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Experimental depression treatment is nearly 80% effective in controlled study

In a double-blind controlled study, high doses of magnetic brain stimulation, given on an accelerated timeline and individually targeted, caused remission in 79% of trial participants with severe depression.

October 28, 2021 - By Mandy Erickson

Since receiving an experimental depression treatment at Stanford, Tommy Van Brocklin has been walking Scout for "the sheer joy of it." Nellie Van Brocklin

A new type of magnetic brain stimulation brought rapid remission to almost 80% of participants with severe depression in a study conducted at the  Stanford University School of Medicine .

The treatment, known as Stanford accelerated intelligent neuromodulation therapy (SAINT) or simply Stanford neuromodulation therapy, is an intensive, individualized form of transcranial magnetic stimulation. In the study, remission typically occurred within days and lasted months. The only side effects were temporary fatigue and headaches.

“It works well, it works quickly and it’s noninvasive,” said  Nolan Williams , MD, an assistant professor of psychiatry and behavioral sciences. “It could be a game changer.” Williams is the senior author of the study, which was published Oct. 29 in the  American Journal of Psychiatry .

Twenty-nine people with treatment-resistant depression participated in the study: About half received SAINT, and the rest underwent a placebo procedure that mimicked the real treatment. After five days of treatment, 78.6% of the participants in the treatment group were no longer depressed, according to several standard methods of evaluation. “It’s quite a dramatic effect, and it’s quite sustained,” said  Alan Schatzberg , MD, the Kenneth T. Norris, Jr. Professor in Psychiatry and Behavioral Sciences, who was a co-author of the study.

A lifetime of depression

Tommy Van Brocklin, 60, has suffered from depression since he was 15. “In 1975, they didn’t have the medication and understanding they do now,” he said. “I was told I wasn’t trying hard enough.”

“I’ve functioned all these years, but it’s been very difficult at times,” the civil engineer added. Talk therapy helped “for about half a day after an appointment.” When selective serotonin reuptake inhibitors became available in the 1990s, he started on paroxetine, commonly sold under the brand name Paxil.

“It worked like a miracle drug,” he said, but after 10 or 15 years it started to lose its effect. After 25 years, it stopped working entirely. He tried other medications, but none helped; one even made him suicidal. 

His sister, who lives near Stanford, connected him with the researchers studying SAINT. He flew from his home in Memphis, Tennessee, and underwent the treatment in September. He felt nothing the first day; on day two, he began feeling emotional — “I felt the struggle of what I’d been through all these years.”

“The next day, all of a sudden, it broke through,” he said. “I felt so much better, and it’s stuck with me.”

Specialized magnetic stimulation

The transcranial magnetic stimulation treatment currently approved by the Food and Drug Administration requires six weeks of once-daily sessions. Only about half of patients who undergo the treatment improve, and only about a third experience remission from depression.

SAINT advances that treatment by targeting the magnetic pulses according to each patient’s neurocircuitry and providing a greater number of pulses at a faster pace.

In the study, the researchers first used MRI to locate the best location to target within each participant’s dorsolateral prefrontal cortex, which regulates executive functions, such as problem solving and inhibiting unwanted responses. They applied the stimulation in a subregion that has the strongest relationship with the subgenual cingulate, a part of the brain that is overactive in people experiencing depression. The transcranial magnetic stimulation strengthens the connection between the two regions, facilitating dorsolateral prefrontal cortex control of the activity in the subgenual cingulate.

The researchers also used 1,800 pulses per session instead of 600. (The larger amount has been used safely in other forms of brain stimulation for neurological disorders such as Parkinson’s disease.) And instead of providing one treatment a day, they gave participants 10 10-minute treatments, with 50-minute breaks in between.

For the control group, the researchers disguised the treatment with a magnetic coil that mimicked the experience of the magnetic pulse; both the control and active treatment groups wore noise-canceling earphones and received a topical ointment to dull sensation. Neither the researcher administering the procedure nor the participant knew whether the participant was receiving real treatment.

A hard-to-treat group

The trial participants ranged in age from 22 to 80; on average, they had suffered depression for nine years. They had tried medications, but either they had had no effect or they had stopped working. During the trial, participants who were on medication maintained their regular dosage; participants who weren’t taking medications did not start any.

