anticipated 40 study completers with paired biomarker data) with an episode of major depression, Bipolar I or Bipolar II and 40 age- and sex-matched healthy controls.

Depression is common in patients with cancer. Current medications for depression, while effective, take several weeks to take effect. Ketamine has emerged as a drug with promise for cancer patients. In two reported cases, a single dose of ketamine induced rapid and moderately sustained symptom reduction in depression and anxiety with no adverse side effects. Benefit was seen in as little as 1 hour and sustained up to 30 days. This study is a randomized, double-blind, placebo-controlled investigation testing whether a single dose of ketamine improves depression and anxiety relative to placebo in patients with cancer.

This study is to learn how effective a night of no sleep, with or without light therapy, is for patients in an inpatient setting who are experiencing Major depression.

To evaluate the safety and efficacy of daily, active Neurostar® TMS (when compared with sham treatment) in adolescents meeting criteria for Major Depressive Disorder (MDD).

The purpose of this study is to evaluate and analyze the clinical data that is already being collected for clinical purposes to determine the long-term effects of the repeated use of subanaesthetic ketamine/esketamine for patients with depression.  We hypothesize that patients who have a greater number of infusions/treatments will be more likely to have increased side effects to the drug.  We would like to be able to also analyze data related to any other assessments that are implemented as part of the clinical practice in the future.

The primary purpose of this study is to compare outcomes of depressive symptoms (PHQ-9 and HAM-D) over 6 months following an eight-week program of SMART-D therapy + treatment as usual versus treatment as usual for patients with major depression in partial-to full-remission.

The purpose of this study is to systematically investigate the use of repetitive transcranial magnetic stimulation (rTMS) as an added treatment for patients who have depression that is not decreasing with standard care.

The purpose of this study is to measure, rank, and categorize the subject sample of depression, stress, resilience, and happiness scores using quantitive surgeys. This research aims to learn how a Three Good Things (3GT) journaling activity affects a subject's symptoms of stress, depression, reslieince, and happiness.  The data will allow the project team to gain an in-depth understanding of the impact of the use of resilience strategies from a patient's perspective. This project aims to review if there is a correlation between stress, depression, resiliency, and happiness scores to the use of Positive Psychology.

The purpose of this study is to explore the role of Cognitive Behavioral Therapy (CBT), a treatment for depression, on self-effectiveness (feeling empowered to accomplish a given task) and depression in persons with chronic pain and depression. Past research has shown that persons with chronic pain show improvement in self-efficacy and depression scores when they are using CBT. The Pain rehabilitation Center (PRC) at Mayo Clinic is adding CBT focused groups to better understand the role of CBT on self-efficacy and depression in persons with chronic pain and depression.

The primary purpose of this study is to evaluate the degree of statistical agreement between observed clinical outcomes (non-response/remission) after 8 weeks of treatment and the outcomes predicted by an Augmented Human Intelligence (AHI)-based clinical decision support tool after 2 weeks of follow up.

In this project the investigators will develop and pilot test a supervised, vigorous intensity exercise intervention for depressed female smokers. If the pilot intervention is successful, the investigators will have a blueprint for a large randomized controlled trial. The long term objective is to develop interventions for depressed women that will ultimately reduce their risk of tobacco-caused disease and mortality.

The purpose of this study is to assess the feasibility and acceptability of passive data collection with a smartphone in depressed patients and investigate how passive data gathered via technology platforms can generate transdiagnostic digital phenotypes that potentially inform the assessment and/or treatment outcome of major mood disorders. This study aims to assess self-reported, behavioral, cognitive, and physiological data gathered from smartphones and smart watches as compared to gold standard clinical measured in treatment seeking depressed patients.

The purpose of this study is to gather information regarding the use of rTMS as a treatment for depression in adolescents with Major Depressive Disorder. The investigators also hope to learn if measures of brain activity (cortical excitability and inhibition) collected with transcranial magnetic stimulation (TMS) can be used to identify which patients will benefit from certain types of rTMS treatment. 

This research proposal aims to better understand the neurobiology of depression in adolescents and how repetitive transcranial magnetic stimulation (rTMS) may therapeutically impact brain function and mood. This investigation also proposes the first study to examine the efficacy of rTMS maintenance therapy in adolescents who have met clinical criteria following acute rTMS treatment. The magnetic resonance (MR) spectroscopy pattern of rTMS response will be analyzed according to previously established protocols.

The overall goal of this investigator-initiated trial is to evaluate the impact of platform algorithm products designed to rapidly identify pharmacokinetic (PK) and/or pharmacodynamic (PD) genomic variation on treatment outcome of depression in adolescents. This new technology may have the potential to optimize treatment selection by improving response, minimizing unfavorable adverse events / side effects and increasing treatment adherence

The purpose of this research study is to find out if the medication known as ketamine can help the symptoms of depression. This drug is approved by the Food and Drug Administration (FDA) but the investigators will use it for a non-FDA approved reason (depression).

The purpose of this study is to explore whether Medibio’s system can provide objective measures of response to standard medication treatment for unipolar depression and bipolar depression, and to see if the system can tell these two conditions apart.

Medibio’s system uses software to analyse a person’s heart rate, activity, and posture to provide objective measures of a person’s autonomic nervous system, sleep, and other daily patterns.

This research study aims to test the safety and effectiveness of repetitive transcranial magnetic stimulation (rTMS) on teens with depression. The study also seeks to understand how rTMS treatment affects the neurobiology of teens with depression.

The purpose of this study is to learn if measures of brain chemicals from a brain scan called Magnetic Resonance Imaging and Spectroscopy (MRI/MRS) and brain activity (known as cortical excitability and inhibition) collected by Transcranial Magnetic Stimulation (TMS) are different in adolescents with depression who are in different stages of treatment. Researchers are conducting this study to learn more about how the brain works in adolescents with depression and without depression (healthy controls). This is important because it may identify a biological marker (a measure of how bad an illness is) for depression that could one day be used ...

The proposed study seeks to obtain preliminary signal of the tolerability and efficacy of transcranial direct current stimulation (tDCS) for depressive symptoms in a sample of adolescents with depression and epilepsy. Additionally, effects of tDCS will be assessed via electroencephalographic, cognitive, and psychosocial measures.

The purpose of this study is to contribute to our understanding of the relationships between social media use in adolescents and psychological development, psychiatric comorbidity, and physiological markers of stress. 

The overall goal of this investigator-initiated trial is to evaluate the treatment outcome of depression utilizing platform algorithm products that can allow rapid identification of pharmacokinetic (PK) and/or pharmacodynamic (PD) genomic variation. This new technology may have the potential to optimize treatment selection by improving response, minimizing unfavorable adverse events / side effects and increasing treatment adherence.

Quetiapine, a second generation antipsychotic, is only available as oral tablets. However, topical and rectal formulations have been produced in compounding pharmacies. There is no data available suggesting that topical or rectal formulations provide serum levels similar to oral medication. In the clinical setting, when oral administration of quetiapine is not possible (for example, when a patient is extremely ill physically or mentally or both), clinicians and pharmacists have collaborated in such cases and have at times had to administer quetiapine compounded in other dosage formulations such as rectal or topical formulations. Despite clinical effectiveness of these "other" formulations, there ...

The purposes of this study are to summarize clinician evaluations of the NNDC battery in the single clinic where the adult battery is currently being administered to adolescents, to determine patient and clinician level of interest in using the NNDC battery in clinics where the adult battery is not currently being administered to adolescent patients (n=14), to measure change in evaluation 3 months post-implementation for any sites that begin administering the NNDC battery to adolescents, and to generate potential new Child and Adolescent Mood Disorders Interest Group (CAMDIG) research protocols for future consideration.

Transcranial Magnetic Stimulation (TMS) is an increasingly accepted neurostimulation- based treatment for major depressive disorder. While there is a growing anecdotal database supporting its use in bipolar depression the investigators propose to collect open label efficacy and safety data in a small population of patients with clinically verified bipolar disorder.

The purpose of this study is to assess the effectiveness and safety of MYDAYIS® as an augmentation agent for bipolar depression.

The purpose of this study is to determine the baseline chronotype patterns (with Morningness-Eveningness Questionnaire (MEQ) ) among inpatients with Major depressive disorder and then compare the chronotype distribution with the control group.

The purpose of this study is to validate measures of depression, anxiety, traumatic stress, and factors related to these outcomes in medical patients, to develop a model for identifying persons with myocarditis who are at risk for depressive and anxiety disorders (clinically significant depressive and anxious symptoms), and for examining the effects of anxiety and depression on quality of life and health outcomes in respondents with myocarditis and caregivers.

The FLAME Study is a 16-week clinical trial to study treatment with lamotrigine or fluoxetine in bipolar I, II and bipolar schizoaffective depressed adults. The purpose of the trial is to have a better understanding of whether individuals with a particular gene type and other inherited biological markers will have a good response to fluoxetine or lamotrigine, or alternatively, would be more likely to have side effects to this medication.

The purpose of this study is to analyze the prevalence of mood disorders in newly-diagnosed breast cancer patients with use of specific questionnaires, aimed to diagnose clinically significant depression and anxiety, at a rural community hospital.

This feasibility study aims to better understand the neurobiology of major depression and how ketamine may therapeutically impact brain function. This research may provide important insights into the mechanism of ketamine response, thus, potentially increasing the likelihood of successful treatment interventions and decrease the number of ineffective treatments and/or risk for serious side effects.

This study aims to assess the level of anxiety and depression in children with epilepsy and compare to the level of anxiety and depression perceived by family by using validated, standardized measures as both comorbid conditions can significantly impact both quality of life and disease course.

People with COPD have a greater risk for symptoms of depression, anxiety, and fear of breathlessness. Those emotions are independently associated with lower physical activity, poorer quality of life, and higher hospitalization and exacerbations; all independent predictors of survival and costs. There is a lack of treatment options to be routinely used in primary clinics for patients with COPD. Systematic reviews suggest that interventions that promote an accepting mode of response, such as mindfulness, might be more appropriate and effective for managing psychological distress in COPD patients, especially breathing-related anxiety. Hypothesis: A home-based 8-week Mindfulness-Based Stress Reduction (MBSR) for COPD ...

The purpose of this study is to examine the effects of a health coaching intervention on the stress and burden of caregivers of patients awaiting heart or lung transplant.

Hypotheses:  Caregivers will have traits and behaviors pre-transplant that will predict caregiver readiness, quality of life, and transplant recipient outcomes. Specifically, thoracic pre-transplant caregivers report stress, symptoms of anxiety or depression, and perceive high caregiver burden. These factors may be amenable to pre-transplant intervention to improve overall patient and caregiver outcomes.

Aims, purpose, or objectives:  We will conduct a pilot trial to test whether caregivers of heart and lung transplant candidates ...

In an effort to understand the effects of evidence-based interventions on children and adolescents, the aims of this study are to 1) evaluate the feasibility of utilizing wearable devices to track health information (i.e., sleep, physical activity); 2) evaluate the effectiveness of evidence-based intervention components on emotional and interpersonal functioning, family engagement, and sleep and physical activity level outcomes.

The purpose of this study is to implement a facilitated peer support group for women that have experienced an unexpected birth process in the last 12 months. 

The goal of this proposed study is to examine the genetic signature of the validated proteomic signature (model) based on a panel of serum proteomic markers that discriminates different mood disorders.

The purpose of this research study is to compare the antidepressant effect of lithium versus placebo in adults receiving ketamine. Lithium is available commercially for depression; ketamine is available commercially and can help the symptoms of depression; however, it has not been approved by the U.S. Food and Drug Administration (FDA) for this use. The FDA has allowed the use of this drug in this research study.

Data collected from the MEVOKED Study #1 (IRB#14-009159) showed wide variability in how participants engaged with and used the MEVOKED program. This study will obtain additional information on participants – in particular PHQ9 depression scores and medication use during their enrollment in the MEVOKED program will provide additional data to support the analysis of the MEVOKED Study #1 (IRB#14-009159).  

The proposed study will examine sequential bilateral accelerated theta burst stimulation (aTBS). Three sessions are administered daily for 10 days (5 days per week). During each session continuous theta burst stimulation (cTBS) in which 1800 pulses are delivered continuously over 120 seconds to the right dorsolateral prefrontal cortex (RDPFC) is administered first, followed by iTBS in which 1800 pulses are delivered in 2 second bursts, repeated every 10 seconds for 570 seconds (1800 pulses) to the left dorsolateral prefrontal cortex (LDPFC). The theta burst stimulation (TBS) parameters were adopted from prior work, with 3-pulse 50 Hz bursts given ...

The purpose of this study is to study brain chemistry in depressed patients compared to healthy patients who are not depressed.

The purpose of this study is to:

  • Increase screening of adolescents for symptoms of depression in primary care La Crosse, WI clinics using the PHQ9M screening tool.Screening to occur at all well child visits and all subsequent visits for adolescents with Depression on their problem list.Clinics to include Pediatrics, Family Medicine, Family Health, Center for Womens Health.
  • Develop a clear care pathway for adolescents identified with clinically meaningful symptoms of depression through increased screening, referral and treatment options.  Pathway may include psychoeducational materials (multimedia options), intake paperwork and process for Department of Behavioral Health locally, and ...

This study will compare glutamate and other neurometabolites measured by proton magnetic resonance spectroscopy (1H-MRS) in bipolar I and II patients currently depressed with age-matched healthy controls. The study will also compare 1H-MRS of bipolar I and II patients before and after taking a 12-week course of lamotrigine. This study requires 8 visits over a 12 week period. These visits need to occur at Mayo Clinic in Rochester, MN.

The overall goal is to better understand the underlying pathophysiology of mood disorders and bipolar disorders in particular. We aim to investigate whether the subclinical atherosclerotic and inflammatory markers differ between patients with bipolar disorder, major depressive disorder, and psychiatric non-mood disorders and healthy subjects.

The purpose of this study is to identify pre-operative emotional factors that may affect surgical outcomes and how a multidisciplinary approach may improve success after urologic surgery for voiding dysfunction. 

The purpose of this study is to promote patient-centered care by efficiently determining the presence of quality of life issues and their relation to depression and psoriatic arthritis in psoriasis patients. Screening for quality of life, depression, and psoriatic arthritis is a standard of care for psoriasis patients.   

The investigators are doing this research study to find out if the Stress Management and Resiliency Training (SMART) therapy will help subjects with their major depression treatment.

The purpose of this study is to evaluate the impact of interventions on important CV biomarkers to provide valuable information on the mechanism linking depression and anxiety to cardiac prognosis resulting in improved quality of life and diagnosis.

Study hypothesis: Do serial low-dose ketamine infusions, followed by weekly maintenance infusions, increase the length of time depressive symptoms stay in remission and the length of time associated suicide risk is improved? Brief Summary: This open label clinical trial is intended to further clarify initial response to low-dose ketamine infusion with repeated dosing and maintenance treatment model. Primary outcomes will be reduction in depression severity and reduction of suicide risk along with duration of response.

The purpose of this research is to gather information from the child and parent with regards to the use of electronic treatment tools to treat those with a mental health illness.

The purpose of this study is to remotely use the Ellipsis Health (EH) voice analysis technology to record the speech patterns and content of individuals with a recent diagnosis of Coronavirus-19 (COVID-19) presenting to the post-COVID-19 clinic at Mayo Clinic, to validate its use as a tool to screen for major depressive disorder (MDD) and generalized anxiety disorder (GAD) against gold-standard questionnaires used in clinical practice namely the PHQ-9 and GAD-7

Primary Aim

            We aim to evaluate: 1) the correlation between patient-reported rectal bleeding and stool frequency and health-related quality of life focused on fatigue, depression and anxiety, and work productivity; and 2) the correlation between the severity of endoscopic inflammation and health-related quality of life focused on fatigue, depression and anxiety, and work productivity.

Secondary Aims

We also aim to evaluate the correlation between the combination of clinical/PRO and the severity of endoscopic inflammation and health-related quality of life focused on fatigue, depression and anxiety, and work productivity.

The purpose of this study is to evaluate the long-term impact of treatment with sertraline on aspects of cognitive, emotional and physical development and maturation at puberty, in pediatric subjects ages 6 to 16 years (inclusive) with a diagnosis of anxiety disorder, depressive disorder or obsessive compulsive disorder.

The purpose of this study is to see if there is a connection between bad experiences in the patient's childhood, either by the patient or the parent, and poor blood sugar control, obesity, poor blood lipid levels, and depression in patients with type 1 diabetes.

Physical activity plays an important role in reducing the adverse effects of cancer treatment. There are few studies using prehabilitation to improve peri-operative outcomes in patients undergoing cancer surgery. This study will pilot a program of structured activity for women undergoing neoadjuvant chemotherapy with the intent to improve their physical state prior to surgical intervention and thus improve outcomes.

It has been shown that patients with advanced ovarian cancer may suffer from high levels of cancer –specific distress, depression and anxiety. It has also been proposed that psychological resilience can favorably affect psychological and treatment-related outcomes in cancer ...

The purpose of this study is to measure the frequency and severity of posttraumatic stress symptoms, depressive symptoms, anxiety symptoms, and cognitive impairment following dismissal from the ICU and three months later. This study also seeks to identify which of the multiple ICUs at Mayo Clinic yields the highest incidence of post-intensive care syndrome so that a future study designed to provide a therapeutic intervention can be implemented in those areas with the greatest potential.

The purpose of this study is to compare the effectiveness of combination therapy with antidepressants (AD), fear avoidance rehabilitation (EFAR) AD+EFAR vs. each treatment alone to improve pain, self-reported function, depression, and anxiety in patients with chronic low back pain and high negative affect.

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Major Depression

Definitions.

Major depression is one of the most common mental disorders in the United States. For some individuals, major depression can result in severe impairments that interfere with or limit one’s ability to carry out major life activities.

Additional information can be found on the NIMH Health Topics page on Depression .

The past year prevalence data presented here for major depressive episode are from the 2021 National Survey on Drug Use and Health  (NSDUH). The NSDUH study definition of major depressive episode is based mainly on the 5th edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5):

  • A period of at least two weeks when a person experienced a depressed mood or loss of interest or pleasure in daily activities, and had a majority of specified symptoms, such as problems with sleep, eating, energy, concentration, or self-worth.
  • No exclusions were made for major depressive episode symptoms caused by medical illness, substance use disorders, or medication.

Prevalence of Major Depressive Episode Among Adults

  • An estimated 21.0 million adults in the United States had at least one major depressive episode. This number represented 8.3% of all U.S. adults.
  • The prevalence of major depressive episode was higher among adult females (10.3%) compared to males (6.2%).
  • The prevalence of adults with a major depressive episode was highest among individuals aged 18-25 (18.6%).
  • The prevalence of major depressive episode was highest among those who report having multiple (two or more) races (13.9%).

*Persons of Hispanic origin may be of any race; all other racial/ethnic groups are non-Hispanic |  AI/AN = American Indian / Alaskan Native | NH/OPI = Native Hawaiian / Other Pacific Islander.

Major Depressive Episode with Impairment Among Adults

  • In 2021, an estimated 14.5 million U.S. adults aged 18 or older had at least one major depressive episode with severe impairment in the past year. This number represented 5.7% of all U.S. adults.

Treatment of Major Depressive Episode Among Adults

  • In 2021, an estimated 61.0% U.S. adults aged 18 or older with major depressive episode received treatment in the past year.
  • Among those individuals with major depressive episode with severe impairment, an estimated 74.8% received treatment in the past year.

Prevalence of Major Depressive Episode Among Adolescents

  • An estimated 5.0 million adolescents aged 12 to 17 in the United States had at least one major depressive episode. This number represented 20.1% of the U.S. population aged 12 to 17.
  • The prevalence of major depressive episode was higher among adolescent females (29.2%) compared to males (11.5%).
  • The prevalence of major depressive episode was highest among adolescents reporting two or more races (27.2%).

*Persons of Hispanic origin may be of any race; all other racial/ethnic groups are non-Hispanic. Note: Estimates for Native Hawaiian / Other Pacific Islander and American Indian / Alaskan Native groups are not reported in the above figure due to low precision of data collection in 2021.

Major Depressive Episode with Impairment Among Adolescents

  • In 2021, an estimated 3.7 million adolescents aged 12 to 17 in the United States had at least one major depressive episode with severe impairment in the past year. This number represented 14.7% of the U.S. population aged 12 to 17.

Treatment of Major Depressive Episode Among Adolescents

  • In 2021, an estimated 40.6% of U.S. adolescents with major depressive episode received treatment in the past year.
  • Among adolescents with major depressive episode with severe impairment, an estimated 44.2% received treatment in the past year.

Data Sources

Substance Abuse and Mental Health Services Administration. (2022). Key substance use and mental health indicators in the United States: Results from the 2021 National Survey on Drug Use and Health (HHS Publication No. PEP22-07-01-005, NSDUH Series H-57). Rockville, MD: Center for Behavioral Health Statistics and Quality, Substance Abuse and Mental Health Services Administration. Retrieved from https://www.samhsa.gov/data/report/2021-nsduh-annual-national-report  .

Statistical Methods and Measurement Caveats

Please see the 2021 National Survey on Drug Use and Health Methodological Summary and Definitions report  and the 2021 NSDUH Frequently Asked Questions page  for information on how these data were collected and calculated. A few specific caveats are noted below.

Diagnostic Assessment:

  • For the NSDUH survey — no exclusions were made for major depressive episode symptoms caused by medical illness, substance use disorders, or medication.
  • For the NSDUH survey, methodology developed prior to the 2013 publication of the current DSM-5 was used to facilitate year-to-year comparisons.
  • The adult and adolescent questions were adapted from the depression module in the National Comorbidity Survey Replication (NCS-R). Revisions to the questions in the modules were made primarily to reduce their length and to modify the NCS-R questions, which are interviewer-administered, to the audio computer-assisted self-interviewing (ACASI) format used in NSDUH. In addition, some revisions, based on cognitive testing, were made to improve comprehension. Furthermore, even though titles similar to those used in the NCS-R were used for the NSDUH modules, the results of these items may not be directly comparable. This is mainly due to differing modes of administration in each survey (ACASI in NSDUH vs. computer-assisted personal interviewing in NCS-R), revisions to wording necessary to maintain the logical processes of the ACASI environment, and possible context effects resulting from deleting questions not explicitly pertinent to major depression.
  • Some questions in the adult depression module differ slightly from questions in the adolescent depression module; as such, major depressive episode data for adults aged 18 or older should not be compared to or combined with major depressive episode data for youths aged 12 to 17.
  • The Sheehan Disability Scale (SDS) was used to assess the impact of major depressive episode on a person’s life. The SDS is a brief self-report tool with ratings from 0 to 10 (with 10 being the highest) for the level of impairment caused by the disorder in each of four role domains: home management, work, close relationships with others, and social life. A rating of ≥7 in at least one domain is considered to be severe impairment. Respondents were excluded if SDS role impairment severity was unknown, or if particular activities listed in the SDS were not applicable. For SDS level of impairment, the role domains for adolescents aged 12 to 17 were slightly modified from those for adults to be made age appropriate.

Population:

  • The entirety of NSDUH respondents for the major depressive episode estimates is the civilian, non-institutionalized population aged 12-17 (adolescents) and 18 years old or older (adults) residing within the United States.
  • The survey covers residents of households (persons living in houses/townhouses, apartments, condominiums; civilians living in housing on military bases, etc.) and persons in non-institutional group quarters (e.g., shelters, rooming/boarding houses, college dormitories, migratory workers' camps, and halfway houses).
  • The survey does not cover persons who, for the entire year, had no fixed address (e.g., homeless and/or transient persons not in shelters); were on active military duty; or who resided in institutional group quarters (e.g., correctional facilities, nursing homes, mental institutions, long-term hospitals).
  • Data regarding sex of the respondent was assessed using male and female categories only. Gender identity information was not collected in the survey.

Interview Response and Completion:

  • In 2021, 54.1% of the selected NSDUH sample (participants ages 12+) did not complete the interview.
  • Reasons for non-response to interviewing include: refusal to participate (27.6%); respondent unavailable or no one at home (23.6%); and other reasons such as physical/mental incompetence or language barriers (2.9%).
  • Adults and adolescents with major depressive episode may disproportionately fall into these non-response categories. While NSDUH weighting includes non-response adjustments to reduce bias, these adjustments may not fully account for differential non-response by mental illness status.

Data Suppression:

  • For some groups, data are not reported due to low precision. Data may be suppressed in the above charts if the data do not meet acceptable ranges for prevalence estimates, standard error estimates, and sample size.

Background on the 2021 NSDUH and the COVID-19 Pandemic:

  • The 2021 NSDUH used multimode (both in-person and virtual) data collection procedures that were first implemented in the fourth quarter of the 2020 NSDUH.
  • Overall, 54.6% of interviews were completed via the web, and 45.4% were completed in person.
  • 2021 NSDUH estimates are not comparable with estimates from prior years given the use of multimode data collection procedures throughout the entire year and the rate of non-response, per SAMHSA methodological investigations  .
  • The demographics (e.g., gender, race, education) of people responding to web interviews differed from people answering in-person.
  • In-person respondents were also more likely to report use of certain substances and were more likely to report experiencing mental health issues.

Last Updated: July 2023

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Psychiatry Online

  • February 01, 2024 | VOL. 181, NO. 2 CURRENT ISSUE pp.83-170
  • January 01, 2024 | VOL. 181, NO. 1 pp.1-82

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Insights and Advances Into Treatments for Major Depression

  • Ned H. Kalin , M.D.

Search for more papers by this author

This issue of the Journal is broadly focused on mood disorders, with an emphasis on understanding how treatments for major depressive disorder may work and how the efficacy of current neuromodulation and antidepressant medication treatment strategies can be enhanced. The issue begins with an overview by Drs. Manish Jha and Sanjay Matthew on treatment-resistant depression ( 1 ); they focus on augmentation strategies with atypical antipsychotic medications as well as other new treatment strategies. This issue also includes 1) a study that starts to provide a genetic framework for understanding heterogeneity in bipolar disorder as characterized by the number of depressive and manic episodes an individual experiences; 2) the long-term relation, and interaction, between different degrees of alcohol use and depression; 3) a study that characterizes functional brain connectivity changes associated with treatment outcomes for cognitive behavioral therapy versus antidepressant medication; and 4) two studies aimed at optimizing treatment outcomes for depressed patients: one addressing the utility of using functionally defined dorsolateral prefrontal cortex coordinates for transcranial magnetic stimulation treatment, the other presenting clinical trial data assessing the efficacy of cariprazine as an adjunctive treatment to enhance antidepressant responses in patients with major depression.

Bipolar Illness Life Course Heterogeneity in Relation to Polygenic Risk Scores

At the individual level, there is marked heterogeneity in the life course of bipolar illness, as it is characterized by varying admixtures of depressive, manic, and mixed episodes. Hasseris et al. ( 2 ) use polygenic risk scores (PRS) for bipolar disorder, major depression, and schizophrenia to help understand the factors underlying this heterogeneity. For this analysis the investigators used data from a sample of 2,705 genotyped individuals drawn from the Integrative Psychiatric Research Case Cohort (iPSYCH2015) who were diagnosed with bipolar disorder at a hospital in Denmark. Individuals were included in the study if they had their first documented episode between 10 and 35 years of age, and the median age of follow-up was 5 years after initial diagnosis. As has been reported in other studies, PRS for bipolar disorder, major depression, and schizophrenia were significantly intercorrelated with each other. The authors also found that the bipolar and schizophrenia PRS were significantly correlated with an individual’s number of affective episodes regardless of polarity. In relation to manic episodes, both bipolar and schizophrenia PRS were related to the number of episodes, whereas the depression PRS were associated with depressive and mixed episodes and negatively associated with manic episodes. The researchers also examined PRS in relation to psychotic symptoms and in these analyses found that the bipolar PRS were associated with both psychotic and nonpsychotic manic episodes, the schizophrenia PRS were only associated with psychotic manic episodes, and the major depression PRS were associated with a reduced likelihood of psychotic symptoms regardless of episode polarity. These findings are interesting because they begin to help explain the genetic differences that are related to the likelihood of experiencing depression, mania, and mixed episodes in the context of a life course of bipolar disorder. In an editorial ( 3 ), Dr. John Kelsoe from the University of California San Diego discusses the genetic findings from this paper in relation to other clinical and treatment outcome data that are associated with bipolar disorder heterogeneity. He also provides a valuable discussion on the use of PRS in psychiatry and their potential limitations.

The Longitudinal Relationship Between Alcohol Use and Depressive Symptoms

Visontay et al. ( 4 ) use a large longitudinal database along with a statistical approach that allows for making assumptions related to causality to understand the association between different amounts of alcohol consumption and depressive symptoms. Data drawn from the National Longitudinal Survey of Youth 1979 came from 5,667 participants beginning at ages 29–37. Longitudinal data up until age 41–49 were available from 3,593 of the participants. At different time points, participants’ alcohol use was assessed and characterized as abstinent (no drinking), occasional consumption (less than 1 day/week; no heavy episodic drinking), moderate consumption (greater than or equal to 1 day/week with no more than seven drinks/week for women and no more than 14 drinks/week for men; no heavy episodic drinking), and consumption above guidelines (greater than or equal to 1 day/week and more than seven drinks/week for women and 14 drinks/week or more for men; and/or heavy episodic drinking). Depression symptoms were derived from the Centre for Epidemiological Studies-Depression Scale short form. Using analytic methods that incorporate marginal structural models, significant protective effects were observed for the consistent occasional and consistent moderate alcohol drinkers such that, compared with abstainers, they were likely to have lower depression scores at 50 years of age. In contrast, when compared with abstainers the consistent above-guideline drinkers were found to have nonsignificantly higher depression symptoms. Similar findings were observed when categorical analyses were performed in relation to the likelihood of individuals having syndromal depression. The authors point out that these findings are consistent with previous reports and with the statistical method used they assert that the results may provide support for a statistically based causal relation between different amounts of alcohol use and depression. Dr. Edward Nunes from Columbia University contributes an editorial ( 5 ) that further discusses the intertwined relation between depression and alcohol use and more specifically addresses the clinical relevance of the findings from this paper.

Functional Brain Changes Associated With the Successful Treatment of Depression With CBT or Antidepressants

Both antidepressants and cognitive behavioral therapy (CBT) are effective treatments for major depression and evidence supports that they are most effective when combined. While the specific mechanisms underlying the efficacy of these treatments are not understood, they are hypothesized to, in part, be due to the modification of different neural pathways. In this regard, Dunlop and colleagues ( 6 ) use resting-state functional MRI to assess brain changes associated with remission from major depression. A primary goal of the study was to compare changes in brain activity between psychotherapeutic and psychopharmacologic interventions. The study used resting-state functional connectivity (RSFC) data from 131 individuals collected at the beginning and end of a randomized clinical trial in which treatment-naive depressed patients received either 16 weeks of CBT, duloxetine 30–60 mg/day, or escitalopram 10–20 mg/day. Seed-based analyses were performed to assess RSFC using a posterior cingulate cortex seed for the default mode network, dorsolateral prefrontal cortex seed for the executive control network, anterior insular cortex seed for the salience network, and subgenual cingulate cortex seed for the affective network. Data from the two antidepressant medication treatment groups were combined in the analysis. First, shared brain changes in remitters were assessed across all treatment groups (N=64 of 131), and next data from antidepressant remitters (N=45 of 91) were compared with data from CBT remitters (N=19 of 40). Across both treatments, remitters (Hamilton Depression Score [HAM-D] ≤ 7), and nonresponders (≥50% reduction HAM-D) demonstrated significantly decreased RSFC between the subgenual anterior cingulate and motor cortices. Numerous differential changes in RSFC were detected when comparing CBT with antidepressant medication remitters involving connectivity patterns of the executive control network, the affective network, and the salience network. For example, when using the dorsolateral prefrontal cortex as a seed, its connectivity with the left inferior parietal lobule increased in CBT remitters and decreased in antidepressant remitters. Likewise, when using the subgenual cingulate cortex seed, increased connectivity with the posterior insula was observed in the CBT responders, whereas decreased connectivity occurred in the antidepressant responders. In the discussion section, the authors emphasize the finding that CBT remitters, and not antidepressant remitters, showed increased connectivity between the executive control network and attention-related regions. In an editorial ( 7 ), Dr. Stephen Strakowski from Indiana University discusses the difficulties in replicating findings in studies of this nature and cautions the reader to consider the findings as preliminary. He also highlights the potential importance and veracity of the findings defining the functional brain changes that are associated with successful CBT treatment.

Assessing the Utility of Functional Connectivity Measures in Directing rTMS Targeting for Treating Depression

The subgenual anterior cingulate cortex (sgACC) serves as an integrative hub between regulatory prefrontal cortical regions and emotion-related limbic structures, such as the amygdala, and altered sgACC function has often been associated with depression. Furthermore, this region has also been used as a deep brain stimulation target for the treatment of refractory depression. In relation to repetitive transcranial magnetic stimulation (rTMS), a number of studies, yielding somewhat mixed results, have assessed the value of using negative functional connectivity measures between the left dorsolateral prefrontal cortex (dlPFC) stimulation site and sgACC as a means to improve rTMS targeting. Elbau et al. ( 8 ) present data from a large sample, 295 participants, with the goal of further understanding the extent to which individualized functional connectivity measures between the left dlPFC stimulation site and sgACC predict treatment outcomes. The resting functional MRI data used for the analyses came from a sample of individuals with treatment-resistant depression that previously participated in a noninferiority clinical trial designed to compare 10Hz rTMS to theta burst TMS ( 9 ). It is important to note that the same neuroanatomical coordinates for the left dlPFC TMS stimulation site were used across all the subjects, and this was based on neuroanatomical coordinates from an earlier study that linked functional connectivity measures to optimal outcomes. In other treatment studies, individualized dlPFC stimulation sites are selected based on the dlPFC region that is most negatively functionally coupled to sgACC ( 10 ). The current study is distinguished by its large sample, and the thorough analytic approach that was used, which included electric field modeling to estimate the actual subregions of dlPFC in which electrical changes were induced. The authors found that pretreatment individual differences in negative functional coupling between the dlPFC stimulation site and sgACC accounted for 3% of the variance in treatment outcomes. While this is a considerably smaller effect than previously reported, it is important to consider that the method used here did not prospectively select the dlPFC site that was most functionally connected with sgACC. It is interesting that the strongest effects for the predictive value of the functional coupling between the stimulation site and sgACC were found to be in a subgroup of patients that had a distinct breathing pattern characterized as “burst breathing.” Burst breathing, which is associated with a pattern of BOLD signal fluctuations across the brain, also has distinct impacts on resting connectivity that differ from individuals that typically engage in other forms of breathing such as deep breathing ( 11 ). In their editorial ( 12 ), Dr. Noah Phillips from Brown University and Dr. Shan Siddiqi from Harvard Medical School discuss this finding in relation to earlier work and comment on important methodological issues as they relate to the small but significant predictive effect that was observed.

A Double-Blind Randomized Clinical Trial Assessing the Efficacy of Cariprazine as an Adjunctive Treatment for Major Depression

Sachs and colleagues ( 13 ) report data from a Phase III study that is aimed at assessing the extent to which cariprazine is an effective add-on treatment for individuals with major depression that have not responded to their current treatment. This study builds on earlier studies with cariprazine and on studies demonstrating the efficacy of other atypical antipsychotic medications as adjunctive treatments for major depressive disorder, some of which have received FDA approval (i.e., aripiprazole, quetiapine, and brexpiprazole). Cariprazine was also recently approved by the FDA as an adjunctive treatment for major depression and is also approved for treating schizophrenia and bipolar disorder (mania, depression, and mixed). Cariprazine has multiple neurochemical effects, including acting as a partial agonist at the D 3 , D 2 , and 5-HT1 A receptors with highest selectivity for D 3 . It also acts as a 5-HT 2B and 5-HT 2A partial antagonist. In this 6-week, double-blind study, patients with major depression remained on their antidepressant treatment and also received either placebo, cariprazine 1.5 mg/day, or cariprazine 1.5 mg for 2 weeks and then increased to 3 mg/day. A total of 751 patients were included in the modified intention-to-treat analysis. In relation to the primary outcome measure, change in Montgomery-Asberg Depression Rating Scale (MADRS), cariprazine 1.5mg/d resulted in significantly greater decreases when compared with placebo; however the effects of the 3.0 mg/day dose were not statistically significant. The effect of the 1.5 mg/day dose was found to be significant after 2 weeks of drug administration. Change in the Clinical Global Inventory scale was used as the secondary outcome measure and while both doses of cariprazine were associated with greater reductions than placebo, neither reached statistical significance. Regarding response and remission rates, the 1.5-mg dose of cariprazine demonstrated significantly greater response rates compared with placebo (≥50% MADRS reduction: cariprazine=44.0%, placebo=34.9%) whereas no significant differences were found for remission rates (MADRS≤10: 25.2% versus 23.3%, respectively. Among the side effects, the cariprazine-treated patients experienced more akathisia (3mg group– 7.9%, 1.5mg group −5.2% compared to placebo group-0.8%). In an editorial ( 14 ), Dr. Michael Thase from the University of Pennsylvania discusses the specific findings related to cariprazine as well as the overall utility of second-generation antipsychotics in treating depression.

Conclusions

Major depression is very common with profound deleterious consequences at individual and societal levels in terms of suffering, disability, increased medical morbidity and mortality, and suicide. We clearly need better treatments for major depression as our current treatments are ineffective or intolerable for numerous individuals. This issue of the Journal brings together papers that are focused on how we can better understand mood disorders and improve the efficacy of our treatments. From these papers we learn: 1) by using polygenic risks scores we can begin to understand the heterogeneity in the course of bipolar disorder; 2) that moderate alcohol intake may be associated with a decreased risk of depression whereas the opposite may be the case with excessive alcohol use; 3) that remission in depressed patients treated with CBT or antidepressants is associated with shared and distinct patterns of treatment-associated change in functional connectivity between specific brain networks; 4) the value of using functional connectivity measures between the dlPFC and sgACC to predict and enhance rTMS treatment outcomes; and 5) the potential efficacy of adjunctive cariprazine treatment, in addition to other atypical antipsychotic medications, for patients not responding to their antidepressant treatment.

The papers in this issue of the Journal are helping to move us in the direction of improving our interventions for depression by building on and attempting to optimize existing treatment strategies. Continued neuroscientific investigations linked with clinical translational efforts are imperative to deepen our understanding of the mechanisms underlying mood disorders with the hope of developing more effective treatments that are directly aimed at these mechanisms.

Disclosures of Editors’ financial relationships appear in the April 2022 issue of the Journal .

1. Jha MK, Mathew SJ : Pharmacotherapies for treatment-resistant depression: how antipsychotics fit in the rapidly evolving therapeutic landscape . Am J Psychiatry 2023 ; 180:190–199 Abstract ,  Google Scholar

2. Hasseris S, Albiñana C, Vilhjalmsson BJ, et al. : Polygenic risk and episode polarity among individuals with bipolar disorder . Am J Psychiatry 2023 ; 180:200–208 Abstract ,  Google Scholar

3. Kelsoe JR : Polygenic polarity in bipolar disorder . Am J Psychiatry 2023 ; 180:177–178 Google Scholar

4. Visontay R, Mewton L, Slade T, et al. : Moderate alcohol consumption and depression: a marginal structural model approach promoting causal inference . Am J Psychiatry 2023 ; 180:209–217 Abstract ,  Google Scholar

5. Nunes EV : Alcohol and the etiology of depression . Am J Psychiatry 2023 ; 180:179–181 Abstract ,  Google Scholar

6. Dunlop BW, Cha J, Choi KS, et al. : Shared and unique changes in brain connectivity among depressed patients after remission with pharmacotherapy versus psychotherapy . Am J Psychiatry 2023 ; 180:218–229 Link ,  Google Scholar

7. Strakowski SM : Applying functional imaging to clinical practice: are we making progress toward its promise? Am J Psychiatry 2023 :180:182–184 Abstract ,  Google Scholar

8. Elbau IG, Lynch CJ, Downar J, et al. : Functional connectivity mapping for rTMS target selection in depression . Am J Psychiatry 2023 ; 180:230–240 Link ,  Google Scholar

9. Blumberger DM, Vila-Rodriguez F, Thorpe KE, et al. : Effectiveness of theta burst versus high-frequency repetitive transcranial magnetic stimulation in patients with depression (THREE-D): a randomised non-inferiority trial . Lancet 2018 ; 391:1683–1692 Crossref , Medline ,  Google Scholar

10. Lynch CJ, Silver BM, Dubin MJ, et al. : Prevalent and sex-biased breathing patterns modify functional connectivity MRI in young adults . Nat Commun 2020 ; 11:5290 Crossref , Medline ,  Google Scholar

11. Cole EJ, Phillips AL, Bentzley BS, et al. : Stanford Neuromodulation Therapy (SNT): a double-blind randomized controlled trial . Am J Psychiatry 2022 ; 179:132–141 Link ,  Google Scholar

12. Siddiqi SH, Philip NS : Hitting the target of image-guided psychiatry? Am J Psychiatry 2023 ; 180:185–187 Abstract ,  Google Scholar

13. Sachs GS, Yeung PP, Rekeda L, et al. : Adjunctive cariprazine for the treatment of patients with major depressive disorder: a randomized, double-blind, placebo-controlled phase 3 study . Am J Psychiatry 2023 ; 180:241–251 Abstract ,  Google Scholar

14. Thase ME : A new option for depressed patients who do not respond to antidepressant medications . Am J Psychiatry 2023 ; 180:188–189 Abstract ,  Google Scholar

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Roots of major depression revealed in all their genetic complexity.

Depressed man sitting on his bed.

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A massive genome-wide association study (GWAS) of genetic and health records of 1.2 million people from four separate data banks has identified 178 gene variants linked to major depression, a disorder that will affect as many as  one in every five people during their lifetimes.

The results of the study, led by the U.S. Department of Veterans Affairs (V.A.) researchers at Yale University School of Medicine and University of California-San Diego (UCSD), may one day help identify people most at risk of depression and related psychiatric disorders and help doctors prescribe drugs best suited to treat the disorder.

The study was published May 27 in the journal Nature Neuroscience .

For the study, the research team analyzed medical records and genomes collected from more than 300,000 participants in the V.A.’s Million Veteran Program (MVP), one of the largest and most diverse databanks of genetic and medical information in the world.

These new data were combined in a meta-analysis with genetic and health records from the UK Biobank, FinnGen (a Finland-based biobank), and results from the consumer genetics company 23andMe. This part of the study included 1.2 million participants. The researchers crosschecked their findings from that analysis with an entirely separate sample of 1.3 million volunteers from 23andMe customers.

When the two sets of data from the different sources were compared, genetic variants linked to depression replicated with statistical significance for most of the markers tested.

“ What is most heartening is we could replicate our findings in independent data sets,” said Daniel Levey , an associate research scientist in the Yale Department of Psychiatry and co-lead author. “Replication is a hallmark of good science, and this paper points to just how reliable and stable results from GWAS studies are becoming.”

Like many mental health disorders, depression is genetically complex and is characterized by combinations of many different genetic variants, the researchers say.

“ That’s why we weren’t surprised by how many variants we found,” said Joel Gelernter , the Foundations Fund Professor of Psychiatry at Yale, professor of genetics and of neuroscience, and co-senior author of the study. “And we don’t know how many more there are left to discover — hundreds? Maybe even thousands?”

The size of the new GWAS study will help clinicians to develop polygenic risk scores to pinpoint those most at risk of developing major depression and other related psychiatric disorders such as anxiety or post-traumatic stress disorder, the authors say.

The study also provides deep insights into the underlying biology of genetic disorders. For instance, one gene variant implicated in depression, NEGR1 , is a neural growth regulator active in the hypothalamus, an area of the brain previously linked to depression. That confirms research done by the late Yale neuroscientist Ronald Duman on the role of neurotrophic factors in depression, Levey said.

“ It’s really striking when completely different kinds of research converge on similar biology, and that’s what’s happening here,” he said.

Insights into the functions of the variants can also help identify many drugs that hold promise in the treatment of depression, the researchers say. For instance, the drug riluzole, which is approved for the treatment of amyotrophic lateral sclerosis (ALS), modulates glutamate transmission in brain. Several gene variants linked by the new study to depression affect the glutamate system, which is actively being studied for depression treatments.

“ One of the real goals of the research is bringing forward new ways to treat people suffering from depression,” added co-senior author Dr. Murray Stein, staff psychiatrist at the V.A. San Diego Healthcare System and Distinguished Professor of Psychiatry and Public Health at UCSD.

Research was primarily funded by the U.S. Department of Veterans Affairs, including the Million Veteran Program and the Cooperative Studies Program. Levey also received support from a NARSAD Young Investigator Award from the Brain & Behavior Research Foundation.

  • Study of veterans details genetic basis for anxiety, links anxiety and depression
  • Immune system may have another job — combatting depression

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Clinical Research Studies

SPECIALIZING IN NOVEL AND INNOVATIVE RESEARCH APPROACHES FOR ALL TYPES OF CLINICAL DEPRESSION

Currently Enrolling Studies

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RELIANCE-II: A Study to Assess the Efficacy and Safety of REL-1017 as Adjunctive Treatment for Major Depressive Disorder (MDD)

This is an outpatient, 2-arm, Phase 3, multicenter, randomized, double-blind, placebo-controlled study to assess the efficacy and safety of REL-1017 once daily (QD) as an adjunctive treatment of Major Depressive Disorder.

Eligible participants will either receive the study drug, REL-1017, or placebo. Esmethadone (also known as dextromethadone) is the active ingredient in REL-1017 tablets. This study drug selectively works on nerve cells that seem to play a role in depression. A placebo is an inactive tablet that looks identical to the study drug (tablet) but does not contain the active study drug. Researchers use a placebo to see if the study drug works better or is safer than taking nothing. The main goals of this study are to learn how safe the study drug is and how well the study drug works when taken with the antidepressants you are currently taking for MDD.

For further details, please see the following link: https://clinicaltrials.gov/ct2/show/NCT04855747

Opiate Suicide Study in Patients with Major Depression

We are doing this study to determine if suicidal thoughts are lessened after an infusion of ketamine followed by 4 weeks of a medication called buprenorphine.   Participants for this research will be currently experiencing depression and will have not responded to treatment with antidepressants or have an intolerance to these types of medicines.   Recent studies have shown a single infusion of ketamine to reduce suicidal ideation within 24 hours and to last for at least one week.  We would like to determine if a single infusion of ketamine followed by 4 weeks of low dose burprenorphine produces longer lasting anti-suicidal effects than does ketamine followed by placebo.

This research study is expected to take approximately 2 years to complete with at least 6 weeks of active participation by each participant.  During this time, participants will make 10 study visits to Stanford University, including an 8-hour infusion visit.

Under the close supervision and monitoring by the study clinicians, eligible subjects will receive a single infusion of ketamine 0.5mg/kg followed by oral buprenorphine or placebo for 4 weeks.

This research study will use either Buprenorphine or a placebo, containing no drug, to study if the benefits experienced from Ketamine can be improved or last longer when buprenorphine is taken for 4 weeks.

To find out if this study is a good fit for you, please   fill out our online survey , call (650) 723-8330, or email  [email protected] .

For further details, please see the following link:   https://clinicaltrials.gov/ct2/show/NCT04116528

Tianeptine for Treatment Resistant Depression

Although not available in the United States, Tianeptine is an atypical antidepressant that has been used clinically in Europe, Asia, and South America since the late 1980s in millions of patients. Until recently tianeptine's molecular mechanism of action had remained unknown. Tianeptine is a different type of antidepressant than those currently approved in the United States in that it has a different mechanism of action than other antidepressants. Eligible participants will receive 8-weeks of treatment with Tianeptine. The major goals of this project are (1) to determine if tianeptine is an effective antidepressant in patients who have failed two previous trials, (2) to define the relationship between opioid signaling deficits and response to tianeptine treatment, and (3) to develop a comprehensive assessment battery capable of identifying endogenous opioid signaling deficits to explore biological heterogeneity in the TRD population. For further details, please see the following link: https://clinicaltrials.gov/ct2/show/NCT04249596

THERAPEUTIC GROUP FOR WOMEN TRAUMA SURVIVORS

We are conducting a research study on the Building Empowerment and Resilience (BEAR) Therapeutic Group for adult women who have experienced interpersonal trauma. We are recruiting women who would like to participate in the therapeutic group, as well as women who prefer not to participate in the group but are willing to complete a series of questionnaires.

The BEAR Therapeutic group includes psychoeducation, psychological skills, and physical empowerment (self-defense) training. The group will run for 12-weeks, for 1.5 hours once per week. The psychological skills portion of the class will cover topics such as assertiveness, communication skills, and boundary setting. In addition, we will cover basic self-defense techniques one can use to protect themselves if the need arises. This project is focusing on women who have been victims of interpersonal violence (e.g., physical, emotional, or sexual abuse/assault). To be eligible:

  • Women ages 18-70 years old
  • History of physical, sexual, or emotional violence with subsequent interpersonal or emotional difficulties related to this history
  • participate in the BEAR therapy group OR
  • to completed a series of questionnaires and not participate in the therapy group

The study is at Stanford University Medical Center during the day. The 12- week program will be provided at no charge or payment to the participants. The study consists of 14 visits: one screening visit, twelve classes, and one debriefing visit. In addition, on-line questionnaires will be completed periodically throughout the study.

For more information, contact us at (650) 724-7184 or email [email protected] .

To fill out a screening for this study, visit https://redcap.link/BEARscreening

All calls/contacts are confidential.

Enrolling Soon

The comp006 study.

man looking to left while two others are riding a bike

Exploring potential new routes away from treatment-resistant depression

Introducing the COMP 006 clinical study Many people who receive antidepressant treatment for their depression do not get an adequate response to the medicines they are taking. If someone is taking two or more antidepressants and they are failing, this is sometimes referred to as treatment-resistant depression or TRD. The COMP 006 study is looking into a new treatment approach for people with TRD using an investigational medicine given with psychological support. The study is suitable for people who have been diagnosed with major depression and are currently experiencing a recurrent or single episode of depression but that have not responded to antidepressant treatment.