Nolan Williams demonstrates SAINT, the magnetic brain stimulation therapy he and his colleagues developed, on Deirdre Lehman, a participant in a previous study of the treatment. Steve Fisch

Within four weeks after treatment, 12 of the 14 participants who had received the treatment improved, and 11 of them met FDA criteria for remission. In contrast, only two of the 15 participants who had received the placebo met the criteria for remission.

Because the study participants typically felt better within days of starting SAINT, the researchers are hoping it can be used to quickly treat patients who are at a crisis point. Patients who start taking medication for depression typically don’t experience any reduction of symptoms for a month.

“We want to get this into emergency departments and psychiatric wards where we can treat people who are in a psychiatric emergency,” Williams said. “The period right after hospitalization is when there’s the highest risk of suicide.”

Van Brocklin said that since he returned home following treatment, he’s made some radical changes. “I have a really strong desire to get my life together,” he said.

“I don’t procrastinate anymore,” he added. “I’m sleeping better. I completely quit alcohol. I’m walking my dog and playing the guitar again, for nothing more than the sheer joy of it.”

Most importantly, he said, “I’m remaining positive and being respectful of others. These are big changes in my life.”

Other Stanford scientists who contributed to the study are former postdoctoral scholars Eleanor Cole, PhD, and Angela Phillips, PhD; Brandon Bentzley, MD, PhD, David Carreon, MD, Jennifer Keller, PhD, Kristin Raj, MD, and Flint Espil, PhD, all clinical assistant professors of psychiatry and behavioral sciences; clinical research coordinators Katy Stimpson, Romina Nejad, Clive Veerapal, Nicole Odenwald and Maureen Chang; former clinical research coordinators Fahim Barmak, MD, Naushaba Khan and Rachel Rapier; postdoctoral scholars Kirsten Cherian, PhD, James Bishop, PhD, Azeezat Azeez, PhD, and John Coetzee, PhD; life science research professional Heather Pankow; clinical research manager Jessica Hawkins; Charles DeBattista, MD, professor of psychiatry and behavioral sciences; and Booil Jo, PhD, associate professor of psychiatry and behavioral sciences.

Scientists from the U.S. Department of Veterans Affairs; Palo Alto University; the Centre for Neuroimaging and Cognitive Genomics at the National University of Ireland; and the School of Medicine at Southern Illinois University, Carbondale, contributed to the research.

The research was funded by a Brain and Behavior Research Foundation Young Investigator Award, Charles R. Schwab, the David and Amanda Chao Fund II, the Amy Roth PhD Fund, the Neuromodulation Research Fund, the Lehman Family, the Still Charitable Trust, the Marshall and Dee Ann Payne Fund, and the Gordie Brookstone Fund.

Stanford’s Department of Psychiatry and Behavioral Sciences also contributed to the work.

If you're interested in participating in a study, please email [email protected] .

About Stanford Medicine

Stanford Medicine is an integrated academic health system comprising the Stanford School of Medicine and adult and pediatric health care delivery systems. Together, they harness the full potential of biomedicine through collaborative research, education and clinical care for patients. For more information, please visit med.stanford.edu .

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• Effect of exercise for...

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.

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.

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.

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).

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.

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.

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

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).

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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Newly discovered trigger for major depression opens new possibilities for treatments

by University of Florida

A common amino acid, glycine, can deliver a "slow-down" signal to the brain, likely contributing to major depression, anxiety and other mood disorders in some people, scientists at the Wertheim UF Scripps Institute for Biomedical Innovation & Technology have found.

The discovery, outlined Thursday in the journal Science , improves understanding of the biological causes of major depression and could accelerate efforts to develop new, faster-acting medications for such hard-to-treat mood disorders , said neuroscientist Kirill Martemyanov, Ph.D., corresponding author of the study.

"Most medications for people with depression take weeks before they kick in, if they do at all. New and better options are really needed," said Martemyanov, who chairs the neuroscience department at the institute in Jupiter.

Major depression is among the world's most urgent health needs. Its numbers have surged in recent years, especially among young adults. As depression's disability, suicide numbers and medical expenses have climbed, a study by the U.S. Centers for Disease Control and Prevention in 2021 put its economic burden at $326 billion annually in the United States.

Martemyanov said he and his team of students and postdoctoral researchers have spent many years working toward this discovery. They didn't set out to find a cause, much less a possible treatment route for depression. Instead, they asked a basic question: How do sensors on brain cells receive and transmit signals into the cells ? Therein lay the key to understanding vision, pain, memory, behavior and possibly much more, Martemyanov suspected.

"It's amazing how basic science goes. Fifteen years ago we discovered a binding partner for proteins we were interested in, which led us to this new receptor," Martemyanov said. "We've been unspooling this for all this time."

In 2018 the Martemyanov team found the new receptor was involved in stress-induced depression. If mice lacked the gene for the receptor, called GPR158, they proved surprisingly resilient to chronic stress.

That offered strong evidence that GPR158 could be therapeutic target , he said. But what sent the signal?

A breakthrough came in 2021, when his team solved the structure of GPR158 . What they saw surprised them. The GPR158 receptor looked like a microscopic clamp with a compartment—akin to something they had seen in bacteria, not human cells.

"We were barking up the completely wrong tree before we saw the structure," Martemyanov said. "We said, 'Wow, that's an amino acid receptor. There are only 20, so we screened them right away and only one fit perfectly. That was it. It was glycine."

That wasn't the only odd thing. The signaling molecule was not an activator in the cells, but an inhibitor. The business end of GPR158 connected to a partnering molecule that hit the brakes rather than the accelerator when bound to glycine.

"Usually receptors like GPR158, known as G protein Coupled Receptors, bind G proteins. This receptor was binding an RGS protein, which is a protein that has the opposite effect of activation," said Thibaut Laboute, Ph.D., a postdoctoral researcher from Martemyanov's group and first author of the study.

Scientists have been cataloging the role of cell receptors and their signaling partners for decades. Those that still don't have known signalers, such as GPR158, have been dubbed "orphan receptors."

The finding means that GPR158 is no longer an orphan receptor, Laboute said. Instead, the team renamed it mGlyR, short for "metabotropic glycine receptor."

"An orphan receptor is a challenge. You want to figure out how it works," Laboute said. "What makes me really excited about this discovery is that it may be important for people's lives. That's what gets me up in the morning."

Laboute and Martemyanov are listed as inventors on a patent application describing methods to study GPR158 activity. Martemyanov is a cofounder of Blueshield Therapeutics, a startup company pursuing GPR158 as a drug target.

Glycine itself is sold as a nutritional supplement billed as improving mood. It is a basic building block of proteins and affects many different cell types, sometimes in complex ways. In some cells, it sends slow-down signals, while in other cell types, it sends excitatory signals. Some studies have linked glycine to the growth of invasive prostate cancer.

More research is needed to understand how the body maintains the right balance of mGlyR receptors and how brain cell activity is affected, he said. He intends to keep at it.

"We are in desperate need of new depression treatments," Martemyanov said. "If we can target this with something specific, it makes sense that it could help. We are working on it now."

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Biological, Psychological, and Social Determinants of Depression: A Review of Recent Literature

Olivia remes.

1 Institute for Manufacturing, University of Cambridge, Cambridge CB3 0FS, UK

João Francisco Mendes

2 NOVA Medical School, Universidade NOVA de Lisboa, 1099-085 Lisbon, Portugal; ku.ca.mac@94cfj

Peter Templeton

3 IfM Engage Limited, Institute for Manufacturing, University of Cambridge, Cambridge CB3 0FS, UK; ku.ca.mac@32twp

4 The William Templeton Foundation for Young People’s Mental Health (YPMH), Cambridge CB2 0AH, UK

Associated Data

Depression is one of the leading causes of disability, and, if left unmanaged, it can increase the risk for suicide. The evidence base on the determinants of depression is fragmented, which makes the interpretation of the results across studies difficult. The objective of this study is to conduct a thorough synthesis of the literature assessing the biological, psychological, and social determinants of depression in order to piece together the puzzle of the key factors that are related to this condition. Titles and abstracts published between 2017 and 2020 were identified in PubMed, as well as Medline, Scopus, and PsycInfo. Key words relating to biological, social, and psychological determinants as well as depression were applied to the databases, and the screening and data charting of the documents took place. We included 470 documents in this literature review. The findings showed that there are a plethora of risk and protective factors (relating to biological, psychological, and social determinants) that are related to depression; these determinants are interlinked and influence depression outcomes through a web of causation. In this paper, we describe and present the vast, fragmented, and complex literature related to this topic. This review may be used to guide practice, public health efforts, policy, and research related to mental health and, specifically, depression.