You may be eligible to participate in a Compass Pathfinder study if you:

  • Are 18 years of age or older
  • Have been diagnosed with major depression (single or recurrent episodes)
  • Are experiencing treatment-resistant depression, defined as failing 2, 3 or 4 pharmacological treatments for your current episode of depression
  • Meet additional study criteria.

About the study The study, which will last up to 16 weeks, will compare the effectiveness of the active investigational medicine given at different dose levels with psychological support. If you join the study, neither you nor your study doctors will know which study treatment you are going to receive because the decision is made randomly by a computer and not revealed to anyone. Participants will receive support from study clinicians to help them taper off any prohibited medications, including current antidepressants. Participants will be asked to remain off prohibited medications for the duration of the study.

Reimbursement for reasonable, out-of-pocket expenses for travel and other expenses may be available to qualified individuals.

Enrollment expected to begin early 2024.

Other Clinical Trial Opportunities for Depression at Stanford Medicine

Current studies in the Brain Stimulation Lab (BSL) Dr. Williams, Assistant Professor of Psychiatry and Behavioral Sciences (General Psychiatry and Psychology) at the Stanford University Medical Center and Director of the Stanford Brain Stimulation Lab

Dr. Nolan Williams

The Brain Stimulation Lab (BSL) utilizes novel brain stimulation techniques to probe and modulate the neural networks underlying neuropsychiatric diseases/disorders in an effort to develop new models and novel treatments.

Learn more here

Current studies in the Heifets Lab Dr. Boris Heifets, Assistant Professor of Anesthesiology, Perioperative and Pain Medicine (Adult MSD) at the Stanford University Medical Center

boris heifets

Our research group is dedicated to understanding and improving on powerful, rapid-acting therapies for psychiatric disease, such as ketamine, MDMA and psilocybin. We bridge basic science and clinical trials, connecting neuroscience, psychiatry and anesthesiology in pursuit of highly effective, safe treatment strategies scalable to the millions of patients who need them.

The genetic basis of major depression

Affiliations.

  • 1 MRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff University, Cardiff, UK.
  • 2 Department of Psychiatry, University of Muenster, Muenster, Germany.
  • 3 Department of Neurology, Klinikum rechts der Isar, School of Medicine, Technical University of Munich, Munich, Germany.
  • 4 Department of Psychiatry, Massachusetts General Hospital, Boston, MA02114, USA.
  • 5 Psychiatric and Neurodevelopmental Genetics Unit, Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA02114, USA.
  • 6 Department of Epidemiology, Harvard TH Chan School of Public Health, Boston, MA02115, USA.
  • 7 Department of Psychiatry, UMC Utrecht Brain Center, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands.
  • 8 Department of Translational Neuroscience, UMC Utrecht Brain Center, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands.
  • 9 Outpatient Second Opinion Clinic, GGNet Mental Health, Warnsveld, The Netherlands.
  • 10 Institute of Psychiatric Phenomics and Genomics (IPPG), University Hospital, LMU Munich, Munich, Germany.
  • 11 Department of Psychiatry and Psychotherapy, University Hospital, LMU Munich, Munich, Germany.
  • 12 Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
  • PMID: 33682643
  • DOI: 10.1017/S0033291721000441

Major depressive disorder (MDD) is a common, debilitating, phenotypically heterogeneous disorder with heritability ranges from 30% to 50%. Compared to other psychiatric disorders, its high prevalence, moderate heritability, and strong polygenicity have posed major challenges for gene-mapping in MDD. Studies of common genetic variation in MDD, driven by large international collaborations such as the Psychiatric Genomics Consortium, have confirmed the highly polygenic nature of the disorder and implicated over 100 genetic risk loci to date. Rare copy number variants associated with MDD risk were also recently identified. The goal of this review is to present a broad picture of our current understanding of the epidemiology, genetic epidemiology, molecular genetics, and gene-environment interplay in MDD. Insights into the impact of genetic factors on the aetiology of this complex disorder hold great promise for improving clinical care.

Publication types

  • Chromosome Mapping
  • DNA Copy Number Variations / genetics*
  • Depressive Disorder, Major* / epidemiology
  • Depressive Disorder, Major* / genetics
  • Genetic Loci
  • Genome-Wide Association Study*
  • Multifactorial Inheritance / genetics*

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Major Depressive Disorder: Advances in Neuroscience Research and Translational Applications

  • Open access
  • Published: 13 February 2021
  • Volume 37 , pages 863–880, ( 2021 )

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  • Zezhi Li 1 , 2 ,
  • Meihua Ruan 3 ,
  • Jun Chen 1 , 5 &
  • Yiru Fang   ORCID: orcid.org/0000-0002-8748-9085 1 , 4 , 5  

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A Correction to this article was published on 17 May 2021

This article has been updated

Major depressive disorder (MDD), also referred to as depression, is one of the most common psychiatric disorders with a high economic burden. The etiology of depression is still not clear, but it is generally believed that MDD is a multifactorial disease caused by the interaction of social, psychological, and biological aspects. Therefore, there is no exact pathological theory that can independently explain its pathogenesis, involving genetics, neurobiology, and neuroimaging. At present, there are many treatment measures for patients with depression, including drug therapy, psychotherapy, and neuromodulation technology. In recent years, great progress has been made in the development of new antidepressants, some of which have been applied in the clinic. This article mainly reviews the research progress, pathogenesis, and treatment of MDD.

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research studies on major depression

Introduction

Neuroimaging advance in depressive disorder.

research studies on major depression

The cellular and molecular basis of major depressive disorder: towards a unified model for understanding clinical depression

Eleni Pitsillou, Sarah M. Bresnehan, … Tom C. Karagiannis

Avoid common mistakes on your manuscript.

Major depressive disorder (MDD) also referred to as depression, is one of the most severe and common psychiatric disorders across the world. It is characterized by persistent sadness, loss of interest or pleasure, low energy, worse appetite and sleep, and even suicide, disrupting daily activities and psychosocial functions. Depression has an extreme global economic burden and has been listed as the third largest cause of disease burden by the World Health Organization since 2008, and is expected to rank the first by 2030 [ 1 , 2 ]. In 2016, the Global Burden of Diseases, Injuries, and Risk Factors Study demonstrated that depression caused 34.1 million of the total years lived with disability (YLDs), ranking as the fifth largest cause of YLD [ 3 ]. Therefore, the research progress and the clinical application of new discoveries or new technologies are imminent. In this review, we mainly discuss the current situation of research, developments in pathogenesis, and the management of depression.

Current Situation of Research on Depression

Analysis of published papers.

In the past decade, the total number of papers on depression published worldwide has increased year by year as shown in Fig. 1 A. Searching the Web of Science database, we found a total of 43,863 papers published in the field of depression from 2009 to 2019 (search strategy: TI = (depression$) or ts = ("major depressive disorder$")) and py = (2009 – 2019), Articles). The top 10 countries that published papers on the topic of depression are shown in Fig. 1 B. Among them, researchers in the USA published the most papers, followed by China. Compared with the USA, the gap in the total number of papers published in China is gradually narrowing (Fig. 1 C), but the quality gap reflected by the index (the total number of citations and the number of citations per paper) is still large, and is lower than the global average (Fig. 1 D). As shown in Fig. 1 E, the hot research topics in depression are as follows: depression management in primary care, interventions to prevent depression, the pathogenesis of depression, comorbidity of depression and other diseases, the risks of depression, neuroimaging studies of depression, and antidepressant treatment.

figure 1

Analysis of published papers around the world from 2009 to 2019 in depressive disorder. A The total number of papers [from a search of the Web of Science database (search strategy: TI = (depression$) or ts = ("major depressive disorder$")) and py = (2009 – 2019), Articles)]. B The top 10 countries publishing on the topic. C Comparison of papers in China and the USA. D Citations for the top 10 countries and comparison with the global average. E Hot topics.

Analysis of Patented Technology Application

There were 16,228 patent applications in the field of depression between 2009 and 2019, according to the Derwent Innovation Patent database. The annual number and trend of these patents are shown in Fig. 2 A. The top 10 countries applying for patents related to depression are shown in Fig. 2 B. The USA ranks first in the number of depression-related patent applications, followed by China. The largest number of patents related to depression is the development of antidepressants, and drugs for neurodegenerative diseases such as dementia comorbid with depression. The top 10 technological areas of patents related to depression are shown in Fig. 2 C, and the trend in these areas have been stable over the past decade (Fig. 2 D).

figure 2

Analysis of patented technology applications from 2009 to 2019 in the field of depressive disorder. A Annual numbers and trends of patents (the Derwent Innovation patent database). B The top 10 countries/regions applying for patents. C The top 10 technological areas of patents. D The trend of patent assignees. E Global hot topic areas of patents.

Analysis of technical hotspots based on keyword clustering was conducted from the Derwent Innovation database using the "ThemeScape" tool. This demonstrated that the hot topic areas are as follows (Fig. 2 E): (1) improvement for formulation and the efficiency of hydrobromide, as well as optimization of the dosage; intervention for depression comorbid with AD, diabetes, and others; (3) development of alkyl drugs; (4) development of pharmaceutical acceptable salts as antidepressants; (5) innovation of the preparation of antidepressants; (6) development of novel antidepressants based on neurotransmitters; (7) development of compositions based on nicotinic acetylcholine receptors; and (8) intervention for depression with traditional Chinese medicine.

Analysis of Clinical Trial

There are 6,516 clinical trials in the field of depression in the ClinicalTrials.gov database, and among them, 1,737 valid trials include the ongoing recruitment of subjects, upcoming recruitment of subjects, and ongoing clinical trials. These clinical trials are mainly distributed in the USA (802 trials), Canada (155), China (114), France (93), Germany (66), UK (62), Spain (58), Denmark (41), Sweden (39), and Switzerland (23). The indications for clinical trials include various types of depression, such as minor depression, depression, severe depression, perinatal depression, postpartum depression, and depression comorbid with other psychiatric disorders or physical diseases, such as schizophrenia, epilepsy, stroke, cancer, diabetes, cardiovascular disease, and Parkinson's disease.

Based on the database of the Chinese Clinical Trial Registry website, a total of 143 clinical trials for depression have been carried out in China. According to the type of research, they are mainly interventional and observational studies, as well as a small number of related factor studies, epidemiological studies, and diagnostic trials. The research content involves postpartum, perinatal, senile, and other age groups with clinical diagnosis (imaging diagnosis) and intervention studies (drugs, acupuncture, electrical stimulation, transcranial magnetic stimulation). It also includes intervention studies on depression comorbid with coronary heart disease, diabetes, and heart failure.

New Medicine Development

According to the Cortellis database, 828 antidepressants were under development by the end of 2019, but only 292 of these are effective and active (Fig. 3 A). Large number of them have been discontinued or made no progress, indicating that the development of new drugs in the field of depression is extremely urgent.

figure 3

New medicine development from 2009 to 2019 in depressive disorder. A Development status of new candidate drugs. B Top target-based actions.

From the perspective of target-based actions, the most common new drugs are NMDA receptor antagonists, followed by 5-HT targets, as well as dopamine receptor agonists, opioid receptor antagonists and agonists, AMPA receptor modulators, glucocorticoid receptor antagonists, NK1 receptor antagonists, and serotonin transporter inhibitors (Fig. 3 B).

Epidemiology of Depression

The prevalence of depression varies greatly across cultures and countries. Previous surveys have demonstrated that the 12-month prevalence of depression was 0.3% in the Czech Republic, 10% in the USA, 4.5% in Mexico, and 5.2% in West Germany, and the lifetime prevalence of depression was 1.0% in the Czech Republic, 16.9% in the USA, 8.3% in Canada, and 9.0% in Chile [ 4 , 5 ]. A recent meta-analysis including 30 Countries showed that lifetime and 12-month prevalence depression were 10.8% and 7.2%, respectively [ 6 ]. In China, the lifetime prevalence of depression ranged from 1.6% to 5.5% [ 7 , 8 , 9 ]. An epidemiological study demonstrated that depression was the most common mood disorder with a life prevalence of 3.4% and a 12-month prevalence of 2.1% in China [ 10 ].

Some studies have also reported the prevalence in specific populations. The National Comorbidity Survey-Adolescent Supplement (NCS-A) survey in the USA showed that the lifetime and 12-month prevalence of depression in adolescents aged 13 to 18 were 11.0% and 7.5%, respectively [ 11 ]. A recent meta-analysis demonstrated that lifetime prevalence and 12-month prevalence were 2.8% and 2.3%, respectively, among the elderly population in China [ 12 ].

Neurobiological Pathogenesis of Depressive Disorder

The early hypothesis of monoamines in the pathophysiology of depression has been accepted by the scientific community. The evidence that monoamine oxidase inhibitors and tricyclic antidepressants promote monoamine neurotransmission supports this theory of depression [ 13 ]. So far, selective serotonin reuptake inhibitors and norepinephrine reuptake inhibitors are still the first-line antidepressants. However, there remain 1/3 to 2/3 of depressed patients who do not respond satisfactorily to initial antidepressant treatment, and even as many as 15%–40% do not respond to several pharmacological medicines [ 14 , 15 ]. Therefore, the underlying pathogenesis of depression is far beyond the simple monoamine mechanism.

Other hypotheses of depression have gradually received increasing attention because of biomarkers for depression and the effects pharmacological treatments, such as the stress-responsive hypothalamic pituitary adrenal (HPA) axis, neuroendocrine systems, the neurotrophic family of growth factors, and neuroinflammation.

Stress-Responsive HPA Axis

Stress is causative or a contributing factor to depression. Particularly, long-term or chronic stress can lead to dysfunction of the HPA axis and promote the secretion of hormones, including cortisol, adrenocorticotropic hormone, corticotropin-releasing hormone, arginine vasopressin, and vasopressin. About 40%–60% of patients with depression display a disturbed HPA axis, including hypercortisolemia, decreased rhythmicity, and elevated cortisol levels [ 16 , 17 ]. Mounting evidence has shown that stress-induced abnormality of the HPA axis is associated with depression and cognitive impairment, which is due to the increased secretion of cortisol and the insufficient inhibition of glucocorticoid receptor regulatory feedback [ 18 , 19 ]. In addition, it has been reported that the increase in cortisol levels is related to the severity of depression, especially in melancholic depression [ 20 , 21 ]. Further, patients with depression whose HPA axis was not normalized after treatment had a worse clinical response and prognosis [ 22 , 23 ]. Despite the above promising insights, unfortunately previous studies have shown that treatments regulating the HPA axis, such as glucocorticoid receptor antagonists, do not attenuate the symptoms of depressed patients [ 24 , 25 ].

Glutamate Signaling Pathway

Glutamate is the main excitatory neurotransmitter released by synapses in the brain; it is involved in synaptic plasticity, cognitive processes, and reward and emotional processes. Stress can induce presynaptic glutamate secretion by neurons and glutamate strongly binds to ionotropic glutamate receptors (iGluRs) including N-methyl-D-aspartate receptors (NMDARs) and α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid receptors (AMPARs) [ 26 ] on the postsynaptic membrane to activate downstream signal pathways [ 27 ]. Accumulating evidence has suggested that the glutamate system is associated with the incidence of depression. Early studies have shown increased levels of glutamate in the peripheral blood, cerebrospinal fluid, and brain of depressed patients [ 28 , 29 ], as well as NMDAR subunit disturbance in the brain [ 30 , 31 ]. Blocking the function of NMDARs has an antidepressant effect and protects hippocampal neurons from morphological abnormalities induced by stress, while antidepressants reduce glutamate secretion and NMDARs [ 32 ]. Most importantly, NMDAR antagonists such as ketamine have been reported to have profound and rapid antidepressant effects on both animal models and the core symptoms of depressive patients [ 33 ]. On the other hand, ketamine can also increase the AMPAR pathway in hippocampal neurons by up-regulating the AMPA glutamate receptor 1 subunit [ 34 ]. Further, the AMPAR pathway may be involved in the mechanism of antidepressant effects. For example, preclinical studies have indicated that AMPAR antagonists might attenuate lithium-induced depressive behavior by increasing the levels of glutamate receptors 1 and 2 in the mouse hippocampus [ 35 ].

Gamma-Aminobutyric Acid (GABA)

Contrary to glutamate, GABA is the main inhibitory neurotransmitter. Although GABA neurons account for only a small proportion compared to glutamate, inhibitory neurotransmission is essential for brain function by balancing excitatory transmission [ 36 ]. Number of studies have shown that patients with depression have neurotransmission or functional defects of GABA [ 37 , 38 ]. Schür et al ., conducted a meta-analysis of magnetic resonance spectroscopy studies, which showed that the brain GABA level in depressive patients was lower than that in healthy controls, but no difference was found in depressive patients in remission [ 39 ]. Several postmortem studies have shown decreased levels of the GABA synthase glutamic acid decarboxylase in the prefrontal cortex of patients with depression [ 40 , 41 ]. It has been suggested that a functional imbalance of the GABA and glutamate systems contributes to the pathophysiology of depression, and activation of the GABA system might induce antidepressant activity, by which GABA A  receptor mediators α2/α3 are considered potential antidepressant candidates [ 42 , 43 ]. Genetic mouse models, such as the GABA A receptor mutant mouse and conditional the Gad1-knockout mouse (GABA in hippocampus and cerebral cortex decreased by 50%) and optogenetic methods have verified that depression-like behavior is induced by changing the level of GABA [ 44 , 45 ].

Neurotrophin Family

The neurotrophin family plays a key role in neuroplasticity and neurogenesis. The neurotrophic hypothesis of depression postulates that a deficit of neurotrophic support leads to neuronal atrophy, the reduction of neurogenesis, and the destruction of glia support, while antidepressants attenuate or reverse these pathophysiological processes [ 46 ]. Among them, the most widely accepted hypothesis involves brain-derived neurotrophic factor (BDNF). This was initially triggered by evidence that stress reduces the BDNF levels in the animal brain, while antidepressants rescue or attenuate this reduction [ 47 , 48 ], and agents involved in the BDNF system have been reported to exert antidepressant-like effects [ 49 , 50 ]. In addition, mounting studies have reported that the BDNF level is decreased in the peripheral blood and at post-mortem in depressive patients, and some have reported that antidepressant treatment normalizes it [ 51 , 52 ]. Furthermore, some evidence also showed that the interaction of BDNF and its receptor gene is associated with treatment-resistant depression [ 15 ].

Recent studies reported that depressed patients have a lower level of the pro-domain of BDNF (BDNF pro-peptide) than controls. This is located presynaptically and promotes long-term depression in the hippocampus, suggesting that it is a promising synaptic regulator [ 53 ].

Neuroinflammation

The immune-inflammation hypothesis has attracted much attention, suggesting that the interactions between inflammatory pathways and neural circuits and neurotransmitters are involved in the pathogenesis and pathophysiological processes of depression. Early evidence found that patients with autoimmune or infectious diseases are more likely to develop depression than the general population [ 54 ]. In addition, individuals without depression may display depressive symptoms after treatment with cytokines or cytokine inducers, while antidepressants relieve these symptoms [ 55 , 56 ]. There is a complex interaction between the peripheral and central immune systems. Previous evidence suggested that peripheral inflammation/infection may spread to the central nervous system in some way and cause a neuroimmune response [ 55 , 57 ]: (1) Some cytokines produced in the peripheral immune response, such as IL-6 and IL-1 β, can leak into the brain through the blood-brain barrier (BBB). (2) Cytokines entering the central nervous system act directly on astrocytes, small stromal cells, and neurons. (3) Some peripheral immune cells can cross the BBB through specific transporters, such as monocytes. (4) Cytokines and chemokines in the circulation activate the central nervous system by regulating the surface receptors of astrocytes and endothelial cells at the BBB. (5) As an intermediary pathway, the immune inflammatory response transmits peripheral danger signals to the center, amplifies the signals, and shows the external phenotype of depressive behavior associated with stress/trauma/infection. (6) Cytokines and chemokines may act directly on neurons, change their plasticity and promote depression-like behavior.

Patients with depression show the core feature of the immune-inflammatory response, that is, increased concentrations of pro-inflammatory cytokines and their receptors, chemokines, and soluble adhesion molecules in peripheral blood and cerebrospinal fluid [ 58 , 59 , 60 ]. Peripheral immune-inflammatory response markers not only change the immune activation state in the brain that affects explicit behavior, but also can be used as an evaluation index or biological index of antidepressant therapy [ 61 , 62 ]. Li et al . showed that the level of TNF-α in patients with depression prior to treatment was higher than that in healthy controls. After treatment with venlafaxine, the level of TNF-α in patients with depression decreased significantly, and the level of TNF-α in the effective group decreased more [ 63 ]. A recent meta-analysis of 1,517 patients found that antidepressants significantly reduced peripheral IL-6, TNF-α, IL-10, and CCL-2, suggesting that antidepressants reduce markers of peripheral inflammatory factors [ 64 ]. Recently, Syed et al . also confirmed that untreated patients with depression had higher levels of inflammatory markers and increased levels of anti-inflammatory cytokines after antidepressant treatment, while increased levels of pro-inflammatory cytokines were found in non-responders [ 62 ]. Clinical studies have also found that anti-inflammatory cytokines, such as monoclonal antibodies and other cytokine inhibitors, may play an antidepressant role by blocking cytokines. The imbalance of pro-inflammatory and anti-inflammatory cytokines may be involved in the pathophysiological process of depression.

In addition, a recent study showed that microglia contribute to neuronal plasticity and neuroimmune interaction that are involved in the pathophysiology of depression [ 65 ]. When activated microglia promote inflammation, especially the excessive production of pro-inflammatory factors and cytotoxins in the central nervous system, depression-like behavior can gradually develop [ 65 , 66 ]. However, microglia change polarization as two types under different inflammatory states, regulating the balance of pro- and anti-inflammatory factors. These two types are M1 and M2 microglia; the former produces large number of pro-inflammatory cytokines after activation, and the latter produces anti-inflammatory cytokines. An imbalance of M1/M2 polarization of microglia may contribute to the pathophysiology of depression [ 67 ].

Microbiome-Gut-Brain Axis

The microbiota-gut-brain axis has recently gained more attention because of its ability to regulate brain activity. Many studies have shown that the microbiota-gut-brain axis plays an important role in regulating mood, behavior, and neuronal transmission in the brain [ 68 , 69 ]. It is well established that comorbidity of depression and gastrointestinal diseases is common [ 70 , 71 ]. Some antidepressants can attenuate the symptoms of patients with irritable bowel syndrome and eating disorders [ 72 ]. It has been reported that gut microbiome alterations are associated with depressive-like behaviors [ 73 , 74 ], and brain function [ 75 ]. Early animal studies have shown that stress can lead to long-term changes in the diversity and composition of intestinal microflora, and is accompanied by depressive behavior [ 76 , 77 ]. Interestingly, some evidence indicates that rodents exhibit depressive behavior after fecal transplants from patients with depression [ 74 ]. On the other hand, some probiotics attenuated depressive-like behavior in animal studies, [ 78 ] and had antidepressant effects on patients with depression in several double-blind, placebo-controlled clinical trials [ 79 , 80 ].

The potential mechanism may be that gut microbiota can interact with the brain through a variety of pathways or systems, including the HPA axis, and the neuroendocrine, autonomic, and neuroimmune systems [ 81 ]. For example, recent evidence demonstrated that gut microbiota can affect the levels of neurotransmitters in the gut and brain, including serotonin, dopamine, noradrenalin, glutamate, and GABA [ 82 ]. In addition, recent studies showed that changes in gut microbiota can also impair the gut barrier and promote higher levels of peripheral inflammatory cytokines [ 83 , 84 ]. Although recent research in this area has made significant progress, more clinical trials are needed to determine whether probiotics have any effect on the treatment of depression and what the potential underlying mechanisms are.

Other Systems and Pathways

There is no doubt that several other systems or pathways are also involved in the pathophysiology of depression, such as oxidant-antioxidant imbalance [ 85 ], mitochondrial dysfunction [ 86 , 87 ], and circadian rhythm-related genes [ 88 ], especially their critical interactions ( e.g. interaction between the HPA and mitochondrial metabolism [ 89 , 90 ], and the reciprocal interaction between oxidative stress and inflammation [ 2 , 85 ]). The pathogenesis of depression is complex and all the hypotheses should be integrated to consider the many interactions between various systems and pathways.

Advances in Various Kinds of Research on Depressive Disorder

Genetic, molecular, and neuroimaging studies continue to increase our understanding of the neurobiological basis of depression. However, it is still not clear to what extent the results of neurobiological studies can help improve the clinical and functional prognosis of patients. Therefore, over the past 10 years, the neurobiological study of depression has become an important measure to understand the pathophysiological mechanism and guide the treatment of depression.

Genetic Studies

Previous twin and adoption studies have indicated that depression has relatively low rate of heritability at 37% [ 91 ]. In addition, environmental factors such as stressful events are also involved in the pathogenesis of depression. Furthermore, complex psychiatric disorders, especially depression, are considered to be polygenic effects that interact with environmental factors [ 13 ]. Therefore, reliable identification of single causative genes for depression has proved to be challenging. The first genome-wide association studies (GWAS) for depression was published in 2009, and included 1,738 patients and 1,802 controls [ 92 , 93 ]. Although many subsequent GWASs have determined susceptible genes in the past decade, the impact of individual genes is so small that few results can be replicated [ 94 , 95 ]. So far, it is widely accepted that specific single genetic mutations may play minor and marginal roles in complex polygenic depression. Another major recognition in GWASs over the past decade is that prevalent candidate genes are usually not associated with depression. Further, the inconsistent results may also be due to the heterogeneity and polygenic nature of genetic and non-genetic risk factors for depression as well as the heterogeneity of depression subtypes [ 95 , 96 ]. Therefore, to date, the quality of research has been improved in two aspects: (1) the sample size has been maximized by combining the data of different evaluation models; and (2) more homogenous subtypes of depression have been selected to reduce phenotypic heterogeneity [ 97 ]. Levinson et al . pointed out that more than 75,000 to 100,000 cases should be considered to detect multiple depression associations [ 95 ]. Subsequently, several recent GWASs with larger sample sizes have been conducted. For example, Okbay et al . identified two loci associated with depression and replicated them in separate depression samples [ 98 ]. Wray et al . also found 44 risk loci associated with depression based on 135,458 cases and 344,901 controls [ 99 ]. A recent GWAS of 807,553 individuals with depression reported that 102 independent variants were associated with depression; these were involved in synaptic structure and neural transmission, and were verified in a further 1,507,153 individuals [ 100 ]. However, even with enough samples, GWASs still face severe challenges. A GWAS only marks the region of the genome and is not directly related to the potential biological function. In addition, a genetic association with the indicative phenotype of depression may only be part of many pathogenic pathways, or due to the indirect influence of intermediate traits in the causal pathway on the final result [ 101 ].

Given the diversity of findings, epigenetic factors are now being investigated. Recent studies indicated that epigenetic mechanisms may be the potential causes of "loss of heritability" in GWASs of depression. Over the past decade, a promising discovery has been that the effects of genetic information can be directly influenced by environment factors, and several specific genes are activated by environmental aspects. This process is described as interactions between genes and the environment, which is identified by the epigenetic mechanism. Environmental stressors cause alterations in gene expression in the brain, which may cause abnormal neuronal plasticity in areas related to the pathogenesis of the disease. Epigenetic events alter the structure of chromatin, thereby regulating gene expression involved in neuronal plasticity, stress behavior, depressive behavior, and antidepressant responses, including DNA methylation, histone acetylation, and the role of non-coding RNA. These new mechanisms of trans-generational transmission of epigenetic markers are considered a supplement to orthodox genetic heredity, providing the possibility for the discovery of new treatments for depression [ 102 , 103 ]. Recent studies imply that life experiences, including stress and enrichment, may affect cellular and molecular signaling pathways in sperm and influence the behavioral and physiological phenotypes of offspring in gender-specific patterns, which may also play an important role in the development of depression [ 103 ].

Brain Imaging and Neuroimaging Studies

Neuroimaging, including magnetic resonance imaging (MRI) and molecular imaging, provides a non-invasive technique for determining the underlying etiology and individualized treatment for depression. MRI can provide important data on brain structure, function, networks, and metabolism in patients with depression; it includes structural MRI (sMRI), functional MRI (fMRI), diffusion tensor imaging, and magnetic resonance spectroscopy.

Previous sMRI studies have found damaged gray matter in depression-associated brain areas, including the frontal lobe, anterior cingulate gyrus, hippocampus, putamen, thalamus, and amygdala. sMRI focuses on the thickness of gray matter and brain morphology [ 104 , 105 ]. A recent meta-analysis of 2,702 elderly patients with depression and 11,165 controls demonstrated that the volumes of the whole brain and hippocampus of patients with depression were lower than those of the control group [ 106 ]. Some evidence also showed that the hippocampal volume in depressive patients was lower than that of controls, and increased after treatment with antidepressants [ 107 ] and electroconvulsive therapy (ECT) [ 108 ], suggesting that the hippocampal volume plays a critical role in the development, treatment response, and clinical prognosis of depression. A recent study also reported that ECT increased the volume of the right hippocampus, amygdala, and putamen in patients with treatment-resistant depression [ 109 ]. In addition, postmortem research supported the MRI study showing that dentate gyrus volume was decreased in drug-naive patients with depression compared to healthy controls, and was potentially reversed by treatment with antidepressants [ 110 ].

Diffusion tensor imaging detects the microstructure of the white matter, which has been reported impaired in patients with depression [ 111 ]. A recent meta-analysis that included first-episode and drug-naïve depressive patients showed that the decrease in fractional anisotropy was negatively associated with illness duration and clinical severity [ 112 ].

fMRI, including resting-state and task-based fMRI, can divide the brain into self-related regions, such as the anterior cingulate cortex, posterior cingulate cortex, medial prefrontal cortex, precuneus, and dorsomedial thalamus. Many previous studies have shown the disturbance of several brain areas and intrinsic neural networks in patients with depression which could be rescued by antidepressants [ 113 , 114 , 115 , 116 ]. Further, some evidence also showed an association between brain network dysfunction and the clinical correlates of patients with depression, including clinical symptoms [ 117 ] and the response to antidepressants [ 118 , 119 ], ECT [ 120 , 121 ], and repetitive transcranial magnetic stimulation [ 122 ].

It is worth noting that brain imaging provides new insights into the large-scale brain circuits that underlie the pathophysiology of depressive disorder. In such studies, large-scale circuits are often referred to as “networks”. There is evidence that a variety of circuits are involved in the mechanisms of depressive disorder, including disruption of the default mode, salience, affective, reward, attention, and cognitive control circuits [ 123 ]. Over the past decade, the study of intra-circuit and inter-circuit connectivity dysfunctions in depression has escalated, in part due to advances in precision imaging and analysis techniques [ 124 ]. Circuit dysfunction is a potential biomarker to guide psychopharmacological treatment. For example, Williams et al . found that hyper-activation of the amygdala is associated with a negative phenotype that can predict the response to antidepressants [ 125 ]. Hou et al . showed that the baseline characteristics of the reward circuit predict early antidepressant responses [ 126 ].

Molecular imaging studies, including single photon emission computed tomography and positron emission tomography, focus on metabolic aspects such as amino-acids, neurotransmitters, glucose, and lipids at the cellular level in patients with depression. A recent meta-analysis examined glucose metabolism and found that glucose uptake dysfunction in different brain regions predicts the treatment response [ 127 ].

The most important and promising studies were conducted by the ENIGMA (Enhancing NeuroImaging Genetics through Meta Analysis) Consortium, which investigated the human brain across 43 countries. The ENIGMA-MDD Working Group was launched in 2012 to detect the structural and functional changes associated with MDD reliably and replicate them in various samples around the world [ 128 ]. So far, the ENIGMA-MDD Working Group has collected data from 4,372 MDD patients and 9,788 healthy controls across 14 countries, including 45 cohorts [ 128 ]. Their findings to date are shown in Table 1 [ 128 , 129 , 130 , 131 , 132 , 133 , 134 , 135 , 136 , 137 ].

Objective Index for Diagnosis of MDD

To date, the clinical diagnosis of depression is subjectively based on interviews according to diagnostic criteria ( e.g. International Classification of Diseases and Diagnostic and Statistical Manual diagnostic systems) and the severity of clinical symptoms are assessed by questionnaires, although patients may experience considerable differences in symptoms and subtypes [ 138 ]. Meanwhile, biomarkers including genetics, epigenetics, peripheral gene and protein expression, and neuroimaging markers may provide a promising supplement for the development of the objective diagnosis of MDD, [ 139 , 140 , 141 ]. However, the development of reliable diagnosis for MDD using biomarkers is still difficult and elusive, and all methods based on a single marker are insufficiently specific and sensitive for clinical use [ 142 ]. Papakostas et al . showed that a multi-assay, serum-based test including nine peripheral biomarkers (soluble tumor necrosis factor alpha receptor type II, resistin, prolactin, myeloperoxidase, epidermal growth factor, BDNF, alpha1 antitrypsin, apolipoprotein CIII, brain-derived neurotrophic factor, and cortisol) yielded a specificity of 81.3% and a sensitivity of 91.7% [ 142 ]. However, the sample size was relatively small and no other studies have yet validated their results. Therefore, further studies are needed to identify biomarker models that integrate all biological variables and clinical features to improve the specificity and sensitivity of diagnosis for MDD.

Management of Depression

The treatment strategies for depression consist of pharmacological treatment and non-pharmacological treatments including psychotherapy, ECT [ 98 ], and transcranial magnetic stimulation. As psychotherapy has been shown to have effects on depression including attenuating depressive symptoms and improving the quality of life [ 143 , 144 ]; several practice guidelines are increasingly recommending psychotherapy as a monotherapy or in combination with antidepressants [ 145 , 146 ].

Current Antidepressant Treatment

Antidepressants approved by the US Food and Drug Administration (FDA) are shown in Table 2 . Due to the relatively limited understanding of the etiology and pathophysiology of depression, almost all the previous antidepressants were discovered by accident a few decades ago. Although most antidepressants are usually safe and effective, there are still some limitations, including delayed efficacy (usually 2 weeks) and side-effects that affect the treatment compliance [ 147 ]. In addition, <50% of all patients with depression show complete remission through optimized treatment, including trials of multiple drugs with and without simultaneous psychotherapy. In the past few decades, most antidepressant discoveries focused on finding faster, safer, and more selective serotonin or norepinephrine receptor targets. In addition, there is an urgent need to develop new approaches to obtain more effective, safer, and faster antidepressants. In 2019, the FDA approved two new antidepressants: Esketamine for refractory depression and Bresanolone for postpartum depression. Esmolamine, a derivative of the anesthetic drug ketamine, was approved by the FDA for the treatment of refractory depression, based on a large number of preliminary clinical studies [ 148 ]. For example, several randomized controlled trials and meta-analysis studies showed the efficacy and safety of Esketamine in depression or treatment-resistant depression [ 26 , 149 , 150 ]. Although both are groundbreaking new interventions for these debilitating diseases and both are approved for use only under medical supervision, there are still concerns about potential misuse and problems in the evaluation of mental disorders [ 151 ].

To date, although several potential drugs have not yet been approved by the FDA, they are key milestones in the development of antidepressants that may be modified and used clinically in the future, such as compounds containing dextromethorphan (a non-selective NMDAR antago–nist), sarcosine (N-methylglycine, a glycine reuptake inhibitor), AMPAR modulators, and mGluR modulators [ 152 ].

Neuromodulation Therapy

Neuromodulation therapy acts through magnetic pulse, micro-current, or neural feedback technology within the treatment dose, acting on the central or peripheral nervous system to regulate the excitatory/inhibitory activity to reduce or attenuate the symptoms of the disease.

ECT is one of most effective treatments for depression, with the implementation of safer equipment and advancement of techniques such as modified ECT [ 153 ]. Mounting evidence from randomized controlled trial (RCT) and meta-analysis studies has shown that rTMS can treat depressive patients with safety [ 154 ]. Other promising treatments for depression have emerged, such as transcranial direct current stimulation (tDCS) [ 155 ], transcranial alternating current stimulation (tACS)[ 156 ], vagal nerve stimulation [ 157 ], deep brain stimulation [ 158 ] , and light therapy [ 159 ], but some of them are still experimental to some extent and have not been widely used. For example, compared to tDCS, tACS displays less sensory experience and adverse reactions with weak electrical current in a sine-wave pattern, but the evidence for the efficacy of tACS in the treatment of depression is still limited [ 160 ]. Alexander et al . recently demonstrated that there was no difference in efficacy among different treatments (sham, 10-Hz and 40-Hz tACS). However, only the 10-Hz tACS group had more responders than the sham and 40-Hz tACS groups at week 2 [ 156 ]. Further RCT studies are needed to verify the efficacy of tACS. In addition, the mechanism of the effect of neuromodulation therapy on depression needs to be further investigated.

Precision Medicine for Depression

Optimizing the treatment strategy is an effective way to improve the therapeutic effect on depression. However, each individual with depression may react very differently to different treatments. Therefore, this raises the question of personalized treatment, that is, which patients are suitable for which treatment. Over the past decade, psychiatrists and psychologists have focused on individual biomarkers and clinical characteristics to predict the efficiency of antidepressants and psychotherapies, including genetics, peripheral protein expression, electrophysiology, neuroimaging, neurocognitive performance, developmental trauma, and personality [ 161 ]. For example, Bradley et al . recently conducted a 12-week RCT, which demonstrated that the response rate and remission rates of the pharmacogenetic guidance group were significantly higher than those of the non-pharmacogenetic guidance group [ 162 ].

Subsequently, Greden et al . conducted an 8-week RCT of Genomics Used to Improve Depression Decisions (GUIDED) on 1,167 MDD patients and demonstrated that although there was no difference in symptom improvement between the pharmacogenomics-guided and non- pharmacogenomics-guided groups, the response rate and remission rate of the pharmacogenomics-guided group increased significantly [ 163 ].

A recent meta-analysis has shown that the baseline default mode network connectivity in patients with depression can predict the clinical responses to treatments including cognitive behavioral therapy, pharmacotherapy, ECT, rTMS, and transcutaneous vagus nerve stimulation [ 164 ]. However, so far, the biomarkers that predict treatment response at the individual level have not been well applied in the clinic, and there is still a lot of work to be conducted in the future.

Future Perspectives

Although considerable progress has been made in the study of depression during a past decade, the heterogeneity of the disease, the effectiveness of treatment, and the gap in translational medicine are critical challenges. The main dilemma is that our understanding of the etiology and pathophysiology of depression is inadequate, so our understanding of depression is not deep enough to develop more effective treatment. Animal models still cannot fully simulate this heterogeneous and complex mental disorder. Therefore, how to effectively match the indicators measured in animals with those measured in genetic research or the development of new antidepressants is another important challenge.

Change history

17 may 2021.

A Correction to this paper has been published: https://doi.org/10.1007/s12264-021-00694-9

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Acknowledgments

This review was supported by the National Basic Research Development Program of China (2016YFC1307100), the National Natural Science Foundation of China (81930033 and 81771465; 81401127), Shanghai Key Project of Science & Technology (2018SHZDZX05), Shanghai Jiao Tong University Medical Engineering Foundation (YG2016MS48), Shanghai Jiao Tong University School of Medicine (19XJ11006), the Sanming Project of Medicine in Shenzhen Municipality (SZSM201612006), the National Key Technologies R&D Program of China (2012BAI01B04), and the Innovative Research Team of High-level Local Universities in Shanghai.

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Zezhi Li, Jun Chen & Yiru Fang

Department of Neurology, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200127, China

Shanghai Institute of Nutrition and Health, Shanghai Information Center for Life Sciences, Chinese Academy of Science, Shanghai, 200031, China

Meihua Ruan

Center for Excellence in Brain Science and Intelligence Technology, Chinese Academy of Science, Shanghai, 200031, China

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Li, Z., Ruan, M., Chen, J. et al. Major Depressive Disorder: Advances in Neuroscience Research and Translational Applications. Neurosci. Bull. 37 , 863–880 (2021). https://doi.org/10.1007/s12264-021-00638-3

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Effect of exercise for depression: systematic review and network meta-analysis of randomised controlled trials

Linked editorial.

Exercise for the treatment of depression

  • Related content
  • Peer review
  • Michael Noetel , senior lecturer 1 ,
  • Taren Sanders , senior research fellow 2 ,
  • Daniel Gallardo-Gómez , doctoral student 3 ,
  • Paul Taylor , deputy head of school 4 ,
  • Borja del Pozo Cruz , associate professor 5 6 ,
  • Daniel van den Hoek , senior lecturer 7 ,
  • Jordan J Smith , senior lecturer 8 ,
  • John Mahoney , senior lecturer 9 ,
  • Jemima Spathis , senior lecturer 9 ,
  • Mark Moresi , lecturer 4 ,
  • Rebecca Pagano , senior lecturer 10 ,
  • Lisa Pagano , postdoctoral fellow 11 ,
  • Roberta Vasconcellos , doctoral student 2 ,
  • Hugh Arnott , masters student 2 ,
  • Benjamin Varley , doctoral student 12 ,
  • Philip Parker , pro vice chancellor research 13 ,
  • Stuart Biddle , professor 14 15 ,
  • Chris Lonsdale , deputy provost 13
  • 1 School of Psychology, University of Queensland, St Lucia, QLD 4072, Australia
  • 2 Institute for Positive Psychology and Education, Australian Catholic University, North Sydney, NSW, Australia
  • 3 Department of Physical Education and Sport, University of Seville, Seville, Spain
  • 4 School of Health and Behavioural Sciences, Australian Catholic University, Strathfield, NSW, Australia
  • 5 Department of Clinical Biomechanics and Sports Science, University of Southern Denmark, Odense, Denmark
  • 6 Biomedical Research and Innovation Institute of Cádiz (INiBICA) Research Unit, University of Cádiz, Spain
  • 7 School of Health and Behavioural Sciences, University of the Sunshine Coast, Petrie, QLD, Australia
  • 8 School of Education, University of Newcastle, Callaghan, NSW, Australia
  • 9 School of Health and Behavioural Sciences, Australian Catholic University, Banyo, QLD, Australia
  • 10 School of Education, Australian Catholic University, Strathfield, NSW, Australia
  • 11 Australian Institute of Health Innovation, Macquarie University, Macquarie Park, NSW, Australia
  • 12 Children’s Hospital Westmead Clinical School, University of Sydney, Westmead, NSW, Australia
  • 13 Australian Catholic University, North Sydney, NSW, Australia
  • 14 Centre for Health Research, University of Southern Queensland, Springfield, QLD, Australia
  • 15 Faculty of Sport and Health Science, University of Jyvaskyla, Jyvaskyla, Finland
  • Correspondence to: M Noetel m.noetel{at}uq.edu.au (or @mnoetel on Twitter)
  • Accepted 15 January 2024

Objective To identify the optimal dose and modality of exercise for treating major depressive disorder, compared with psychotherapy, antidepressants, and control conditions.

Design Systematic review and network meta-analysis.

Methods Screening, data extraction, coding, and risk of bias assessment were performed independently and in duplicate. Bayesian arm based, multilevel network meta-analyses were performed for the primary analyses. Quality of the evidence for each arm was graded using the confidence in network meta-analysis (CINeMA) online tool.

Data sources Cochrane Library, Medline, Embase, SPORTDiscus, and PsycINFO databases.

Eligibility criteria for selecting studies Any randomised trial with exercise arms for participants meeting clinical cut-offs for major depression.

Results 218 unique studies with a total of 495 arms and 14 170 participants were included. Compared with active controls (eg, usual care, placebo tablet), moderate reductions in depression were found for walking or jogging (n=1210, κ=51, Hedges’ g −0.62, 95% credible interval −0.80 to −0.45), yoga (n=1047, κ=33, g −0.55, −0.73 to −0.36), strength training (n=643, κ=22, g −0.49, −0.69 to −0.29), mixed aerobic exercises (n=1286, κ=51, g −0.43, −0.61 to −0.24), and tai chi or qigong (n=343, κ=12, g −0.42, −0.65 to −0.21). The effects of exercise were proportional to the intensity prescribed. Strength training and yoga appeared to be the most acceptable modalities. Results appeared robust to publication bias, but only one study met the Cochrane criteria for low risk of bias. As a result, confidence in accordance with CINeMA was low for walking or jogging and very low for other treatments.

Conclusions Exercise is an effective treatment for depression, with walking or jogging, yoga, and strength training more effective than other exercises, particularly when intense. Yoga and strength training were well tolerated compared with other treatments. Exercise appeared equally effective for people with and without comorbidities and with different baseline levels of depression. To mitigate expectancy effects, future studies could aim to blind participants and staff. These forms of exercise could be considered alongside psychotherapy and antidepressants as core treatments for depression.

Systematic review registration PROSPERO CRD42018118040.

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Introduction

Major depressive disorder is a leading cause of disability worldwide 1 and has been found to lower life satisfaction more than debt, divorce, and diabetes 2 and to exacerbate comorbidities, including heart disease, 3 anxiety, 4 and cancer. 5 Although people with major depressive disorder often respond well to drug treatments and psychotherapy, 6 7 many are resistant to treatment. 8 In addition, access to treatment for many people with depression is limited, with only 51% treatment coverage for high income countries and 20% for low and lower-middle income countries. 9 More evidence based treatments are therefore needed.

Exercise may be an effective complement or alternative to drugs and psychotherapy. 10 11 12 13 14 In addition to mental health benefits, exercise also improves a range of physical and cognitive outcomes. 15 16 17 Clinical practice guidelines in the US, UK, and Australia recommend physical activity as part of treatment for depression. 18 19 20 21 But these guidelines do not provide clear, consistent recommendations about dose or exercise modality. British guidelines recommend group exercise programmes 20 21 and offer general recommendations to increase any form of physical activity, 21 the American Psychiatric Association recommends any dose of aerobic exercise or resistance training, 20 and Australian and New Zealand guidelines suggest a combination of strength and vigorous aerobic exercises, with at least two or three bouts weekly. 19

Authors of guidelines may find it hard to provide consistent recommendations on the basis of existing mainly pairwise meta-analyses—that is, assessing a specific modality versus a specific comparator in a distinct group of participants. 12 13 22 These meta-analyses have come under scrutiny for pooling heterogeneous treatments and heterogenous comparisons leading to ambiguous effect estimates. 23 Reviews also face the opposite problem, excluding exercise treatments such as yoga, tai chi, and qigong because grouping them with strength training might be inappropriate. 23 Overviews of reviews have tried to deal with this problem by combining pairwise meta-analyses on individual treatments. A recent such overview found no differences between exercise modalities. 13 Comparing effect sizes between different pairwise meta-analyses can also lead to confusion because of differences in analytical methods used between meta-analysis, such as choice of a control to use as the referent. Network meta-analyses are a better way to precisely quantify differences between interventions as they simultaneously model the direct and indirect comparisons between interventions. 24

Network meta-analyses have been used to compare different types of psychotherapy and pharmacotherapy for depression. 6 25 26 For exercise, they have shown that dose and modality influence outcomes for cognition, 16 back pain, 15 and blood pressure. 17 Two network meta-analyses explored the effects of exercise on depression: one among older adults 27 and the other for mental health conditions. 28 Because of the inclusion criteria and search strategies used, these reviews might have been under-powered to explore moderators such as dose and modality (κ=15 and κ=71, respectively). To resolve conflicting findings in existing reviews, we comprehensively searched randomised trials on exercise for depression to ensure our review was adequately powered to identify the optimal dose and modality of exercise. For example, a large overview of reviews found effects on depression to be proportional to intensity, with vigorous exercise appearing to be better, 13 but a later meta-analysis found no such effects. 22 We explored whether recommendations differ based on participants’ sex, age, and baseline level of depression.

Given the challenges presented by behaviour change in people with depression, 29 we also identified autonomy support or behaviour change techniques that might improve the effects of intervention. 30 Behaviour change techniques such as self-monitoring and action planning have been shown to influence the effects of physical activity interventions in adults (>18 years) 31 and older adults (>60 years) 32 with differing effectiveness of techniques in different populations. We therefore tested whether any intervention components from the behaviour change technique taxonomy were associated with higher or lower intervention effects. 30 Other meta-analyses found that physical activity interventions work better when they provide people with autonomy (eg, choices, invitational language). 33 Autonomy is not well captured in the taxonomy for behaviour change technique. We therefore tested whether effects were stronger in studies that provided more autonomy support to patients. Finally, to understand the mechanism of intervention effects, such as self-confidence, affect, and physical fitness, we collated all studies that conducted formal mediation analyses.

Our findings are presented according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses-Network Meta-analyses (PRISMA-NMA) guidelines (see supplementary file, section S0; all supplementary files, data, and code are also available at https://osf.io/nzw6u/ ). 34 We amended our analysis strategy after registering our review; these changes were to better align with new norms established by the Cochrane Comparing Multiple Interventions Methods Group. 35 These norms were introduced between the publication of our protocol and the preparation of this manuscript. The largest change was using the confidence in network meta-analysis (CINeMA) 35 online tool instead of the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) guidelines and adopting methods to facilitate assessments—for example, instead of using an omnibus test for all treatments, we assessed publication bias for each treatment compared with active controls. We also modelled acceptability (through dropout rate), which was not predefined but was adopted in response to a reviewer’s comment.

Eligibility criteria

To be eligible for inclusion, studies had to be randomised controlled trials that included exercise as a treatment for depression and included participants who met the criteria for major depressive disorder, either clinician diagnosed or identified through participant self-report as exceeding established clinical thresholds (eg, scored >13 on the Beck depression inventory-II). 36 Studies could meet these criteria when all the participants had depression or when the study reported depression outcomes for a subgroup of participants with depression at the start of the study.

We defined exercise as “planned, structured and repetitive bodily movement done to improve or maintain one or more components of physical fitness.” 37 Unlike recent reviews, 12 22 we included studies with more than one exercise arm and multifaceted interventions (eg, health and exercise counselling) as long as they contained a substantial exercise component. These trials could be included because network meta-analysis methods allows for the grouping of those interventions into homogenous nodes. Unlike the most recent Cochrane review, 12 we also included participants with physical comorbidities such as arthritis and participants with postpartum depression because the Diagnostic Statistical Manual of Mental Health Disorders , fifth edition, removed the postpartum onset specifier after that analysis was completed. 23 Studies were excluded if interventions were shorter than one week, depression was not reported as an outcome, and data were insufficient to calculate an effect size for each arm. Any comparison condition was included, allowing us to quantify the effects against established treatments (eg, selective serotonin reuptake inhibitors (SSRIs), cognitive behavioural therapy), active control conditions (usual care, placebo tablet, stretching, educational control, and social support), or waitlist control conditions. Published and unpublished studies were included, with no restrictions on language applied.