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. According to the World Health Organization, depression is a leading cause of disability; research shows that it is a burdensome condition with a negative impact on educational trajectories, work performance, and other areas of life [ 1 , 3 ]. Depression can start early in the lifecourse and, if it remains unmanaged, may increase the risk for substance abuse, chronic conditions, such as cardiovascular disease, and premature mortality [ 4 , 5 , 6 , 7 , 8 ].

Treatment for depression exists, such as pharmacotherapy, cognitive behavioural therapy, and other modalities. A meta-analysis of randomized, placebo-controlled trials of patients shows that 56–60% of people respond well to active treatment with antidepressants (selective serotonin reuptake inhibitors, tricyclic antidepressants) [ 9 ]. However, pharmacotherapy may be associated with problems, such as side-effects, relapse issues, a potential duration of weeks until the medication starts working, and possible limited efficacy in mild cases [ 10 , 11 , 12 , 13 , 14 ]. Psychotherapy is also available, but access barriers can make it difficult for a number of people to get the necessary help.

Studies on depression have increased significantly over the past few decades. However, the literature remains fragmented and the interpretation of heterogeneous findings across studies and between fields is difficult. The cross-pollination of ideas between disciplines, such as genetics, neurology, immunology, and psychology, is limited. Reviews on the determinants of depression have been conducted, but they either focus exclusively on a particular set of determinants (ex. genetic risk factors [ 15 ]) or population sub-group (ex. children and adolescents [ 16 ]) or focus on characteristics measured predominantly at the individual level (ex. focus on social support, history of depression [ 17 ]) without taking the wider context (ex. area-level variables) into account. An integrated approach paying attention to key determinants from the biological, psychological, and social spheres, as well as key themes, such as the lifecourse perspective, enables clinicians and public health authorities to develop tailored, person-centred approaches.

The primary aim of this literature review: to address the aforementioned challenges, we have synthesized recent research on the biological, psychological, and social determinants of depression and we have reviewed research from fields including genetics, immunology, neurology, psychology, public health, and epidemiology, among others.

The subsidiary aim: we have paid special attention to important themes, including the lifecourse perspective and interactions between determinants, to guide further efforts by public health and medical professionals.

This literature review can be used as an evidence base by those in public health and the clinical setting and can be used to inform targeted interventions.

2. Materials and Methods

We conducted a review of the literature on the biological, psychological, and social determinants of depression in the last 4 years. We decided to focus on these determinants after discussions with academics (from the Manchester Metropolitan University, University of Cardiff, University of Colorado, Boulder, University of Cork, University of Leuven, University of Texas), charity representatives, and people with lived experience at workshops held by the University of Cambridge in 2020. In several aspects, we attempted to conduct this review according to PRISMA guidelines [ 18 ].

The inclusion and exclusion criteria are the following:

• - We included documents, such as primary studies, literature reviews, systematic reviews, meta-analyses, reports, and commentaries on the determinants of depression. The determinants refer to variables that appear to be linked to the development of depression, such as physiological factors (e.g., the nervous system, genetics), but also factors that are further away or more distal to the condition. Determinants may be risk or protective factors, and individual- or wider-area-level variables.
• - We focused on major depressive disorder, treatment-resistant depression, dysthymia, depressive symptoms, poststroke depression, perinatal depression, as well as depressive-like behaviour (common in animal studies), among others.
• - We included papers regardless of the measurement methods of depression.
• - We included papers that focused on human and/or rodent research.
• - This review focused on articles written in the English language.
• - Documents published between 2017–2020 were captured to provide an understanding of the latest research on this topic.
• - Studies that assessed depression as a comorbidity or secondary to another disorder.
• - Studies that did not focus on rodent and/or human research.
• - Studies that focused on the treatment of depression. We made this decision, because this is an in-depth topic that would warrant a separate stand-alone review.
• Next, we searched PubMed (2017–2020) using keywords related to depression and determinants. Appendix A contains the search strategy used. We also conducted focused searches in Medline, Scopus, and PsycInfo (2017–2020).
• Once the documents were identified through the databases, the inclusion and exclusion criteria were applied to the titles and abstracts. Screening of documents was conducted by O.R., and a subsample was screened by J.M.; any discrepancies were resolved through a communication process.
• The full texts of documents were retrieved, and the inclusion and exclusion criteria were again applied. A subsample of documents underwent double screening by two authors (O.R., J.M.); again, any discrepancies were resolved through communication.
• a. A data charting form was created to capture the data elements of interest, including the authors, titles, determinants (biological, psychological, social), and the type of depression assessed by the research (e.g., major depression, depressive symptoms, depressive behaviour).
• b. The data charting form was piloted on a subset of documents, and refinements to it were made. The data charting form was created with the data elements described above and tested in 20 studies to determine whether refinements in the wording or language were needed.
• c. Data charting was conducted on the documents.
• d. Narrative analysis was conducted on the data charting table to identify key themes. When a particular finding was noted more than once, it was logged as a potential theme, with a review of these notes yielding key themes that appeared on multiple occasions. When key themes were identified, one researcher (O.R.) reviewed each document pertaining to that theme and derived concepts (key determinants and related outcomes). This process (a subsample) was verified by a second author (J.M.), and the two authors resolved any discrepancies through communication. Key themes were also checked as to whether they were of major significance to public mental health and at the forefront of public health discourse according to consultations we held with stakeholders from the Manchester Metropolitan University, University of Cardiff, University of Colorado, Boulder, University of Cork, University of Leuven, University of Texas, charity representatives, and people with lived experience at workshops held by the University of Cambridge in 2020.

We condensed the extensive information gleaned through our review into short summaries (with key points boxes for ease of understanding and interpretation of the data).

Through the searches, 6335 documents, such as primary studies, literature reviews, systematic reviews, meta-analyses, reports, and commentaries, were identified. After applying the inclusion and exclusion criteria, 470 papers were included in this review ( Supplementary Table S1 ). We focused on aspects related to biological, psychological, and social determinants of depression (examples of determinants and related outcomes are provided under each of the following sections.

3.1. Biological Factors

The following aspects will be discussed in this section: physical health conditions; then specific biological factors, including genetics; the microbiome; inflammatory factors; stress and hypothalamic–pituitary–adrenal (HPA) axis dysfunction, and the kynurenine pathway. Finally, aspects related to cognition will also be discussed in the context of depression.

3.1.1. Physical Health Conditions

Studies on physical health conditions—key points:

• The presence of a physical health condition can increase the risk for depression
• Psychological evaluation in physically sick populations is needed
• There is large heterogeneity in study design and measurement; this makes the comparison of findings between and across studies difficult

A number of studies examined the links between the outcome of depression and physical health-related factors, such as bladder outlet obstruction, cerebral atrophy, cataract, stroke, epilepsy, body mass index and obesity, diabetes, urinary tract infection, forms of cancer, inflammatory bowel disorder, glaucoma, acne, urea accumulation, cerebral small vessel disease, traumatic brain injury, and disability in multiple sclerosis [ 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 , 58 , 59 , 60 , 61 , 62 , 63 , 64 , 65 , 66 , 67 , 68 , 69 , 70 , 71 ]. For example, bladder outlet obstruction has been linked to inflammation and depressive behaviour in rodent research [ 24 ]. The presence of head and neck cancer also seemed to be related to an increased risk for depressive disorder [ 45 ]. Gestational diabetes mellitus has been linked to depressive symptoms in the postpartum period (but no association has been found with depression in the third pregnancy trimester) [ 50 ], and a plethora of other such examples of relationships between depression and physical conditions exist. As such, the assessment of psychopathology and the provision of support are necessary in individuals of ill health [ 45 ]. Despite the large evidence base on physical health-related factors, differences in study methodology and design, the lack of standardization when it comes to the measurement of various physical health conditions and depression, and heterogeneity in the study populations makes it difficult to compare studies [ 50 ].