Information sources

We adapted the search strategy from the most recent Cochrane review, 12 adding keywords for yoga, tai chi, and qigong, as they met our definition for exercise. We conducted database searches, without filters or date limits, in The Cochrane Library via CENTRAL, SPORTDiscus via Embase, and Medline, Embase, and PsycINFO via Ovid. Searches of the databases were conducted on 17 December 2018 and 7 August 2020 and last updated on 3 June 2023 (see supplementary file section S1 for full search strategies). We assessed full texts of all included studies from two systematic reviews of exercise for depression. 12 22

Study selection and data collection

To select studies, we removed duplicate records in Covidence 38 and then screened each title and abstract independently and in duplicate. Conflicts were resolved through discussion or consultation with a third reviewer. The same methods were used for full text screening.

We used the Extraction 1.0 randomised controlled trial data extraction forms in Covidence. 38 Data were extracted independently and in duplicate, with conflicts resolved through discussion with a third reviewer.

For each study, we extracted a description of the interventions, including frequency, intensity, and type and time of each exercise intervention. Using the Compendium of Physical Activities, 39 we calculated the energy expenditure dose of exercise for each arm as metabolic equivalents of task (METs) min/week. Two authors evaluated each exercise intervention using the Behaviour Change Taxonomy version 1 30 for behaviour change techniques explicitly described in each exercise arm. They also rated the level of autonomy offered to participants, on a scale from 1 (no choice) to 10 (full autonomy). We also extracted descriptions of the other arms within the randomised trials, including other treatment or control conditions; participants’ age, sex, comorbidities, and baseline severity of depressive symptoms; and each trial’s location and whether or not the trial was funded.

Risk of bias in individual studies

We used Cochrane’s risk of bias tool for randomised controlled trials. 40 Risk of bias was rated independently and in duplicate, with conflicts resolved through discussion with a third reviewer.

Summary measures and synthesis

For main and moderation analyses, we used bayesian arm based multilevel network meta-analysis models. 41 All network meta-analytical approaches allow users to assess the effects of treatments against a range of comparisons. The bayesian arm based models allowed us to also assess the influence of hypothesised moderators, such as intensity, dose, age, and sex. Many network meta-analyses use contrast based methods, comparing post-test scores between study arms. 41 Arm based meta-analyses instead describe the population-averaged absolute effect size for each treatment arm (ie, each arm’s change score). 41 As a result, the summary measure we used was the standardised mean change from baseline, calculated as standardised mean differences with correction for small studies (Hedges’ g). In keeping with the norms from the included studies, effect sizes describe treatment effects on depression, such that larger negative numbers represent stronger effects on symptoms. Using National Institute for Health and Care Excellence guidelines, 42 we standardised change scores for different depression scales (eg, Beck depression inventory, Hamilton depression rating scale) using an internal reference standard for each scale (for each scale, the average of pooled standard deviations at baseline) reported in our meta-analysis. Because depression scores generally show regression to the mean, even in control conditions, we present effect sizes as improvements beyond active control conditions. This convention makes our results comparable to existing, contrast based meta-analyses.

Active control conditions (usual care, placebo tablet, stretching, educational control, and social support) were grouped to increase power for moderation analyses, for parsimony in the network graph, and because they all showed similar arm based pooled effect sizes (Hedges’ g between −0.93 and −1.00 for all, with no statistically significant differences). We separated waitlist control from these active control conditions because it typically shows poorer effects in treatment for depression. 43

Bayesian meta-analyses were conducted in R 44 using the brms package. 45 We preregistered informative priors based on the distributional parameters of our meta-analytical model. 46 We nested effects within arms to manage dependency between multiple effect sizes from the same participants. 46 For example, if one study reported two self-reported measures of depression, or reported both self-report and clinician rated depression, we nested these effect sizes within the arm to account for both pieces of information while controlling for dependency between effects. 46 Finally, we compared absolute effect sizes against a standardised minimum clinically important difference, 0.5 standard deviations of the change score. 47 From our data, this corresponded to a large change in before and after scores (Hedges’ g −1.16), a moderate change compared with waitlist control (g −0.55), or a small benefit when compared with active controls (g −0.20). For credibility assessments comparing exercise modalities, we used the netmeta package 48 and CINeMA. 49 We also used netmeta to model acceptability, comparing the odds ratio for drop-out rate in each arm.

Additional analyses

All prespecified moderation and sensitivity analyses were performed. We moderated for participant characteristics, including participants’ sex, age, baseline symptom severity, and presence or absence of comorbidities; duration of the intervention (weeks); weekly dose of the intervention; duration between completion of treatment and measurement, to test robustness to remission (in response to a reviewer’s suggestion); amount of autonomy provided in the exercise prescription; and presence of each behaviour change technique. As preregistered, we moderated for behaviour change techniques in three ways: through meta-regression, including all behaviour change techniques simultaneously for primary analysis; including one behaviour change technique at a time (using 99% credible intervals to somewhat control for multiple comparisons) in exploratory analyses; and through meta-analytical classification and regression trees (metaCART), which allowed for interactions between moderating variables (eg, if goal setting combined with feedback had synergistic effects). 50 We conducted sensitivity analyses for risk of bias, assessing whether studies with low versus unclear or high risk of bias on each domain showed statistically significant differences in effect sizes.

Credibility assessment

To assess the credibility of each comparison against active control, we used CINeMA. 35 49 This online tool was designed by the Cochrane Comparing Multiple Interventions Methods Group as an adaptation of GRADE for network meta-analyses. 35 In line with recommended guidelines, for each comparison we made judgements for within study bias, reporting bias, indirectness, imprecision, heterogeneity, and incoherence. Similar to GRADE, we considered the evidence for comparisons to show high confidence then downgraded on the basis of concerns in each domain, as follows:

Within study bias —Comparisons were downgraded when most of the studies providing direct evidence for comparisons were unclear or high risk.

Reporting bias —Publication bias was assessed in three ways. For each comparison with at least 10 studies 51 we created funnel plots, including estimates of effect sizes after removing studies with statistically significant findings (ie, worst case estimates) 52 ; calculated an s value, representing how strong publication bias would need to be to nullify meta-analytical effects 52 ; and conducted a multilevel Egger’s regression test, indicative of small study bias. Given these tests are not recommended for comparisons with fewer than 10 studies, 51 those comparisons were considered to show “some concerns.”

Indirectness — Our primary population of interest was adults with major depression. Studies were considered to be indirect if they focused on one sex only (>90% male or female), participants with comorbidities (eg, heart disease), adolescents and young adults (14-20 years), or older adults (>60 years). We flagged these studies as showing some concerns if one of these factors was present, and as “major concerns” if two of these factors were present. Evidence from comparisons was classified as some concerns or major concerns using majority rating for studies directly informing the comparison.

Imprecision — As per CINeMA, we used the clinically important difference of Hedges’ g=0.2 to ascribe a zone of equivalence, where differences were not considered clinically significant (−0.2<g<0.2). Studies were flagged as some concerns for imprecision if the bounds of the 95% credible interval extended across that zone, and they were flagged as major concerns if the bounds extended to the other side of the zone of equivalence (such that effects could be harmful).

Heterogeneity — Prediction intervals account for heterogeneity differently from credible intervals. 35 As a result, CINeMA accounts for heterogeneity by assessing whether the prediction intervals and the credible intervals lead to different conclusions about clinical significance (using the same zone of equivalence from imprecision). Comparisons are flagged as some concerns if the prediction interval crosses into, or out of, the zone of equivalence once (eg, from helpful to no meaningful effect), and as major concerns if the prediction interval crosses the zone twice (eg, from helpful and harmful).

Incoherence — Incoherence assesses whether the network meta-analysis provides similar estimates when using direct evidence (eg, randomised controlled trials on strength training versus SSRI) compared with indirect evidence (eg, randomised controlled trials where either strength training or SSRI uses waitlist control). Incoherence provides some evidence the network may violate the assumption of transitivity: that the only systematic difference between arms is the treatment, not other confounders. We assessed incoherence using two methods: Firstly, a global design-by-treatment interaction to assess for incoherence across the whole network, 35 49 and, secondly, separating indirect and direct evidence (SIDE method) for each comparison through netsplitting to see whether differences between those effect estimates were statistically significant. We flagged comparisons as some concerns if either no direct comparisons were available or direct and indirect evidence gave different conclusions about clinical significance (eg, from helpful to no meaningful effect, as per imprecision and heterogeneity). Again, we classified comparisons as major concerns if the direct and indirect evidence changed the sign of the effect or changed both limits of the credible interval. 35 49

Patient and public involvement

We discussed the aims and design of this study with members of the public, including those who had experienced depression. Several of our authors have experienced major depressive episodes, but beyond that we did not include patients in the conduct of this review.

Study selection

The PRISMA flow diagram outlines the study selection process ( fig 1 ). We used two previous reviews to identify potentially eligible studies for inclusion. 12 22 Database searches identified 18 658 possible studies. After 5505 duplicates had been removed, two reviewers independently screened 13 115 titles and abstracts. After screening, two reviewers independently reviewed 1738 full text articles. Supplementary file section S2 shows the consensus reasons for exclusion. A total of 218 unique studies described in 246 reports were included, totalling 495 arms and 14 170 participants. Supplementary file section S3 lists the references and characteristics of the included studies.

Fig 1

Flow of studies through review

Network geometry

As preregistered, we removed nodes with fewer than 100 participants. Using this filter, most interventions contained comparisons with at least four other nodes in the network geometry ( fig 2 ). The results of the global test design-by-treatment interaction model were not statistically significant, supporting the assumption of transitivity (χ 2 =94.92, df=75, P=0.06). When net-splitting was used on all possible combinations in the network, for two out of the 120 comparisons we found statistically significant incoherence between direct and indirect evidence (SSRI v waitlist control; cognitive behavioural therapy v tai chi or qigong). Overall, we found little statistical evidence that the model violated the assumption of transitivity. Qualitative differences were, however, found for participant characteristics between different arms (see supplementary file, section S4). For example, some interventions appeared to be prescribed more frequently among people with severe depression (eg, 7/16 studies using SSRIs) compared with other interventions (eg, 1/15 studies using aerobic exercise combined with therapy). Similarly, some interventions appeared more likely to be prescribed for older adults (eg, mean age, tai chi=59 v dance=31) or women (eg, per cent female: dance=88% v cycling=53%). Given that plausible mechanisms exist for these systematic differences (eg, the popularity of tai chi among older adults), 53 there are reasons to believe that allocation to treatment arms would be less than perfectly random. We have factored these biases in our certainty estimates through indirectness ratings.

Fig 2

Network geometry indicating number of participants in each arm (size of points) and number of comparisons between arms (thickness of lines). SSRI=selective serotonin reuptake inhibitor

Risk of bias within studies

Supplementary file section S5 provides the risk of bias ratings for each study. Few studies explicitly blinded participants and staff ( fig 3 ). As a result, overall risk of bias for most studies was unclear or high, and effect sizes could include expectancy effects, among other biases. However, sensitivity analyses suggested that effect sizes were not influenced by any risk of bias criteria owing to wide credible intervals (see supplementary file, section S6). Nevertheless, certainty ratings for all treatments arms were downgraded owing to high risk of bias in the studies informing the comparison.

Fig 3

Risk of bias summary plot showing percentage of included studies judged to be low, unclear, or high risk across Cochrane criteria for randomised trials

Synthesis of results

Supplementary file section S7 presents a forest plot of Hedges’ g values for each study. Figure 4 shows the predicted effects of each treatment compared with active controls. Compared with active controls, large reductions in depression were found for dance (n=107, κ=5, Hedges’ g −0.96, 95% credible interval −1.36 to −0.56) and moderate reductions for walking or jogging (n=1210, κ=51, g −0.63, −0.80 to −0.46), yoga (n=1047, κ=33, g=−0.55, −0.73 to −0.36), strength training (n=643, κ=22, g=−0.49, −0.69 to −0.29), mixed aerobic exercises (n=1286, κ=51, g=−0.43, −0.61 to −0.25), and tai chi or qigong (n=343, κ=12, g=−0.42, −0.65 to −0.21). Moderate, clinically meaningful effects were also present when exercise was combined with SSRIs (n=268, κ=11, g=−0.55, −0.86 to −0.23) or aerobic exercise was combined with psychotherapy (n=404, κ=15, g=−0.54, −0.76 to −0.32). All these treatments were significantly stronger than the standardised minimum clinically important difference compared with active control (g=−0.20), equating to an absolute g value of −1.16. Dance, exercise combined with SSRIs, and walking or jogging were the treatments most likely to perform best when modelling the surface under the cumulative ranking curve ( fig 4 ). For acceptability, the odds of participants dropping out of the study were lower for strength training (n=247, direct evidence κ=6, odds ratio 0.55, 95% credible interval 0.31 to 0.99) and yoga (n=264, κ=5, 0.57, 0.35 to 0.94) than for active control. The rate of dropouts was not significantly different from active control in any other arms (see supplementary file, section S8).

Fig 4

Predicted effects of different exercise modalities on major depression compared with active controls (eg, usual care), with 95% credible intervals. The estimate of effects for the active control condition was a before and after change of Hedges’ g of −0.95 (95% credible interval −1.10 to −0.79), n=3554, κ =113. Colour represents SUCRA from most likely to be helpful (dark purple) to least likely to be helpful (light purple). SSRI=selective serotonin reuptake inhibitor; SUCRA=surface under the cumulative ranking curve

Consistent with other meta-analyses, effects were moderate for cognitive behaviour therapy alone (n=712, κ=20, g=−0.55, −0.75 to −0.37) and small for SSRIs (n=432, κ=16, g=−0.26, −0.50 to −0.01) compared with active controls ( fig 4 ). These estimates are comparable to those of reviews that focused directly on psychotherapy (g=−0.67, −0.79 to −0.56) 7 or pharmacotherapy (g=−0.30, –0.34 to −0.26). 25 However, our review was not designed to find all studies of these treatments, so these estimates should not usurp these directly focused systematic reviews.

Despite the large number of studies in the network, confidence in the effects were low ( fig 5 ). This was largely due to the high within study bias described in the risk of bias summary plot. Reporting bias was also difficult to robustly assess because direct comparison with active control was often only provided in fewer than 10 studies. Many studies focused on one sex only, older adults, or those with comorbidities, so most arms had some concerns about indirect comparisons. Credible intervals were seldom wide enough to change decision making, so concerns about imprecision were few. Heterogeneity did plausibly change some conclusions around clinical significance. Few studies showed problematic incoherence, meaning direct and indirect evidence usually agreed. Overall, walking or jogging had low confidence, with other modalities being very low.

Fig 5

Summary table for credibility assessment using confidence in network meta-analysis (CINeMA). SSRI=selective serotonin reuptake inhibitor

Moderation by participant characteristics

The optimal modality appeared to be moderated by age and sex. Compared with models that only included exercise modality (R 2 =0.65), R 2 was higher for models that included interactions with sex (R 2 =0.71) and age (R 2 =0.69). R 2 showed no substantial increase for models including baseline depression (R 2 =0.67) or comorbidities (R 2 =0.66; see supplementary file, section S9).

Effects appeared larger for women than men for strength training and cycling ( fig 6 ). Effects appeared to be larger for men than women when prescribing yoga, tai chi, and aerobic exercise alongside psychotherapy. Yoga and aerobic exercise alongside psychotherapy appeared more effective for older participants than younger people ( fig 7 ). Strength training appeared more effective when prescribed to younger participants than older participants. Some estimates were associated with substantial uncertainty because some modalities were not well studied in some groups (eg, tai chi for younger adults), and mean age of the sample was only available for 71% of the studies.

Fig 6

Effects of interventions versus active control on depression (lower is better) by sex. Shading represents 95% credible intervals

Fig 7

Effects of interventions versus active control on depression (lower is better) by age. Shading represents 95% credible intervals

Moderation by intervention and design characteristics

Across modalities, a clear dose-response curve was observed for intensity of exercise prescribed ( fig 8 ). Although light physical activity (eg, walking, hatha yoga) still provided clinically meaningful effects (g=−0.58, −0.82 to −0.33), expected effects were stronger for vigorous exercise (eg, running, interval training; g=−0.74, −1.10 to −0.38). This finding did not appear to be due to increased weekly energy expenditure: credible intervals were wide, which meant that the dose-response curve for METs/min prescribed per week was unclear (see supplementary file, section S10). Weak evidence suggested that shorter interventions (eg, 10 weeks: g=−0.53, −0.71 to −0.35) worked somewhat better than longer ones (eg, 30 weeks: g=−0.37, −0.79 to 0.03), with wide credible intervals again indicating high uncertainty (see supplementary file, section S11). We also moderated for the lag between the end of treatment and the measurement of the outcome. We found no indication that participants were likely to relapse within the measurement period (see supplementary file, section S12); effects remained steady when measured either directly after the intervention (g=−0.59, −0.80 to −0.39) or up to six months later (g=−0.63, −0.87 to −0.40).

Fig 8

Dose-response curve for intensity (METs) across exercise modalities compared with active control. METs=metabolic equivalents of task

Supplementary file section S13 provides coding for the behaviour change techniques and autonomy for each exercise arm. None of the behaviour change techniques significantly moderated overall effects. Contrary to expectations, studies describing a level of participant autonomy (ie, choice over frequency, intensity, type, or time) tended to show weaker effects (g=−0.28, −0.78 to 0.23) than those that did not (g=−0.75, −1.17 to −0.33; see supplementary file, section S14). This effect was consistent whether or not we included studies that used physical activity counselling (usually high autonomy).

Use of group exercise appeared to moderate the effects: although the overall effects were similar for individual (g=−1.10, −1.57 to −0.64) and group exercise (g=−1.16, −1.61 to −0.73), some interventions were better delivered in groups (yoga) and some were better delivered individually (strength training, mixed aerobic exercise; see supplementary file, section S15).

As preregistered, we tested whether study funding moderated effects. Models that included whether a study was funded did explain more variance (R 2 =0.70) compared with models that included treatment alone (R 2 =0.65). Funded studies showed stronger effects (g=−1.01, −1.19 to −0.82) than unfunded studies (g=−0.77, −1.09 to −0.46). We also moderated for the type of measure (self-report v clinician report). This did not explain a substantial amount of variance in the outcome (R 2 =0.66).

Sensitivity analyses

Evidence of publication bias was found for overall estimates of exercise on depression compared with active controls, although not enough to nullify effects. The multilevel Egger’s test showed significance (F 1,98 =23.93, P<0.001). Funnel plots showed asymmetry, but the result of pooled effects remained statistically significant when only including non-significant studies (see supplementary file, section S16). No amount of publication bias would be sufficient to shrink effects to zero (s value=not possible). To reduce effects below clinical significance thresholds, studies with statistically significant results would need to be reported 58 times more frequently than studies with non-significant results.

Qualitative synthesis of mediation effects

Only a few of the studies used explicit mediation analyses to test hypothesised mechanisms of action. 54 55 56 57 58 59 One study found that both aerobic exercise and yoga led to decreased depression because participants ruminated less. 54 The study found that the effects of aerobic exercise (but not yoga) were mediated by increased acceptance. 54 “Perceived hassles” and awareness were not statistically significant mediators. 54 Another study found that the effects of yoga were mediated by increased self-compassion, but not rumination, self-criticism, tolerance of uncertainty, body awareness, body trust, mindfulness, and attentional biases. 55 One study found that the effects from an aerobic exercise intervention were not mediated by long term physical activity, but instead were mediated by exercise specific affect regulation (eg, self-control for exercise). 57 Another study found that neither exercise self-efficacy nor depression coping self-efficacy mediated effects of aerobic exercise. 56 Effects of aerobic exercise were not mediated by the N2 amplitude from electroencephalography, hypothesised as a neuro-correlate of cognitive control deficits. 58 Increased physical activity did not appear to mediate the effects of physical activity counselling on depression. 59 It is difficult to infer strong conclusions about mechanisms on the basis of this small number of studies with low power.

Summary of evidence

In this systematic review and meta-analysis of randomised controlled trials, exercise showed moderate effects on depression compared with active controls, either alone or in combination with other established treatments such as cognitive behaviour therapy. In isolation, the most effective exercise modalities were walking or jogging, yoga, strength training, and dancing. Although walking or jogging were effective for both men and women, strength training was more effective for women, and yoga or qigong was more effective for men. Yoga was somewhat more effective among older adults, and strength training was more effective among younger people. The benefits from exercise tended to be proportional to the intensity prescribed, with vigorous activity being better. Benefits were equally effective for different weekly doses, for people with different comorbidities, or for different baseline levels of depression. Although confidence in many of the results was low, treatment guidelines may be overly conservative by conditionally recommending exercise as complementary or alternative treatment for patients in whom psychotherapy or pharmacotherapy is either ineffective or unacceptable. 60 Instead, guidelines for depression ought to include prescriptions for exercise and consider adapting the modality to participants’ characteristics and recommending more vigorous intensity exercises.

Our review did not uncover clear causal mechanisms, but the trends in the data are useful for generating hypotheses. It is unlikely that any single causal mechanism explains all the findings in the review. Instead, we hypothesise that a combination of social interaction, 61 mindfulness or experiential acceptance, 62 increased self-efficacy, 33 immersion in green spaces, 63 neurobiological mechanisms, 64 and acute positive affect 65 combine to generate outcomes. Meta-analyses have found each of these factors to be associated with decreases in depressive symptoms, but no single treatment covers all mechanisms. Some may more directly promote mindfulness (eg, yoga), be more social (eg, group exercise), be conducted in green spaces (eg, walking), provide a more positive affect (eg, “runner’s high”’), or be more conducive to acute adaptations that may increase self-efficacy (eg, strength). 66 Exercise modalities such as running may satisfy many of the mechanisms, but they are unlikely to directly promote the mindful self-awareness provided by yoga and qigong. Both these forms of exercise are often practised in groups with explicit mindfulness but seldom have fast and objective feedback loops that improve self-efficacy. Adequately powered studies testing multiple mediators may help to focus more on understanding why exercise helps depression and less on whether exercise helps. We argue that understanding these mechanisms of action is important for personalising prescriptions and better understanding effective treatments.

Our review included more studies than many existing reviews on exercise for depression. 13 22 27 28 As a result, we were able to combine the strengths of various approaches to exercise and to make more nuanced and precise conclusions. For example, even taking conservative estimates (ie, the least favourable end of the credible interval), practitioners can expect patients to experience clinically significant effects from walking, running, yoga, qigong, strength training, and mixed aerobic exercise. Because we simultaneously assessed more than 200 studies, credible intervals were narrower than those in most existing meta-analyses. 13 We were also able to explore non-linear relationships between outcomes and moderators, such as frequency, intensity, and time. These analyses supported some existing findings—for example, our study and the study by Heissel et al 22 found that shorter interventions had stronger effects, at least for six months; our study and the study by Singh et al 13 both found that effects were stronger with vigorous intensity exercise compared with light and moderate exercise. However, most existing reviews found various treatment modalities to be equally effective. 13 27 In our review, some types of exercise had stronger effect sizes than others. We attribute this to the study level data available in a network meta-analysis compared with an overview of reviews 24 and higher power compared with meta-analyses with smaller numbers of included studies. 22 28 Overviews of reviews have the ability to more easily cover a wider range of participants, interventions, and outcomes, but also risk double counting randomised trials that are included in separate meta-analyses. They often include heterogeneous studies without having as much control over moderation analyses (eg, Singh et al included studies covering both prevention and treatment 13 ). Some of those reviews grouped interventions such as yoga with heterogeneous interventions such as stretching and qigong. 13 This practise of combining different interventions makes it harder to interpret meta-analytical estimates. We used methods that enabled us to separately analyse the effects of these treatment modalities. In so doing, we found that these interventions do have different effects, with yoga being an intervention with strong effects and stretching being better described as an active control condition. Network meta-analyses revealed the same phenomenon with psychotherapy: researchers once concluded there was a dodo bird verdict, whereby “everybody has won, and all must have prizes,” 67 until network meta-analyses showed some interventions were robustly more effective than others. 6 26

Predictors of acceptability and outcomes

We found evidence to suggest good acceptability of yoga and strength training; although the measurement of study drop-out is an imperfect proxy of adherence. Participants may complete the study without doing any exercise or may continue exercising and drop out of the study for other reasons. Nevertheless, these are useful data when considering adherence.

Behaviour change techniques, which are designed to increase adherence, did not meaningfully moderate the effect sizes from exercise. This may be due to several factors. It may be that the modality explains most of the variance between effects, such that behaviour change techniques (eg, presence or absence of feedback) did not provide a meaningful contribution. Many forms of exercise potentially contain therapeutic benefits beyond just energy expenditure. These characteristics of a modality may be more influential than coexisting behaviour change techniques. Alternatively, researchers may have used behaviour change techniques such as feedback or goal setting without explicitly reporting them in the study methods. Given the inherent challenges of behaviour change among people with depression, 29 and the difficulty in forecasting which strategies are likely to be effective, 68 we see the identification of effective techniques as important.