The next subsections discuss specific biological factors, including genetics; the microbiome; inflammatory factors; stress and hypothalamic–pituitary–adrenal (HPA) axis dysfunction, and the kynurenine pathway; and aspects related to cognition.

3.1.2. Genetics

Studies on genetics—key points:

There were associations between genetic factors and depression; for example:

• The brain-derived neurotrophic factor (BDNF) plays an important role in depression
• Links exist between major histocompatibility complex region genes, as well as various gene polymorphisms and depression
• Single nucleotide polymorphisms (SNPs) of genes involved in the tryptophan catabolites pathway are of interest in relation to depression

A number of genetic-related factors, genomic regions, polymorphisms, and other related aspects have been examined with respect to depression [ 61 , 72 , 73 , 74 , 75 , 76 , 77 , 78 , 79 , 80 , 81 , 82 , 83 , 84 , 85 , 86 , 87 , 88 , 89 , 90 , 91 , 92 , 93 , 94 , 95 , 96 , 97 , 98 , 99 , 100 , 101 , 102 , 103 , 104 , 105 , 106 , 107 , 108 , 109 , 110 , 111 , 112 , 113 , 114 , 115 , 116 , 117 , 118 , 119 , 120 , 121 , 122 , 123 , 124 , 125 , 126 , 127 , 128 , 129 , 130 , 131 , 132 , 133 , 134 , 135 , 136 , 137 , 138 , 139 , 140 ]. The influence of BDNF in relation to depression has been amply studied [ 117 , 118 , 141 , 142 , 143 ]. Research has shown associations between depression and BDNF (as well as candidate SNPs of the BDNF gene, polymorphisms of the BDNF gene, and the interaction of these polymorphisms with other determinants, such as stress) [ 129 , 144 , 145 ]. Specific findings have been reported: for example, a study reported a link between the BDNF rs6265 allele (A) and major depressive disorder [ 117 ].

Other research focused on major histocompatibility complex region genes, endocannabinoid receptor gene polymorphisms, as well as tissue-specific genes and gene co-expression networks and their links to depression [ 99 , 110 , 112 ]. The SNPs of genes involved in the tryptophan catabolites pathway have also been of interest when studying the pathogenesis of depression.

The results from genetics studies are compelling; however, the findings remain mixed. One study indicated no support for depression candidate gene findings [ 122 ]. Another study found no association between specific polymorphisms and major depressive disorder [ 132 ]. As such, further research using larger samples is needed to corroborate the statistically significant associations reported in the literature.

3.1.3. Microbiome

Studies on the microbiome—key points:

• The gut bacteria and the brain communicate via both direct and indirect pathways called the gut-microbiota-brain axis (the bidirectional communication networks between the central nervous system and the gastrointestinal tract; this axis plays an important role in maintaining homeostasis).
• A disordered microbiome can lead to inflammation, which can then lead to depression
• There are possible links between the gut microbiome, host liver metabolism, brain inflammation, and depression

The common themes of this review have focused on the microbiome/microbiota or gut metabolome [ 146 , 147 , 148 , 149 , 150 , 151 , 152 , 153 , 154 , 155 , 156 , 157 , 158 , 159 , 160 , 161 ], the microbiota-gut-brain axis, and related factors [ 152 , 162 , 163 , 164 , 165 , 166 , 167 ]. When there is an imbalance in the intestinal bacteria, this can interfere with emotional regulation and contribute to harmful inflammatory processes and mood disorders [ 148 , 151 , 153 , 155 , 157 ]. Rodent research has shown that there may be a bidirectional association between the gut microbiota and depression: a disordered gut microbiota can play a role in the onset of this mental health problem, but, at the same time, the existence of stress and depression may also lead to a lower level of richness and diversity in the microbiome [ 158 ].

Research has also attempted to disentangle the links between the gut microbiome, host liver metabolism, brain inflammation, and depression, as well as the role of the ratio of lactobacillus to clostridium [ 152 ]. The literature has also examined the links between medication, such as antibiotics, and mood and behaviour, with the findings showing that antibiotics may be related to depression [ 159 , 168 ]. The links between the microbiome and depression are complex, and further studies are needed to determine the underpinning causal mechanisms.