We did find that autonomy, as provided in the methods of included studies, predicted effects, but in the opposite direction to our hypotheses: more autonomy was associated with weaker effects. Physical activity counselling, which usually provides a great deal of patient autonomy, was among the lowest effect sizes in our meta-analysis. Higher autonomy judgements were associated with weaker outcomes regardless of whether physical activity counselling was included in the model. One explanation for these data is that people with depression benefit from the clear direction and accountability of a standardised prescription. When provided with more freedom, the low self-efficacy that is symptomatic of depression may stop patients from setting an appropriate level of challenge (eg, they may be less likely to choose vigorous exercise). Alternatively, participants were likely autonomous when self-selecting into trials with exercise modalities they enjoyed, or those that fit their social circumstances. After choosing something value aligned, autonomy within the trial may not have helpful. Either way, data should be interpreted with caution. Our judgement of the autonomy provided in the methods may not reflect how much autonomy support patients actually felt. The patient’s perceived autonomy is likely determined by a range of factors not described in the methods (eg, the social environment created by those delivering the programme, or their social identity), so other studies that rely on patient reports of the motivational climate are likely to be more reliable. 33 Our findings reiterate the importance of considering these patient reports in future research of exercise for depression.

Our findings suggest that practitioners could advocate for most patients to engage in exercise. Those patients may benefit from guidance on intensity (ie, vigorous) and types of exercise that appear to work well (eg, walking, running, mixed aerobic exercise, strength training, yoga, tai chi, qigong) and be well tolerated (eg, strength training and yoga). If social determinants permit, 66 engaging in group exercise or structured programmes could provide support and guidance to achieve better outcomes. Health services may consider offering these programmes as an alternative or adjuvant treatment for major depression. Specifically, although the confidence in the evidence for exercise is less strong than for cognitive behavioural therapy, the effect sizes seem comparable, so it may be an alternative for patients who prefer not to engage in psychotherapy. Previous reviews on those with mild-moderate depression have found similar effects for exercise or SSRIs, or the two combined. 13 14 In contrast, we found some forms of exercise to have stronger effects than SSRIs alone. Our findings are likely related to the larger power in our review (n=14 170) compared with previous reviews (eg, n=2551), 14 and our ability to better account for heterogeneity in exercise prescriptions. Exercise may therefore be considered a viable alternative to drug treatment. We also found evidence that exercise increases the effects of SSRIs, so offering exercise may act as an adjuvant for those already taking drugs. We agree with consensus statements that professionals should still account for patients’ values, preferences, and constraints, ensuring there is shared decision making around what best suits the patient. 66 Our review provides data to help inform that decision.

Strengths, limitations, and future directions

Based on our findings, dance appears to be a promising treatment for depression, with large effects found compared with other interventions in our review. But the small number of studies, low number of participants, and biases in the study designs prohibits us from recommending dance more strongly. Given most research for the intervention has been in young women (88% female participants, mean age 31 years), it is also important for future research to assess the generalisability of the effects to different populations, using robust experimental designs.

The studies we found may be subject to a range of experimental biases. In particular, researchers seldom blinded participants or staff delivering the intervention to the study’s hypotheses. Blinding for exercise interventions may be harder than for drugs 23 ; however, future studies could attempt to blind participants and staff to the study’s hypotheses to avoid expectancy effects. 69 Some of our ratings are for studies published before the proliferation of reporting checklists, so the ratings might be too critical. 23 For example, before CONSORT, few authors explicitly described how they generated a random sequence. 23 Therefore, our risk of bias judgements may be too conservative. Similarly, we planned to use the Cochrane risk of bias (RoB) 1 tool 40 so we could use the most recent Cochrane review of exercise and depression 12 to calibrate our raters, and because RoB 2 had not yet been published. 70 Although assessments of bias between the two tools are generally comparable, 71 the RoB 1 tool can be more conservative when assessing open label studies with subjective assessments (eg, unblinded studies with self-reported measures for depression). 71 As a result, future reviews should consider using the latest risk of bias tool, which may lead to different assessments of bias in included studies.

Most of the main findings in this review appear robust to risks from publication bias. Specifically, pooled effect sizes decreased when accounting for risk of publication bias, but no degree of publication bias could nullify effects. We did not exclude grey literature, but our search strategy was not designed to systematically search grey literature or trial registries. Doing so can detect additional eligible studies 72 and reveal the numbers of completed studies that remain unpublished. 73 Future reviews should consider more systematic searches for this kind of literature to better quantify and mitigate risk of publication bias.

Similarly, our review was able to integrate evidence that directly compared exercise with other treatment modalities such as SSRIs or psychotherapy, while also informing estimates using indirect evidence (eg, comparing the relative effects of strength training and SSRIs when tested against a waitlist control). Our review did not, however, include all possible sources of indirect evidence. Network meta-analyses exist that directly focus on psychotherapy 7 and pharmacotherapy, 25 and these combined for treating depression. 6 Those reviews include more than 500 studies comparing psychological or drug interventions with controls. Harmonising the findings of those reviews with ours would provide stronger data on indirect effects.

Our review found some interesting moderators by age and sex, but these were at the study level rather than individual level—that is, rather than being able to determine whether women engaging in a strength intervention benefit more than men, we could only conclude that studies with more women showed larger effects than studies with fewer women. These studies may have been tailored towards women, so effects may be subject to confounding, as both sex and intervention may have changed. The same finding applied to age, where studies on older adults were likely adapted specifically to this age group. These between study differences may explain the heterogeneity in the effects of interventions, and confounding means our moderators for age and sex should be interpreted cautiously. Future reviews should consider individual patient meta-analyses to allow for more detailed assessments of participant level moderators.

Finally, for many modalities, the evidence is derived from small trials (eg, the median number of walking or jogging arms was 17). In addition to reducing risks from bias, primary research may benefit from deconstruction designs or from larger, head-to-head analyses of exercise modalities to better identify what works best for each candidate.

Clinical and policy implications

Our findings support the inclusion of exercise as part of clinical practice guidelines for depression, particularly vigorous intensity exercise. Doing so may help bridge the gap in treatment coverage by increasing the range of first line options for patients and health systems. 9 Globally there has been an attempt to reduce stigma associated with seeking treatment for depression. 74 Exercise may support this effort by providing patients with treatment options that carry less stigma. In low resource or funding constrained settings, group exercise interventions may provide relatively low cost alternatives for patients with depression and for health systems. When possible, ideal treatment may involve individualised care with a multidisciplinary team, where exercise professionals could take responsibility for ensuring the prescription is safe, personalised, challenging, and supported. In addition, those delivering psychotherapy may want to direct some time towards tackling cognitive and behavioural barriers to exercise. Exercise professionals might need to be trained in the management of depression (eg, managing risk) and to be mindful of the scope of their practice while providing support to deal with this major cause of disability.

Conclusions

Depression imposes a considerable global burden. Many exercise modalities appear to be effective treatments, particularly walking or jogging, strength training, and yoga, but confidence in many of the findings was low. We found preliminary data that may help practitioners tailor interventions to individuals (eg, yoga for older men, strength training for younger women). The World Health Organization recommends physical activity for everyone, including those with chronic conditions and disabilities, 75 but not everyone can access treatment easily. Many patients may have physical, psychological, or social barriers to participation. Still, some interventions with few costs, side effects, or pragmatic barriers, such as walking and jogging, are effective across people with different personal characteristics, severity of depression, and comorbidities. Those who are able may want to choose more intense exercise in a structured environment to further decrease depression symptoms. Health systems may want to provide these treatments as alternatives or adjuvants to other established interventions (cognitive behaviour therapy, SSRIs), while also attenuating risks to physical health associated with depression. 3 Therefore, effective exercise modalities could be considered alongside those intervention as core treatments for depression.

What is already known on this topic

Depression is a leading cause of disability, and exercise is often recommended alongside first line treatments such as pharmacotherapy and psychotherapy

Treatment guidelines and previous reviews disagree on how to prescribe exercise to best treat depression

What this study adds

Various exercise modalities are effective (walking, jogging, mixed aerobic exercise, strength training, yoga, tai chi, qigong) and well tolerated (especially strength training and yoga)

Effects appeared proportional to the intensity of exercise prescribed and were stronger for group exercise and interventions with clear prescriptions

Preliminary evidence suggests interactions between types of exercise and patients’ personal characteristics

Ethics statements

Ethical approval.

Not required.

Acknowledgments

We thank Lachlan McKee for his assistance with data extraction. We also thank Juliette Grosvenor and another librarian (anonymous) for their review of our search strategy.

Contributors: MN led the project, drafted the manuscript, and is the guarantor. MN, TS, PT, MM, BdPC, PP, SB, and CL drafted the initial study protocol. MN, TS, PT, BdPC, DvdH, JS, MM, RP, LP, RV, HA, and BV conducted screening, extraction, and risk of bias assessment. MN, JS, and JM coded methods for behaviour change techniques. MN and DGG conducted statistical analyses. PP, SB, and CL provided supervision and mentorship. All authors reviewed and approved the final manuscript. The corresponding author attests that all listed authors meet authorship criteria and that no others meeting the criteria have been omitted.

Funding: None received.

Competing interests: All authors have completed the ICMJE uniform disclosure form at www.icmje.org/disclosure-of-interest/ and declare: no support from any organisation for the submitted work; no financial relationships with any organisations that might have an interest in the submitted work in the previous three years; no other relationships or activities that could appear to have influenced the submitted work.

Data sharing Data and code for reproducing analyses are available on the Open Science Framework ( https://osf.io/nzw6u/ ).

The lead author (MN) affirms that the manuscript is an honest, accurate, and transparent account of the study being reported; that no important aspects of the study have been omitted; and that any discrepancies from the study as planned (and, if relevant, registered) have been explained.

Dissemination to participants and related patient and public communities: We plan to disseminate the findings of this study to lay audiences through mainstream and social media.

Provenance and peer review: Not commissioned; externally peer reviewed.

This is an Open Access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/ .

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research studies on major depression

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Americans who live alone report depression at higher rates, but social support helps.

Rhitu Chatterjee

research studies on major depression

The number of people living alone in the U.S. went from nearly 5 million to about 38 million in a decade. A new study shows those who live alone report depression more than those who live with others. Yana Iskayeva/Getty Images hide caption

The number of people living alone in the U.S. went from nearly 5 million to about 38 million in a decade. A new study shows those who live alone report depression more than those who live with others.

People living alone are more likely to report feeling depressed compared to those living with others, according to a new study by the CDC's National Center for Health Statistics . And that effect is particularly stark for people living alone who say they have little or no social and emotional support.

"The most interesting takeaway from this study was the importance of feeling supported," says social scientist Kasley Killam , who wasn't involved in the new study. "And this is consistent with other evidence showing that social support and emotional support really play a pivotal role in people's overall health and well-being."

The new study comes at a time when the number of single person households in the U.S. has skyrocketed. In the decade from 2012 to 2022, the number of Americans living alone jumped by nearly 5 million to 37.9 million.

The study relies on 2021 data from the annual National Health Interview Survey , which interviews people in a nationally representative sample of households across the country. It found that a little over 6% of those living alone reported feelings of depression, compared to 4% of people living with others.

The good news about the findings, says author Laryssa Mykyta , is that the vast majority of people living alone didn't report adverse mental health symptoms. "Most adults who live alone – 93% – report either no feelings of depression or low feelings of depression," she says.

The survey also asked respondents about the levels of social and emotional support in their lives. "Respondents were asked, 'How often do you get the social and emotional support you need? Would you say always, usually, sometimes, rarely or never?'" says Mykyta.

Those who live alone and receive little or no social and emotional support were far more likely to report feelings of depression compared to people who live with others who also had little or no support. On the other hand, there were no differences in reports of depression between people living alone and those living with others if they had social and emotional support.

That finding is the "most compelling and most interesting," says Mykyta, because it shows the importance of social and emotional support in people's mood and wellbeing.

Social isolation and loneliness are increasingly being recognized as a public health problem. Studies have shown them to be linked to a higher risk of mental and physical illnesses.

How to combat loneliness

How to combat loneliness

"They're associated with a whole host of negative outcomes, including diabetes, depression –like we saw in this study – dementia, heart disease and even mortality," says Killam, who's the author of the upcoming book The Art and Science of Connection . "So they truly are risk factors for people's health and well-being."

In 2023, the U.S. Surgeon General Dr. Vivek Murthy released an advisory to raise awareness about loneliness and social isolation as a public health crisis. Murthy has also penned a book on the topic, titled Together .

In 'Together,' Former Surgeon General Writes About Importance Of Human Connection

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In 'together,' former surgeon general writes about importance of human connection.

"As health care providers, we need to be asking, is there someone there for you?" says psychiatrist Dr. Tom Insel , author of Healing: Our Path from Mental Illness to Mental Health . "And that's different from saying that you're living alone, because a lot of people who live alone have plenty of social support."

Asking that question, he says, will allow healthcare professionals to help address their patients' social isolation.

"You know, we can help people to find community," he says. "We can make sure we can prescribe social interaction. We can prescribe ways for people to actually become more engaged and to get the kind of social-emotional support they need."

Correction Feb. 15, 2024

The audio version of this story and an earlier digital version overstate how quickly the number of single-person households in the U.S. is growing. The number grew by 4.8 million to reach nearly 38 million. It did not jump from 4.8 million to 37.9 million in a decade.

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StatPearls [Internet].

Major depressive disorder.

Navneet Bains ; Sara Abdijadid .

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Last Update: April 10, 2023 .

  • Continuing Education Activity

Major depressive disorder (MDD) has been ranked as the third cause of the burden of disease worldwide in 2008 by WHO, which has projected that this disease will rank first by 2030. It is diagnosed when an individual has a persistently low or depressed mood, anhedonia or decreased interest in pleasurable activities, feelings of guilt or worthlessness, lack of energy, poor concentration, appetite changes, psychomotor retardation or agitation, sleep disturbances, or suicidal thoughts. This activity reviews the evaluation and management of major depressive disorder which is one of the main causes of disability in the world and highlights the role of the interprofessional team.

  • Identify the etiology of major depressive disorder.
  • Review the appropriate management of major depressive disorder.
  • Outline the typical presentation of a patient with major depressive disorder.
  • Review the importance of improving care coordination among interprofessional team members to improve outcomes for patients affected by major depressive disorder.
  • Introduction

Major depressive disorder (MDD) has been ranked as the third cause of the burden of disease worldwide in 2008 by WHO, which has projected that this disease will rank first by 2030. [1] It is diagnosed when an individual has a persistently low or depressed mood, anhedonia or decreased interest in pleasurable activities, feelings of guilt or worthlessness, lack of energy, poor concentration, appetite changes, psychomotor retardation or agitation, sleep disturbances, or suicidal thoughts. Per the Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-5), an individual must have five of the above-mentioned symptoms, of which one must be a depressed mood or anhedonia causing social or occupational impairment, to be diagnosed with MDD. History of a manic or hypomanic episode must be ruled out to make a diagnosis of MDD. Children and adolescents with MDD may present with irritable mood.

Per DSM-5, other types of depression falling under the category of depressive disorders are:

  • Persistent depressive disorder, formerly known as dysthymia
  • Disruptive mood dysregulation disorder 
  • Premenstrual dysphoric disorder
  • Substance/medication-induced depressive disorder
  • Depressive disorder due to another medical condition
  • Unspecified depressive disorder

The etiology of Major depressive disorder is believed to be multifactorial, including biological, genetic, environmental, and psychosocial factors. MDD was earlier considered to be mainly due to abnormalities in neurotransmitters, especially serotonin, norepinephrine, and dopamine. This has been evidenced by the use of different antidepressants such as selective serotonin receptor inhibitors, serotonin-norepinephrine receptor inhibitors, dopamine-norepinephrine receptor inhibitors in the treatment of depression. People with suicidal ideations have been found to have low levels of serotonin metabolites. However, recent theories indicate that it is associated primarily with more complex neuroregulatory systems and neural circuits, causing secondary disturbances of neurotransmitter systems.

GABA, an inhibitory neurotransmitter, and glutamate and glycine, both of which are major excitatory neurotransmitters are found to play a role in the etiology of depression as well. Depressed patients have been found to have lower plasma, CSF, and brain GABA levels. GABA is considered to exert its antidepressant effect by inhibiting the ascending monoamine pathways, including mesocortical and mesolimbic systems. Drugs that antagonize NMDA receptors have been researched to have antidepressant properties. Thyroid and growth hormonal abnormalities have also been implicated in the etiology of mood disorders. Multiple adverse childhood experiences and trauma are associated with the development of depression later in life. [2] [3]

Severe early stress can result in drastic alterations in neuroendocrine and behavioral responses, which can cause structural changes in the cerebral cortex, leading to severe depression later in life. Structural and functional brain imaging of depressed individuals has shown increased hyperintensities in the subcortical regions, and reduced anterior brain metabolism on the left side, respectively. Family, adoption, and twin studies have indicated the role of genes in the susceptibility of depression. Genetic studies show a very high concordance rate for twins to have MDD, particularly monozygotic twins. [4]  Life events and personality traits have shown to play an important role, as well. The learned helplessness theory has associated the occurrence of depression with the experience of uncontrollable events. Per cognitive theory, depression occurs as a result of cognitive distortions in persons who are susceptible to depression.

  • Epidemiology

Major depressive disorder is a highly prevalent psychiatric disorder. It has a lifetime prevalence of about 5 to 17 percent, with the average being 12 percent. The prevalence rate is almost double in women than in men. [5]  This difference has been considered to be due to the hormonal differences, childbirth effects, different psychosocial stressors in men and women, and behavioral model of learned helplessness. Though the mean age of onset is about 40 years, recent surveys show trends of increasing incidence in younger population due to the use of alcohol and other drugs of abuse.

MDD is more common in people without close interpersonal relationships, and who are divorced or separated, or widowed. No difference in the prevalence of MDD has been found among races and socioeconomic status. Individuals with MDD often have comorbid disorders such as substance use disorders, panic disorder, social anxiety disorder, and obsessive-compulsive disorder. The presence of these comorbid disorders in those diagnosed with MDD increases their risk of suicide. In older adults, depression is prevalent among those with comorbid medical illnesses. [6]  Depression is found to be more prevalent in rural areas than in urban areas. 

  • History and Physical

Major depressive disorder is a clinical diagnosis; it is mainly diagnosed by the clinical history given by the patient and mental status examination. The clinical interview must include medical history, family history, social history, and substance use history along with the symptomatology. Collateral information from a patient's family/friends is a very important part of psychiatric evaluation.

A complete physical examination, including neurological examination, should be performed. It is important to rule out any underlying medical/organic causes of a depressive disorder. A full medical history, along with the family medical and psychiatric history, should be assessed. Mental status examination plays an important role in the diagnosis and evaluation of MDD. 

Although there is no objective testing available to diagnose depression, routine laboratory work including complete blood account with differential, comprehensive metabolic panel, thyroid-stimulating hormone, free T4, vitamin D, urinalysis, and toxicology screening is done to rule out organic or medical causes of depression.

Individuals with depression often present to their primary care physicians for somatic complaints stemming from depression, rather than seeing a mental health professional. In almost half of the cases, patients deny having depressive feelings, and they are often brought for treatment by the family or sent by the employer to be evaluated for social withdrawal and decreased activity. It is very important to evaluate a patient for suicidal or homicidal ideations at each visit.

In primary care settings, the Patient Health Questionnaire-9 (PHQ-9), which is a self-report, standardized depression rating scale is commonly used for screening, diagnosing, and monitoring treatment response for MDD. [7]  The PHQ-9 uses 9 items corresponding to the DSM-5 criteria for MDD and also assesses for psychosocial impairment. The PHQ-9 scores 0 to 27, with scores of equal to or more than 10, indicate a possible MDD.

In most hospital settings, the Hamilton Rating Scale for Depression (HAM-D), which is a clinician-administered depression rating scale is commonly used for the assessment of depression. The original HAM-D uses 21 items about symptoms of depression, but the scoring is based only on the first 17 items.

Other scales include the Montgomery-Asberg Depression Rating Scale (MADRS), the Beck Depression Inventory (BDI), the Zung Self-Rating Depression Scale, the Raskin Depression Rating Scale, and other questionnaires.

  • Treatment / Management

Major depressive disorder can be managed with various treatment modalities, including pharmacological, psychotherapeutic, interventional, and lifestyle modification. The initial treatment of MDD includes medications or/and psychotherapy. Combination treatment, including both medications and psychotherapy, has been found to be more effective than either of these treatments alone. [8] [9]  Electroconvulsive therapy is found to be more efficacious than any other form of treatment for severe major depression. [10]

FDA-approved medications for the treatment of MDD are as follows:  All antidepressants are equally effective but differ in side-effect profiles.

  • Selective serotonin reuptake inhibitors (SSRIs) include fluoxetine, sertraline, citalopram, escitalopram, paroxetine, and fluvoxamine. They are usually the first line of treatment and the most widely prescribed antidepressants.
  • Serotonin-norepinephrine reuptake inhibitors (SNRIs) include venlafaxine, duloxetine, desvenlafaxine, levomilnacipran, and milnacipran. They are often used for depressed patients with comorbid pain disorders.
  • Serotonin modulators are trazodone, vilazodone, and vortioxetine.
  • Atypical antidepressants include bupropion and mirtazapine. They are often prescribed as monotherapy or as augmenting agents when patients develop sexual side-effects due to SSRIs or SNRIs.
  • Tricyclic antidepressants (TCAs) are amitriptyline, imipramine, clomipramine, doxepin, nortriptyline, and desipramine.
  • Monoamine oxidase inhibitors (MAOIs) available are tranylcypromine, phenelzine, selegiline, and isocarboxazid. MAOIs and TCAs are not commonly used due to the high incidence of side-effects and lethality in overdose.
  • Other medications include mood-stabilizers, antipsychotics which may be added to enhance antidepressant effects.

Psychotherapy  

  • Cognitive-behavioral therapy
  • Interpersonal therapy 

Electroconvulsive Therapy (ECT)

  • Acute suicidality 
  • Severe depression during pregnancy 
  • Refusal to eat/drink
  • Severe psychosis

Transcranial Magnetic Stimulation (TMS)

  • FDA-approved for treatment-resistant/refractory depression; for patients who have failed at least one medication trial

Vagus Nerve Stimulation (VNS)

  • FDA-approved as a long-term adjunctive treatment for treatment-resistant depression; for patients who have failed at least 4 medication trials
  • Nasal spray to be used in conjunction with an oral antidepressant in treatment-resistant depression; for patients who have failed other antidepressant medications
  • Differential Diagnosis

While evaluating for MDD, it is important to rule out depressive disorder due to another medical condition, substance/medication-induced depressive disorder, dysthymia, cyclothymia, bereavement, adjustment disorder with depressed mood, bipolar disorder, schizoaffective disorder, schizophrenia, anxiety disorders, and eating disorders for the appropriate management. Depressive symptoms can be secondary to the following causes:

  • Neurological causes such as cerebrovascular accident, multiple sclerosis, subdural hematoma, epilepsy, Parkinson disease, Alzheimer disease 
  • Endocrinopathies such as diabetes, thyroid disorders, adrenal disorders
  • Metabolic disturbances such as hypercalcemia, hyponatremia
  • Medications/substances of abuse: steroids, antihypertensives, anticonvulsants, antibiotics, sedatives, hypnotics, alcohol, stimulant withdrawal
  • Nutritional deficiencies such as vitamin D, B12, B6 deficiency, iron or folate deficiency
  • Infectious diseases such as HIV and syphilis
  • Malignancies

Untreated depressive episodes in major depressive disorder can last from 6 to 12 months. About two-thirds of the individuals with MDD contemplate suicide, and about 10 to 15 percent commit suicide. MDD is a chronic, recurrent illness; the recurrence rate is about 50% after the first episode, 70% after the second episode, and 90% after the third episode. About 5 to 10 percent of the patients with MDD eventually develop bipolar disorder. [11]  The prognosis of MDD is good in patients with mild episodes, the absence of psychotic symptoms, better treatment compliance, a strong support system, and good premorbid functioning. The prognosis is poor in the presence of a comorbid psychiatric disorder, personality disorder, multiple hospitalizations, and advanced age of onset.

  • Complications

MDD is one of the leading causes of disability worldwide. It not only causes a severe functional impairment but also adversely affects the interpersonal relationships, thus lowering the quality of life. Individuals with MDD are at a high risk of developing comorbid anxiety disorders and substance use disorders, which further increases their risk of suicide. Depression can aggravate medical comorbidities such as diabetes, hypertension, chronic obstructive pulmonary disease, and coronary artery disease. Depressed individuals are at high risk of developing self-destructive behavior as a coping mechanism. MDD is often very debilitating if left untreated.

  • Deterrence and Patient Education

Patient education has a profound impact on the overall outcome of major depressive disorder. Since MDD is one of the most common psychiatric disorders causing disability worldwide and people in different parts of the world are hesitant to discuss and seek treatment for depression due to the stigma associated with mental illness, educating patients is very crucial for their better understanding of the mental illness and better compliance with the mental health treatment. Family education also plays an important role in the successful treatment of MDD.

  • Enhancing Healthcare Team Outcomes

An interdisciplinary approach is essential for the effective and successful treatment of MDD. Primary care physicians and psychiatrists, along with nurses, therapists, social workers, and case managers, form an integral part of these collaborated services. In the majority of cases, PCPs are the first providers to whom individuals with MDD present mostly with somatic complaints. Depression screening in primary care settings is very imperative. The regular screening of the patients using depression rating scales such as PHQ-9 can be very helpful in the early diagnosis and intervention, thus improving the overall outcome of MDD. Psychoeducation plays a significant role in improving patient compliance and medication adherence. Recent evidence also supports that lifestyle modification, including moderate exercises, can help to improve mild-to-moderate depression. Suicide screening at each psychiatric visit can be helpful to lower suicide incidence. Since patients with MDD are at increased risk of suicide, close monitoring, and follow up by mental health workers becomes necessary to ensure safety and compliance with mental health treatment. The involvement of families can further add to a better outcome of the overall mental health treatment. Meta-analyses of randomized trials have shown that depression outcomes are superior when using collaborative care as compared with usual care. [12]

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Disclosure: Navneet Bains declares no relevant financial relationships with ineligible companies.

Disclosure: Sara Abdijadid declares no relevant financial relationships with ineligible companies.

This book is distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0) ( http://creativecommons.org/licenses/by-nc-nd/4.0/ ), which permits others to distribute the work, provided that the article is not altered or used commercially. You are not required to obtain permission to distribute this article, provided that you credit the author and journal.

  • Cite this Page Bains N, Abdijadid S. Major Depressive Disorder. [Updated 2023 Apr 10]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2024 Jan-.

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  • Systematic Review
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  • Published: 20 July 2022

The serotonin theory of depression: a systematic umbrella review of the evidence

  • Joanna Moncrieff 1 , 2 ,
  • Ruth E. Cooper 3 ,
  • Tom Stockmann 4 ,
  • Simone Amendola 5 ,
  • Michael P. Hengartner 6 &
  • Mark A. Horowitz 1 , 2  

Molecular Psychiatry volume  28 ,  pages 3243–3256 ( 2023 ) Cite this article

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  • Diagnostic markers

The serotonin hypothesis of depression is still influential. We aimed to synthesise and evaluate evidence on whether depression is associated with lowered serotonin concentration or activity in a systematic umbrella review of the principal relevant areas of research. PubMed, EMBASE and PsycINFO were searched using terms appropriate to each area of research, from their inception until December 2020. Systematic reviews, meta-analyses and large data-set analyses in the following areas were identified: serotonin and serotonin metabolite, 5-HIAA, concentrations in body fluids; serotonin 5-HT 1A receptor binding; serotonin transporter (SERT) levels measured by imaging or at post-mortem; tryptophan depletion studies; SERT gene associations and SERT gene-environment interactions. Studies of depression associated with physical conditions and specific subtypes of depression (e.g. bipolar depression) were excluded. Two independent reviewers extracted the data and assessed the quality of included studies using the AMSTAR-2, an adapted AMSTAR-2, or the STREGA for a large genetic study. The certainty of study results was assessed using a modified version of the GRADE. We did not synthesise results of individual meta-analyses because they included overlapping studies. The review was registered with PROSPERO (CRD42020207203). 17 studies were included: 12 systematic reviews and meta-analyses, 1 collaborative meta-analysis, 1 meta-analysis of large cohort studies, 1 systematic review and narrative synthesis, 1 genetic association study and 1 umbrella review. Quality of reviews was variable with some genetic studies of high quality. Two meta-analyses of overlapping studies examining the serotonin metabolite, 5-HIAA, showed no association with depression (largest n  = 1002). One meta-analysis of cohort studies of plasma serotonin showed no relationship with depression, and evidence that lowered serotonin concentration was associated with antidepressant use ( n  = 1869). Two meta-analyses of overlapping studies examining the 5-HT 1A receptor (largest n  = 561), and three meta-analyses of overlapping studies examining SERT binding (largest n  = 1845) showed weak and inconsistent evidence of reduced binding in some areas, which would be consistent with increased synaptic availability of serotonin in people with depression, if this was the original, causal abnormaly. However, effects of prior antidepressant use were not reliably excluded. One meta-analysis of tryptophan depletion studies found no effect in most healthy volunteers ( n  = 566), but weak evidence of an effect in those with a family history of depression ( n  = 75). Another systematic review ( n  = 342) and a sample of ten subsequent studies ( n  = 407) found no effect in volunteers. No systematic review of tryptophan depletion studies has been performed since 2007. The two largest and highest quality studies of the SERT gene, one genetic association study ( n  = 115,257) and one collaborative meta-analysis ( n  = 43,165), revealed no evidence of an association with depression, or of an interaction between genotype, stress and depression. The main areas of serotonin research provide no consistent evidence of there being an association between serotonin and depression, and no support for the hypothesis that depression is caused by lowered serotonin activity or concentrations. Some evidence was consistent with the possibility that long-term antidepressant use reduces serotonin concentration.

Introduction

The idea that depression is the result of abnormalities in brain chemicals, particularly serotonin (5-hydroxytryptamine or 5-HT), has been influential for decades, and provides an important justification for the use of antidepressants. A link between lowered serotonin and depression was first suggested in the 1960s [ 1 ], and widely publicised from the 1990s with the advent of the Selective Serotonin Reuptake Inhibitor (SSRI) antidepressants [ 2 , 3 , 4 ]. Although it has been questioned more recently [ 5 , 6 ], the serotonin theory of depression remains influential, with principal English language textbooks still giving it qualified support [ 7 , 8 ], leading researchers endorsing it [ 9 , 10 , 11 ], and much empirical research based on it [ 11 , 12 , 13 , 14 ]. Surveys suggest that 80% or more of the general public now believe it is established that depression is caused by a ‘chemical imbalance’ [ 15 , 16 ]. Many general practitioners also subscribe to this view [ 17 ] and popular websites commonly cite the theory [ 18 ].

It is often assumed that the effects of antidepressants demonstrate that depression must be at least partially caused by a brain-based chemical abnormality, and that the apparent efficacy of SSRIs shows that serotonin is implicated. Other explanations for the effects of antidepressants have been put forward, however, including the idea that they work via an amplified placebo effect or through their ability to restrict or blunt emotions in general [ 19 , 20 ].

Despite the fact that the serotonin theory of depression has been so influential, no comprehensive review has yet synthesised the relevant evidence. We conducted an ‘umbrella’ review of the principal areas of relevant research, following the model of a similar review examining prospective biomarkers of major depressive disorder [ 21 ]. We sought to establish whether the current evidence supports a role for serotonin in the aetiology of depression, and specifically whether depression is associated with indications of lowered serotonin concentrations or activity.

Search strategy and selection criteria

The present umbrella review was reported in accordance with the 2009 PRISMA statement [ 22 ]. The protocol was registered with PROSPERO in December 2020 (registration number CRD42020207203) ( https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=207203 ). This was subsequently updated to reflect our decision to modify the quality rating system for some studies to more appropriately appraise their quality, and to include a modified GRADE to assess the overall certainty of the findings in each category of the umbrella review.

In order to cover the different areas and to manage the large volume of research that has been conducted on the serotonin system, we conducted an ‘umbrella’ review. Umbrella reviews survey existing systematic reviews and meta-analyses relevant to a research question and represent one of the highest levels of evidence synthesis available [ 23 ]. Although they are traditionally restricted to systematic reviews and meta-analyses, we aimed to identify the best evidence available. Therefore, we also included some large studies that combined data from individual studies but did not employ conventional systematic review methods, and one large genetic study. The latter used nationwide databases to capture more individuals than entire meta-analyses, so is likely to provide even more reliable evidence than syntheses of individual studies.

We first conducted a scoping review to identify areas of research consistently held to provide support for the serotonin hypothesis of depression. Six areas were identified, addressing the following questions: (1) Serotonin and the serotonin metabolite 5-HIAA–whether there are lower levels of serotonin and 5-HIAA in body fluids in depression; (2) Receptors - whether serotonin receptor levels are altered in people with depression; (3) The serotonin transporter (SERT) - whether there are higher levels of the serotonin transporter in people with depression (which would lower synaptic levels of serotonin); (4) Depletion studies - whether tryptophan depletion (which lowers available serotonin) can induce depression; (5) SERT gene – whether there are higher levels of the serotonin transporter gene in people with depression; (6) Whether there is an interaction between the SERT gene and stress in depression.

We searched for systematic reviews, meta-analyses, and large database studies in these six areas in PubMed, EMBASE and PsycINFO using the Healthcare Databases Advanced Search tool provided by Health Education England and NICE (National Institute for Health and Care Excellence). Searches were conducted until December 2020.

We used the following terms in all searches: (depress* OR affective OR mood) AND (systematic OR meta-analysis), and limited searches to title and abstract, since not doing so produced numerous irrelevant hits. In addition, we used terms specific to each area of research (full details are provided in Table  S1 , Supplement). We also searched citations and consulted with experts.

Inclusion criteria were designed to identify the best available evidence in each research area and consisted of:

Research synthesis including systematic reviews, meta-analysis, umbrella reviews, individual patient meta-analysis and large dataset analysis.

Studies that involve people with depressive disorders or, for experimental studies (tryptophan depletion), those in which mood symptoms are measured as an outcome.

Studies of experimental procedures (tryptophan depletion) involving a sham or control condition.

Studies published in full in peer reviewed literature.

Where more than five systematic reviews or large analyses exist, the most recent five are included.

Exclusion criteria consisted of:

Animal studies.

Studies exclusively concerned with depression in physical conditions (e.g. post stroke or Parkinson’s disease) or exclusively focusing on specific subtypes of depression such as postpartum depression, depression in children, or depression in bipolar disorder.

No language or date restrictions were applied. In areas in which no systematic review or meta-analysis had been done within the last 10 years, we also selected the ten most recent studies at the time of searching (December 2020) for illustration of more recent findings. We performed this search using the same search string for this domain, without restricting it to systematic reviews and meta-analyses.

Data analysis

Each member of the team was allocated one to three domains of serotonin research to search and screen for eligible studies using abstract and full text review. In case of uncertainty, the entire team discussed eligibility to reach consensus.

For included studies, data were extracted by two reviewers working independently, and disagreement was resolved by consensus. Authors of papers were contacted for clarification when data was missing or unclear.

We extracted summary effects, confidence intervals and measures of statistical significance where these were reported, and, where relevant, we extracted data on heterogeneity. For summary effects in the non-genetic studies, preference was given to the extraction and reporting of effect sizes. Mean differences were converted to effect sizes where appropriate data were available.

We did not perform a meta-analysis of the individual meta-analyses in each area because they included overlapping studies [ 24 ]. All extracted data is presented in Table  1 . Sensitivity analyses were reported where they had substantial bearing on interpretation of findings.

The quality rating of systematic reviews and meta-analyses was assessed using AMSTAR-2 (A MeaSurement Tool to Assess systematic Reviews) [ 25 ]. For two studies that did not employ conventional systematic review methods [ 26 , 27 ] we used a modified version of the AMSTAR-2 (see Table  S3 ). For the genetic association study based on a large database analysis we used the STREGA assessment (STrengthening the REporting of Genetic Association Studies) (Table  S4 ) [ 28 ]. Each study was rated independently by at least two authors. We report ratings of individual items on the relevant measure, and the percentage of items that were adequately addressed by each study (Table  1 , with further detail in Tables  S3 and S4 ).

Alongside quality ratings, two team members (JM, MAH) rated the certainty of the results of each study using a modified version of the GRADE guidelines [ 29 ]. Following the approach of Kennis et al. [ 21 ], we devised six criteria relevant to the included studies: whether a unified analysis was conducted on original data; whether confounding by antidepressant use was adequately addressed; whether outcomes were pre-specified; whether results were consistent or heterogeneity was adequately addressed if present; whether there was a likelihood of publication bias; and sample size. The importance of confounding by effects of current or past antidepressant use has been highlighted in several studies [ 30 , 31 ]. The results of each study were scored 1 or 0 according to whether they fulfilled each criteria, and based on these ratings an overall judgement was made about the certainty of evidence across studies in each of the six areas of research examined. The certainty of each study was based on an algorithm that prioritised sample size and uniform analysis using original data (explained more fully in the supplementary material), following suggestions that these are the key aspects of reliability [ 27 , 32 ]. An assessment of the overall certainty of each domain of research examining the role of serotonin was determined by consensus of at least two authors and a direction of effect indicated.

Search results and quality rating

Searching identified 361 publications across the 6 different areas of research, among which seventeen studies fulfilled inclusion criteria (see Fig.  1 and Table  S1 for details of the selection process). Included studies, their characteristics and results are shown in Table  1 . As no systematic review or meta-analysis had been performed within the last 10 years on serotonin depletion, we also identified the 10 latest studies for illustration of more recent research findings (Table  2 ).

figure 1

Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) flow diagramme.

Quality ratings are summarised in Table  1 and reported in detail in Tables  S2 – S3 . The majority (11/17) of systematic reviews and meta-analyses satisfied less than 50% of criteria. Only 31% adequately assessed risk of bias in individual studies (a further 44% partially assessed this), and only 50% adequately accounted for risk of bias when interpreting the results of the review. One collaborative meta-analysis of genetic studies was considered to be of high quality due to the inclusion of several measures to ensure consistency and reliability [ 27 ]. The large genetic analysis of the effect of SERT polymorphisms on depression, satisfied 88% of the STREGA quality criteria [ 32 ].

Serotonin and 5-HIAA

Serotonin can be measured in blood, plasma, urine and CSF, but it is rapidly metabolised to 5-hydroxyindoleacetic acid (5-HIAA). CSF is thought to be the ideal resource for the study of biomarkers of putative brain diseases, since it is in contact with brain interstitial fluid [ 33 ]. However, collecting CSF samples is invasive and carries some risk, hence large-scale studies are scarce.

Three studies fulfilled inclusion criteria (Table  1 ). One meta-analysis of three large observational cohort studies of post-menopausal women, revealed lower levels of plasma 5-HT in women with depression, which did not, however, reach statistical significance of p  < 0.05 after adjusting for multiple comparisons. Sensitivity analyses revealed that antidepressants were strongly associated with lower serotonin levels independently of depression.

Two meta-analyses of a total of 19 studies of 5-HIAA in CSF (seven studies were included in both) found no evidence of an association between 5-HIAA concentrations and depression.

Fourteen different serotonin receptors have been identified, with most research on depression focusing on the 5-HT 1A receptor [ 11 , 34 ]. Since the functions of other 5-HT receptors and their relationship to depression have not been well characterised, we restricted our analysis to data on 5-HT 1A receptors [ 11 , 34 ]. 5-HT 1A receptors, known as auto-receptors, inhibit the release of serotonin pre-synaptically [ 35 ], therefore, if depression is the result of reduced serotonin activity caused by abnormalities in the 5-HT 1A receptor, people with depression would be expected to show increased activity of 5-HT 1A receptors compared to those without [ 36 ].

Two meta-analyses satisfied inclusion criteria, involving five of the same studies [ 37 , 38 ] (see Table  1 ). The majority of results across the two analyses suggested either no difference in 5-HT 1A receptors between people with depression and controls, or a lower level of these inhibitory receptors, which would imply higher concentrations or activity of serotonin in people with depression. Both meta-analyses were based on studies that predominantly involved patients who were taking or had recently taken (within 1–3 weeks of scanning) antidepressants or other types of psychiatric medication, and both sets of authors commented on the possible influence of prior or current medication on findings. In addition, one analysis was of very low quality [ 37 ], including not reporting on the numbers involved in each analysis and using one-sided p-values, and one was strongly influenced by three studies and publication bias was present [ 38 ].

The serotonin transporter (SERT)

The serotonin transporter protein (SERT) transports serotonin out of the synapse, thereby lowering the availability of serotonin in the synapse [ 39 , 40 ]. Animals with an inactivated gene for SERT have higher levels of extra-cellular serotonin in the brain than normal [ 41 , 42 , 43 ] and SSRIs are thought to work by inhibiting the action of SERT, and thus increasing levels of serotonin in the synaptic cleft [ 44 ]. Although changes in SERT may be a marker for other abnormalities, if depression is caused by low serotonin availability or activity, and if SERT is the origin of that deficit, then the amount or activity of SERT would be expected to be higher in people with depression compared to those without [ 40 ]. SERT binding potential is an index of the concentration of the serotonin transporter protein and SERT concentrations can also be measured post-mortem.

Three overlapping meta-analyses based on a total of 40 individual studies fulfilled inclusion criteria (See Table  1 ) [ 37 , 39 , 45 ]. Overall, the data indicated possible reductions in SERT binding in some brain areas, although areas in which effects were detected were not consistent across the reviews. In addition, effects of antidepressants and other medication cannot be ruled out, since most included studies mainly or exclusively involved people who had a history of taking antidepressants or other psychiatric medications. Only one meta-analysis tested effects of antidepressants, and although results were not influenced by the percentage of drug-naïve patients in each study, numbers were small so it is unlikely that medication-related effects would have been reliably detected [ 45 ]. All three reviews cited evidence from animal studies that antidepressant treatment reduces SERT [ 46 , 47 , 48 ]. None of the analyses corrected for multiple testing, and one review was of very low quality [ 37 ]. If the results do represent a positive finding that is independent of medication, they would suggest that depression is associated with higher concentrations or activity of serotonin.

Depletion studies

Tryptophan depletion using dietary means or chemicals, such as parachlorophenylalanine (PCPA), is thought to reduce serotonin levels. Since PCPA is potentially toxic, reversible tryptophan depletion using an amino acid drink that lacks tryptophan is the most commonly used method and is thought to affect serotonin within 5–7 h of ingestion. Questions remain, however, about whether either method reliably reduces brain serotonin, and about other effects including changes in brain nitrous oxide, cerebrovascular changes, reduced BDNF and amino acid imbalances that may be produced by the manipulations and might explain observed effects independent of possible changes in serotonin activity [ 49 ].

One meta-analysis and one systematic review fulfilled inclusion criteria (see Table  1 ). Data from studies involving volunteers mostly showed no effect, including a meta-analysis of parallel group studies [ 50 ]. In a small meta-analysis of within-subject studies involving 75 people with a positive family history, a minor effect was found, with people given the active depletion showing a larger decrease in mood than those who had a sham procedure [ 50 ]. Across both reviews, studies involving people diagnosed with depression showed slightly greater mood reduction following tryptophan depletion than sham treatment overall, but most participants had taken or were taking antidepressants and participant numbers were small [ 50 , 51 ].

Since these research syntheses were conducted more than 10 years ago, we searched for a systematic sample of ten recently published studies (Table  2 ). Eight studies conducted with healthy volunteers showed no effects of tryptophan depletion on mood, including the only two parallel group studies. One study presented effects in people with and without a family history of depression, and no differences were apparent in either group [ 52 ]. Two cross-over studies involving people with depression and current or recent use of antidepressants showed no convincing effects of a depletion drink [ 53 , 54 ], although one study is reported as positive mainly due to finding an improvement in mood in the group given the sham drink [ 54 ].

SERT gene and gene-stress interactions

A possible link between depression and the repeat length polymorphism in the promoter region of the SERT gene (5-HTTLPR), specifically the presence of the short repeats version, which causes lower SERT mRNA expression, has been proposed [ 55 ]. Interestingly, lower levels of SERT would produce higher levels of synaptic serotonin. However, more recently, this hypothesis has been superseded by a focus on the interaction effect between this polymorphism, depression and stress, with the idea that the short version of the polymorphism may only give rise to depression in the presence of stressful life events [ 55 , 56 ]. Unlike other areas of serotonin research, numerous systematic reviews and meta-analyses of genetic studies have been conducted, and most recently a very large analysis based on a sample from two genetic databanks. Details of the five most recent studies that have addressed the association between the SERT gene and depression, and the interaction effect are detailed in Table  1 .

Although some earlier meta-analyses of case-control studies showed a statistically significant association between the 5-HTTLPR and depression in some ethnic groups [ 57 , 58 ], two recent large, high quality studies did not find an association between the SERT gene polymorphism and depression [ 27 , 32 ]. These two studies consist of  by far the largest and most comprehensive study to date [ 32 ] and a high-quality meta-analysis that involved a consistent re-analysis of primary data across all conducted studies, including previously unpublished data, and other comprehensive quality checks [ 27 , 59 ] (see Table  1 ).

Similarly, early studies based on tens of thousands of participants suggested a statistically significant interaction between the SERT gene, forms of stress or maltreatment and depression [ 60 , 61 , 62 ], with a small odds ratio in the only study that reported this (1.18, 95% CI 1.09 to 1.28) [ 62 ]. However, the two recent large, high-quality studies did not find an interaction between the SERT gene and stress in depression (Border et al [ 32 ] and Culverhouse et al.) [ 27 ] (see Table  1 ).

Overall results

Table  3 presents the modified GRADE ratings for each study and the overall rating of the strength of evidence in each area. Areas of research that provided moderate or high certainty of evidence such as the studies of plasma serotonin and metabolites and the genetic and gene-stress interaction studies all showed no association between markers of serotonin activity and depression. Some other areas suggested findings consistent with increased serotonin activity, but evidence was of very low certainty, mainly due to small sample sizes and possible residual confounding by current or past antidepressant use. One area - the tryptophan depletion studies - showed very low certainty evidence of lowered serotonin activity or availability in a subgroup of volunteers with a family history of depression. This evidence was considered very low certainty as it derived from a subgroup of within-subject studies, numbers were small, and there was no information on medication use, which may have influenced results. Subsequent research has not confirmed an effect with numerous negative studies in volunteers.

Our comprehensive review of the major strands of research on serotonin shows there is no convincing evidence that depression is associated with, or caused by, lower serotonin concentrations or activity. Most studies found no evidence of reduced serotonin activity in people with depression compared to people without, and methods to reduce serotonin availability using tryptophan depletion do not consistently lower mood in volunteers. High quality, well-powered genetic studies effectively exclude an association between genotypes related to the serotonin system and depression, including a proposed interaction with stress. Weak evidence from some studies of serotonin 5-HT 1A receptors and levels of SERT points towards a possible association between increased serotonin activity and depression. However, these results are likely to be influenced by prior use of antidepressants and its effects on the serotonin system [ 30 , 31 ]. The effects of tryptophan depletion in some cross-over studies involving people with depression may also be mediated by antidepressants, although these are not consistently found [ 63 ].

The chemical imbalance theory of depression is still put forward by professionals [ 17 ], and the serotonin theory, in particular, has formed the basis of a considerable research effort over the last few decades [ 14 ]. The general public widely believes that depression has been convincingly demonstrated to be the result of serotonin or other chemical abnormalities [ 15 , 16 ], and this belief shapes how people understand their moods, leading to a pessimistic outlook on the outcome of depression and negative expectancies about the possibility of self-regulation of mood [ 64 , 65 , 66 ]. The idea that depression is the result of a chemical imbalance also influences decisions about whether to take or continue antidepressant medication and may discourage people from discontinuing treatment, potentially leading to lifelong dependence on these drugs [ 67 , 68 ].

As with all research synthesis, the findings of this umbrella review are dependent on the quality of the included studies, and susceptible to their limitations. Most of the included studies were rated as low quality on the AMSTAR-2, but the GRADE approach suggested some findings were reasonably robust. Most of the non-genetic studies did not reliably exclude the potential effects of previous antidepressant use and were based on relatively small numbers of participants. The genetic studies, in particular, illustrate the importance of methodological rigour and sample size. Whereas some earlier, lower quality, mostly smaller studies produced marginally positive findings, these were not confirmed in better-conducted, larger and more recent studies [ 27 , 32 ]. The identification of depression and assessment of confounders and interaction effects were limited by the data available in the original studies on which the included reviews and meta-analyses were based. Common methods such as the categorisation of continuous measures and application of linear models to non-linear data may have led to over-estimation or under-estimation of effects [ 69 , 70 ], including the interaction between stress and the SERT gene. The latest systematic review of tryptophan depletion studies was conducted in 2007, and there has been considerable research produced since then. Hence, we provided a snapshot of the most recent evidence at the time of writing, but this area requires an up to date, comprehensive data synthesis. However, the recent studies were consistent with the earlier meta-analysis with little evidence for an effect of tryptophan depletion on mood.

Although umbrella reviews typically restrict themselves to systematic reviews and meta-analyses, we aimed to provide the most comprehensive possible overview. Therefore, we chose to include meta-analyses that did not involve a systematic review and a large genetic association study on the premise that these studies contribute important data on the question of whether the serotonin hypothesis of depression is supported. As a result, the AMSTAR-2 quality rating scale, designed to evaluate the quality of conventional systematic reviews, was not easily applicable to all studies and had to be modified or replaced in some cases.

One study in this review found that antidepressant use was associated with a reduction of plasma serotonin [ 26 ], and it is possible that the evidence for reductions in SERT density and 5-HT 1A receptors in some of the included imaging study reviews may reflect compensatory adaptations to serotonin-lowering effects of prior antidepressant use. Authors of one meta-analysis also highlighted evidence of 5-HIAA levels being reduced after long-term antidepressant treatment [ 71 ]. These findings suggest that in the long-term antidepressants might produce compensatory changes [ 72 ] that are opposite to their acute effects [ 73 , 74 ]. Lowered serotonin availability has also been demonstrated in animal studies following prolonged antidepressant administration [ 75 ]. Further research is required to clarify the effects of different drugs on neurochemical systems, including the serotonin system, especially during and after long-term use, as well as the physical and psychological consequences of such effects.

This review suggests that the huge research effort based on the serotonin hypothesis has not produced convincing evidence of a biochemical basis to depression. This is consistent with research on many other biological markers [ 21 ]. We suggest it is time to acknowledge that the serotonin theory of depression is not empirically substantiated.

Data availability

All extracted data is available in the paper and supplementary materials. Further information about the decision-making for each rating for categories of the AMSTAR-2 and STREGA are available on request.

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There was no specific funding for this review. MAH is supported by a Clinical Research Fellowship from North East London NHS Foundation Trust (NELFT). This funder had no role in study design, data collection, data analysis, data interpretation, or writing of the report.

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JM conceived the idea for the study. JM, MAH, MPH, TS and SA designed the study. JM, MAH, MPH, TS, and SA screened articles and abstracted data. JM drafted the first version of the manuscript. JM, MAH, MPH, TS, SA, and REC contributed to the manuscript’s revision and interpretation of findings. All authors had full access to all the data in the study and had final responsibility for the decision to submit for publication.

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All authors have completed the Unified Competing Interest form at http://www.icmje.org/coi_disclosure.pdf (available on request from the corresponding author). SA declares no conflicts of interest. MAH reports being co-founder of a company in April 2022, aiming to help people safely stop antidepressants in Canada. MPH reports royalties from Palgrave Macmillan, London, UK for his book published in December, 2021, called “Evidence-biased Antidepressant Prescription.” JM receives royalties for books about psychiatric drugs, reports grants from the National Institute of Health Research outside the submitted work, that she is co-chairperson of the Critical Psychiatry Network (an informal group of psychiatrists) and a board member of the unfunded organisation, the Council for Evidence-based Psychiatry. Both are unpaid positions. TS is co-chairperson of the Critical Psychiatry Network. RC is an unpaid board member of the International Institute for Psychiatric Drug Withdrawal.

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Moncrieff, J., Cooper, R.E., Stockmann, T. et al. The serotonin theory of depression: a systematic umbrella review of the evidence. Mol Psychiatry 28 , 3243–3256 (2023). https://doi.org/10.1038/s41380-022-01661-0

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Published : 20 July 2022

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DOI : https://doi.org/10.1038/s41380-022-01661-0

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Science News

Social media harms teens’ mental health, mounting evidence shows. what now.

Understanding what is going on in teens’ minds is necessary for targeted policy suggestions

A teen scrolls through social media alone on her phone.

Most teens use social media, often for hours on end. Some social scientists are confident that such use is harming their mental health. Now they want to pinpoint what explains the link.

Carol Yepes/Getty Images

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By Sujata Gupta

February 20, 2024 at 7:30 am

In January, Mark Zuckerberg, CEO of Facebook’s parent company Meta, appeared at a congressional hearing to answer questions about how social media potentially harms children. Zuckerberg opened by saying: “The existing body of scientific work has not shown a causal link between using social media and young people having worse mental health.”

But many social scientists would disagree with that statement. In recent years, studies have started to show a causal link between teen social media use and reduced well-being or mood disorders, chiefly depression and anxiety.

Ironically, one of the most cited studies into this link focused on Facebook.

Researchers delved into whether the platform’s introduction across college campuses in the mid 2000s increased symptoms associated with depression and anxiety. The answer was a clear yes , says MIT economist Alexey Makarin, a coauthor of the study, which appeared in the November 2022 American Economic Review . “There is still a lot to be explored,” Makarin says, but “[to say] there is no causal evidence that social media causes mental health issues, to that I definitely object.”

The concern, and the studies, come from statistics showing that social media use in teens ages 13 to 17 is now almost ubiquitous. Two-thirds of teens report using TikTok, and some 60 percent of teens report using Instagram or Snapchat, a 2022 survey found. (Only 30 percent said they used Facebook.) Another survey showed that girls, on average, allot roughly 3.4 hours per day to TikTok, Instagram and Facebook, compared with roughly 2.1 hours among boys. At the same time, more teens are showing signs of depression than ever, especially girls ( SN: 6/30/23 ).

As more studies show a strong link between these phenomena, some researchers are starting to shift their attention to possible mechanisms. Why does social media use seem to trigger mental health problems? Why are those effects unevenly distributed among different groups, such as girls or young adults? And can the positives of social media be teased out from the negatives to provide more targeted guidance to teens, their caregivers and policymakers?

“You can’t design good public policy if you don’t know why things are happening,” says Scott Cunningham, an economist at Baylor University in Waco, Texas.

Increasing rigor

Concerns over the effects of social media use in children have been circulating for years, resulting in a massive body of scientific literature. But those mostly correlational studies could not show if teen social media use was harming mental health or if teens with mental health problems were using more social media.

Moreover, the findings from such studies were often inconclusive, or the effects on mental health so small as to be inconsequential. In one study that received considerable media attention, psychologists Amy Orben and Andrew Przybylski combined data from three surveys to see if they could find a link between technology use, including social media, and reduced well-being. The duo gauged the well-being of over 355,000 teenagers by focusing on questions around depression, suicidal thinking and self-esteem.

Digital technology use was associated with a slight decrease in adolescent well-being , Orben, now of the University of Cambridge, and Przybylski, of the University of Oxford, reported in 2019 in Nature Human Behaviour . But the duo downplayed that finding, noting that researchers have observed similar drops in adolescent well-being associated with drinking milk, going to the movies or eating potatoes.

Holes have begun to appear in that narrative thanks to newer, more rigorous studies.

In one longitudinal study, researchers — including Orben and Przybylski — used survey data on social media use and well-being from over 17,400 teens and young adults to look at how individuals’ responses to a question gauging life satisfaction changed between 2011 and 2018. And they dug into how the responses varied by gender, age and time spent on social media.

Social media use was associated with a drop in well-being among teens during certain developmental periods, chiefly puberty and young adulthood, the team reported in 2022 in Nature Communications . That translated to lower well-being scores around ages 11 to 13 for girls and ages 14 to 15 for boys. Both groups also reported a drop in well-being around age 19. Moreover, among the older teens, the team found evidence for the Goldilocks Hypothesis: the idea that both too much and too little time spent on social media can harm mental health.

“There’s hardly any effect if you look over everybody. But if you look at specific age groups, at particularly what [Orben] calls ‘windows of sensitivity’ … you see these clear effects,” says L.J. Shrum, a consumer psychologist at HEC Paris who was not involved with this research. His review of studies related to teen social media use and mental health is forthcoming in the Journal of the Association for Consumer Research.

Cause and effect

That longitudinal study hints at causation, researchers say. But one of the clearest ways to pin down cause and effect is through natural or quasi-experiments. For these in-the-wild experiments, researchers must identify situations where the rollout of a societal “treatment” is staggered across space and time. They can then compare outcomes among members of the group who received the treatment to those still in the queue — the control group.

That was the approach Makarin and his team used in their study of Facebook. The researchers homed in on the staggered rollout of Facebook across 775 college campuses from 2004 to 2006. They combined that rollout data with student responses to the National College Health Assessment, a widely used survey of college students’ mental and physical health.

The team then sought to understand if those survey questions captured diagnosable mental health problems. Specifically, they had roughly 500 undergraduate students respond to questions both in the National College Health Assessment and in validated screening tools for depression and anxiety. They found that mental health scores on the assessment predicted scores on the screenings. That suggested that a drop in well-being on the college survey was a good proxy for a corresponding increase in diagnosable mental health disorders. 

Compared with campuses that had not yet gained access to Facebook, college campuses with Facebook experienced a 2 percentage point increase in the number of students who met the diagnostic criteria for anxiety or depression, the team found.

When it comes to showing a causal link between social media use in teens and worse mental health, “that study really is the crown jewel right now,” says Cunningham, who was not involved in that research.

A need for nuance

The social media landscape today is vastly different than the landscape of 20 years ago. Facebook is now optimized for maximum addiction, Shrum says, and other newer platforms, such as Snapchat, Instagram and TikTok, have since copied and built on those features. Paired with the ubiquity of social media in general, the negative effects on mental health may well be larger now.

Moreover, social media research tends to focus on young adults — an easier cohort to study than minors. That needs to change, Cunningham says. “Most of us are worried about our high school kids and younger.” 

And so, researchers must pivot accordingly. Crucially, simple comparisons of social media users and nonusers no longer make sense. As Orben and Przybylski’s 2022 work suggested, a teen not on social media might well feel worse than one who briefly logs on. 

Researchers must also dig into why, and under what circumstances, social media use can harm mental health, Cunningham says. Explanations for this link abound. For instance, social media is thought to crowd out other activities or increase people’s likelihood of comparing themselves unfavorably with others. But big data studies, with their reliance on existing surveys and statistical analyses, cannot address those deeper questions. “These kinds of papers, there’s nothing you can really ask … to find these plausible mechanisms,” Cunningham says.

One ongoing effort to understand social media use from this more nuanced vantage point is the SMART Schools project out of the University of Birmingham in England. Pedagogical expert Victoria Goodyear and her team are comparing mental and physical health outcomes among children who attend schools that have restricted cell phone use to those attending schools without such a policy. The researchers described the protocol of that study of 30 schools and over 1,000 students in the July BMJ Open.

Goodyear and colleagues are also combining that natural experiment with qualitative research. They met with 36 five-person focus groups each consisting of all students, all parents or all educators at six of those schools. The team hopes to learn how students use their phones during the day, how usage practices make students feel, and what the various parties think of restrictions on cell phone use during the school day.

Talking to teens and those in their orbit is the best way to get at the mechanisms by which social media influences well-being — for better or worse, Goodyear says. Moving beyond big data to this more personal approach, however, takes considerable time and effort. “Social media has increased in pace and momentum very, very quickly,” she says. “And research takes a long time to catch up with that process.”

Until that catch-up occurs, though, researchers cannot dole out much advice. “What guidance could we provide to young people, parents and schools to help maintain the positives of social media use?” Goodyear asks. “There’s not concrete evidence yet.”

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PsyPost

Home-based brain stimulation ineffective for major depression, study finds

A recent study found that unsupervised home-use brain stimulation combined with digital psychological interventions was not more effective than placebo treatments in alleviating symptoms of major depression. This finding challenges the current understanding of home-based mental health treatments and opens new questions about the most effective ways to treat this widespread condition. The research has been published in JAMA Psychiatry .

The study was motivated by the urgent need to find effective treatments for major depression, a condition affecting over 300 million people worldwide. Traditional treatments, such as antidepressant drugs, cognitive behavioral therapy, and noninvasive brain stimulation, have limitations.

For instance, a significant portion of patients does not respond to medications, and other treatments like cognitive therapy are not always accessible. Noninvasive brain stimulation methods such as transcranial magnetic stimulation are costly and require daily clinic visits, while electroconvulsive therapy has associated neurocognitive effects.

Transcranial direct current stimulation (tDCS) emerged as a promising alternative. It’s a noninvasive technique that involves applying low electrical currents through electrodes placed on the scalp. This method, known for being portable, simple, and inexpensive, was thought to potentially offer an accessible treatment option if it could be effectively administered at home.

The study, known as the Portable Transcranial Electrical Stimulation and Internet-Based Behavioral Therapy for Major Depression Study (PSYLECT), was conducted from April 2021 to October 2022. It involved 210 participants, mostly female, with an average age of 38.9 years, representing a diverse racial background. These participants were diagnosed with major depression and were in the midst of a depressive episode.

Participants were randomly assigned to one of three groups: a ‘double active’ group receiving tDCS and a digital psychological intervention, a ‘tDCS only’ group receiving tDCS and a digital placebo, and a ‘double sham’ group receiving sham tDCS and a digital placebo. The tDCS sessions were conducted at home using a special headset and were to be performed at least 24 hours apart, 5 times a week for the first 3 weeks and then twice a week for the remaining 3 weeks.

The digital psychological intervention included modules based on behavioral therapy concepts, such as mindfulness, physical exercise, and sleep hygiene, delivered through an application. The primary outcome measure was the change in the Hamilton Depression Rating Scale (HDRS-17) scores, a commonly used tool to assess the severity of depression.

The researchers found no significant difference in the reduction of depressive symptoms between the groups receiving the active treatments and the placebo group. This was true for both the primary outcome of depression severity and secondary outcomes like response and remission rates.

Participants generally adhered well to the treatment protocols, and the treatments were deemed easy to use. However, despite these positive aspects of the trial, the main finding was clear: unsupervised home-use tDCS combined with digital therapy did not outperform placebo treatments in reducing symptoms of major depression.

“We could not show that the active interventions differed from sham in improving depressive symptoms. These findings indicate that unsupervised home use should not currently be recommended as a tDCS modality in clinical practice,” the researchers concluded.

However, the duration of the study, six weeks, might have been too short to observe the full effects of the treatment. Additionally, the fixed settings for the brain stimulation device didn’t account for individual differences among participants, which could have influenced the outcomes. The diverse socioeconomic backgrounds of the participants also suggest that the effectiveness of digital health technologies could vary across different population groups.

Looking forward, researchers emphasize the need for longer studies with more tailored approaches to tDCS. The variability in how individuals respond to digital interventions and brain stimulation highlights the complexity of treating depression and the necessity for personalized treatment strategies. As digital and remote healthcare options continue to evolve, understanding their efficacy in mental health treatment remains a crucial area of research.

The study, “ Home-Use Transcranial Direct Current Stimulation for the Treatment of a Major Depressive Episode: A Randomized Clinical Trial “, was authored by Lucas Borrione, Beatriz A. Cavendish, Luana V. M. Aparicio, Matthias S. Luethi, Stephan Goerigk, Adriana M. Carneiro, Leandro Valiengo, Darin O. Moura, Juliana P. de Souza, Mariana Baptista, Valquiria Aparecida da Silva, Izio Klein, Paulo Suen, José Gallucci-Neto, Frank Padberg, Lais B. Razza, Marie-Anne Vanderhasselt, Paulo A. Lotufo, Isabela M. Bensenor, Felipe Fregni, and Andre R. Brunoni.

(Photo credit: Adobe Stock)

At the Human Longevity Lab, studying methods to slow or reverse aging

Longevity Lab

  • Feinberg School of Medicine

The Potocsnak Longevity Institute at Northwestern University Feinberg School of Medicine has launched the Human Longevity Laboratory, a longitudinal,  cross-sectional study that will investigate the relationship between chronological age and biological age across different organ systems and validate interventions that may reverse or slow down the processes of aging.

“The relationship between chronological age (how many years old you are) and biological age (how old your body appears in terms of your overall health), and how they may differ, is key to understanding human longevity,” said Dr. Douglas Vaughan, director of the Potocsnak Longevity Institute. “Knowledge gained from this research may allow scientists to develop methods to slow the process of aging and push back the onset of aging-related disease, hopefully extending the ‘healthspan.’”

Anyone is eligible to participate in the Northwestern research study, but the scientists are focused on studying people who are disadvantaged with respect to biological aging, including those with HIV.

Our primary aim is to find ways to slow down the rate of aging in people that are aging too quickly and provide them with an opportunity to extend their healthspan.”

“We are particularly interested in bringing in people who are at risk for accelerated aging — people with chronic HIV infections, patients with chronic kidney disease, people exposed to toxic substances regularly (smoke and chemicals) and others,” Vaughan said. “Our primary aim is to find ways to slow down the rate of aging in people that are aging too quickly and provide them with an opportunity to extend their healthspan.”

The comprehensive research protocol includes assessments across various systems (cardiovascular, respiratory, neurocognitive, metabolic, and musculoskeletal), and novel molecular profiling of the epigenome. The studies will be performed at no cost to participants at Northwestern Medicine.

Over the next year, the team plans to enroll a diverse cohort representing individuals of all ages, ethnicities and socioeconomic backgrounds to form a picture of how aging affects all members of the population.

A participant’s results will be reviewed with them after their testing is complete. “That is information that might motivate some participants to improve their lifestyle, exercise more, lose weight or change their diet,” said Dr. John Wilkins, associate director of the Human Longevity Laboratory. Wilkins is also an associate professor of medicine in cardiology and of preventive medicine at the Feinberg School of Medicine, as well as a Northwestern Medicine physician.

Ultimately, the Human Longevity Laboratory will launch clinical trials designed to test therapeutics or interventions that might slow the velocity of aging.

View this site for more information on the study.

research studies on major depression

Dr. Vaughan plans to develop a network of sites duplicating the Human Longevity Laboratory with partners in the U.S. and globally. 

“We hope to clone our laboratory in terms of basic equipment and the protocol,” Vaughan said. “We intend to build a large database that is the most diverse and comprehensive in the world that will contribute significantly to our research.” Potential collaborative partners and sites have already been identified in Asia, Brazil, the Netherlands and in West Africa.

The Human Longevity Laboratory is part of the multi-center Potocsnak Longevity Institute , whose goal is to foster new discoveries and build on Northwestern’s ongoing research in the rapidly advancing science of aging. The Institute is funded by a gift from Chicago industrialist John Potocsnak and family.

“Aging is a primary risk factor for every disease affecting adults — including diabetes, arthritis, dementia, heart disease, diabetes, aging-related cancer, hypertension and frailty,” Vaughan said. “The biological processes that drive aging may be malleable. We think we can slow that process down, delay it, even theoretically reverse it. The curtain is being pulled back on what drives aging. We want to contribute to that larger discovery process.”

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IMAGES

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  2. Read Handbook of Studies on Depression Online by Elsevier Science

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  3. Clinical Depression Test Canada

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COMMENTS

  1. Major depressive disorder: Validated treatments and future challenges

    Abstract Depression is a prevalent psychiatric disorder that often leads to poor quality of life and impaired functioning. Treatment during the acute phase of a major depressive episode aims to help the patient reach a remission state and eventually return to their baseline level of functioning.

  2. Depression (Major Depressive Disorder) Clinical Trials

    This study is a 12 week open trial that will enroll approximately 80 participants (anticipated 40 study completers with paired biomarker data) with an episode of major depression, Bipolar I or Bipolar II and 40 age- and sex-matched healthy controls.

  3. Major Depression

    Definitions Major depression is one of the most common mental disorders in the United States. For some individuals, major depression can result in severe impairments that interfere with or limit one's ability to carry out major life activities. Additional information can be found on the NIMH Health Topics page on Depression.

  4. Major Depressive Disorder: Advances in Neuroscience Research and

    As shown in Fig. 1 E, the hot research topics in depression are as follows: depression management in primary care, interventions to prevent depression, the pathogenesis of depression, comorbidity of depression and other diseases, the risks of depression, neuroimaging studies of depression, and antidepressant treatment.

  5. Prognosis and improved outcomes in major depression: a review

    Major depressive disorder (MDD) is the most common psychiatric disease and a worldwide leading cause of years lived with disability 1, 2. In addition, the bulk of suicides are linked to a...

  6. Insights and Advances Into Treatments for Major Depression

    In this 6-week, double-blind study, patients with major depression remained on their antidepressant treatment and also received either placebo, cariprazine 1.5 mg/day, or cariprazine 1.5 mg for 2 weeks and then increased to 3 mg/day. A total of 751 patients were included in the modified intention-to-treat analysis.

  7. Global prevalence and burden of depressive and anxiety disorders in 204

    Findings We identified 5683 unique data sources, of which 48 met inclusion criteria (46 studies met criteria for major depressive disorder and 27 for anxiety disorders).

  8. Advances in depression research: second special issue, 2020, with

    The current speed of progress in depression research is simply remarkable. We have therefore been able to create a second special issue of Molecular Psychiatry, 2020, focused on depression,...

  9. Major depressive disorder

    Major depressive disorder (MDD) is a common mental disorder that affects ~185 million people globally 1. Manifestations of MDD include depressed mood, reduced interest or pleasure in previously ...

  10. Biological, Psychological, and Social Determinants of Depression: A

    1. Introduction Depression is one of the most common mental health issues, with an estimated prevalence of 5% among adults [ 1, 2 ]. Symptoms may include anhedonia, feelings of worthlessness, concentration and sleep difficulties, and suicidal ideation.

  11. Treatment outcomes for depression: challenges and opportunities

    In the past decades, more than 500 randomised trials have examined the effects of antidepressant medications, and more than 600 trials have examined the effects of psychotherapies for depression (although comparatively few are conducted for early-onset depression).

  12. Roots of major depression revealed in all their genetic complexity

    A massive genome-wide association study (GWAS) of genetic and health records of 1.2 million people from four separate data banks has identified 178 gene variants linked to major depression, a disorder that will affect as many as one in every five people during their lifetimes. The results of the study, led by the U.S. Department of Veterans Affairs (V.A.) researchers at Yale University School ...

  13. Depression: Latest Research

    5 min read If you're one of more than 17 million adults or 3.2 million teens in the United States with major depression, you may know that treatment often falls short. The latest research on...

  14. Research

    The main goals of this study are to learn how safe the study drug is and how well the study drug works when taken with the antidepressants you are currently taking for MDD. To find out if this study is a good fit for you, please fill out our online survey, call (650) 723-8330, or email [email protected].

  15. Single-Dose Psilocybin for a Treatment-Resistant Episode of Major

    In this phase 2 double-blind trial, we randomly assigned adults with treatment-resistant depression to receive a single dose of a proprietary, synthetic formulation of psilocybin at a dose of 25 ...

  16. The genetic basis of major depression

    Multifactorial Inheritance / genetics*. Phenotype. Major depressive disorder (MDD) is a common, debilitating, phenotypically heterogeneous disorder with heritability ranges from 30% to 50%. Compared to other psychiatric disorders, its high prevalence, moderate heritability, and strong polygenicity have posed major challenges for gene-mapping in ...

  17. Major Depressive Disorder: Advances in Neuroscience Research and

    95 Citations 16 Altmetric 1 Mention Explore all metrics A Correction to this article was published on 17 May 2021 This article has been updated Abstract Major depressive disorder (MDD), also referred to as depression, is one of the most common psychiatric disorders with a high economic burden.

  18. PDF National Health Statistics Reports

    depression if they report "daily" feelings of depression "a lot" of the time, "daily" feelings of depression "somewhere in between a little and a lot of the time," or "weekly" feelings of depression "a lot" of the time. SOURCE: National Center for Health Statistics, National Health Interview Survey, 2021. Percent 0 2 4 6 ...

  19. Effect of exercise for depression: systematic review and network meta

    Objective To identify the optimal dose and modality of exercise for treating major depressive disorder, compared with psychotherapy, antidepressants, and control conditions. Design Systematic review and network meta-analysis. Methods Screening, data extraction, coding, and risk of bias assessment were performed independently and in duplicate. Bayesian arm based, multilevel network meta ...

  20. Clinical Research Studies

    This clinical research study is looking to learn more about how well an investigational study drug works in addition to standard treatment for people with Major Depressive Disorder (MDD). Type of study: Interventional (Investigational Drug) Who can participate: Individuals with a diagnosis of Major Depressive Disorder, ages 18- 65

  21. Efficacy and Safety of Antidiabetic Agents for Major Depressive

    Background: This meta-analysis aimed to determine the efficacy and safety of antidiabetic agents in the treatment of major depressive disorder and bipolar depression. Methods: Randomized controlled trials (RCTs) of antidiabetic agents in major depressive disorder or bipolar depression were searched in three electronic databases and three clinical trial registry websites from their inception up ...

  22. 6% of Americans who live alone report depression, a new CDC study finds

    The number of people living alone in the U.S. jumped to nearly 38 million. A new study shows people who live alone are more likely to report depression if they didn't have other social supports.

  23. Major Depressive Disorder

    Major depressive disorder (MDD) has been ranked as the third cause of the burden of disease worldwide in 2008 by WHO, which has projected that this disease will rank first by 2030.

  24. Walking, yoga and strength training may treat depression as well as

    Researchers analyzed data from 218 studies on exercise and depression, with more than 14,000 people included. While there was risk for bias in the studies, the whole-body benefits of exercise ...

  25. The serotonin theory of depression: a systematic umbrella ...

    The serotonin hypothesis of depression is still influential. We aimed to synthesise and evaluate evidence on whether depression is associated with lowered serotonin concentration or activity in...

  26. New study of adolescents and young adults reveals that cognitive

    The research team used data from the 2021 National Survey on Drug Use and Health to conduct descriptive and multivariable analyses to estimate the national prevalence of nicotine vaping by disability type and examined major depressive episodes (MDEs) as a risk factor for nicotine vaping.

  27. Social media harms teens' mental health, mounting evidence shows. What now?

    In recent years, studies have started to show a causal link between teen social media use and reduced well-being or mood disorders, chiefly depression and anxiety.

  28. Home-based brain stimulation ineffective for major depression, study finds

    The study, known as the Portable Transcranial Electrical Stimulation and Internet-Based Behavioral Therapy for Major Depression Study (PSYLECT), was conducted from April 2021 to October 2022.

  29. At the Human Longevity Lab, studying methods to slow or reverse aging

    The Potocsnak Longevity Institute at Northwestern University Feinberg School of Medicine has launched the Human Longevity Laboratory, a longitudinal, cross-sectional study that will investigate the relationship between chronological age and biological age across different organ systems and validate interventions that may reverse or slow down the processes of aging.