3.1.4. Inflammation

Studies on inflammation—key points:

• Pro-inflammatory cytokines are linked to depression
• Pro-inflammatory cytokines, such as the tumour necrosis factor (TNF)-alpha, may play an important role
• Different methods of measurement are used, making the comparison of findings across studies difficult

Inflammation has been a theme in this literature review [ 60 , 161 , 164 , 169 , 170 , 171 , 172 , 173 , 174 , 175 , 176 , 177 , 178 , 179 , 180 , 181 , 182 , 183 , 184 ]. The findings show that raised levels of inflammation (because of factors such as pro-inflammatory cytokines) have been associated with depression [ 60 , 161 , 174 , 175 , 178 ]. For example, pro-inflammatory cytokines, such as tumour necrosis factor (TNF)-alpha, have been linked to depression [ 185 ]. Various determinants, such as early life stress, have also been linked to systemic inflammation, and this can increase the risk for depression [ 186 ].

Nevertheless, not everyone with elevated inflammation develops depression; therefore, this is just one route out of many linked to pathogenesis. Despite the compelling evidence reported with respect to inflammation, it is difficult to compare the findings across studies because of different methods used to assess depression and its risk factors.

3.1.5. Stress and HPA Axis Dysfunction

Studies on stress and HPA axis dysfunction—key points:

• Stress is linked to the release of proinflammatory factors
• The dysregulation of the HPA axis is linked to depression
• Determinants are interlinked in a complex web of causation

Stress was studied in various forms in rodent populations and humans [ 144 , 145 , 155 , 174 , 176 , 180 , 185 , 186 , 187 , 188 , 189 , 190 , 191 , 192 , 193 , 194 , 195 , 196 , 197 , 198 , 199 , 200 , 201 , 202 , 203 , 204 , 205 , 206 , 207 , 208 , 209 , 210 , 211 ].

Although this section has some overlap with others (as is to be expected because all of these determinants and body systems are interlinked), a number of studies have focused on the impact of stress on mental health. Stress has been mentioned in the literature as a risk factor of poor mental health and has emerged as an important determinant of depression. The effects of this variable are wide-ranging, and a short discussion is warranted.

Stress has been linked to the release of inflammatory factors, as well as the development of depression [ 204 ]. When the stress is high or lasts for a long period of time, this may negatively impact the brain. Chronic stress can impact the dendrites and synapses of various neurons, and may be implicated in the pathway leading to major depressive disorder [ 114 ]. As a review by Uchida et al. indicates, stress may be associated with the “dysregulation of neuronal and synaptic plasticity” [ 114 ]. Even in rodent studies, stress has a negative impact: chronic and unpredictable stress (and other forms of tension or stress) have been linked to unusual behaviour and depression symptoms [ 114 ].

The depression process and related brain changes, however, have also been linked to the hyperactivity or dysregulation of the HPA axis [ 127 , 130 , 131 , 182 , 212 ]. One review indicates that a potential underpinning mechanism of depression relates to “HPA axis abnormalities involved in chronic stress” [ 213 ]. There is a complex relationship between the HPA axis, glucocorticoid receptors, epigenetic mechanisms, and psychiatric sequelae [ 130 , 212 ].

In terms of the relationship between the HPA axis and stress and their influence on depression, the diathesis–stress model offers an explanation: it could be that early stress plays a role in the hyperactivation of the HPA axis, thus creating a predisposition “towards a maladaptive reaction to stress”. When this predisposition then meets an acute stressor, depression may ensue; thus, in line with the diathesis–stress model, a pre-existing vulnerability and stressor can create fertile ground for a mood disorder [ 213 ]. An integrated review by Dean and Keshavan [ 213 ] suggests that HPA axis hyperactivity is, in turn, related to other determinants, such as early deprivation and insecure early attachment; this again shows the complex web of causation between the different determinants.

3.1.6. Kynurenine Pathway

Studies on the kynurenine pathway—key points:

• The kynurenine pathway is linked to depression
• Indolamine 2,3-dioxegenase (IDO) polymorphisms are linked to postpartum depression

The kynurenine pathway was another theme that emerged in this review [ 120 , 178 , 181 , 184 , 214 , 215 , 216 , 217 , 218 , 219 , 220 , 221 ]. The kynurenine pathway has been implicated not only in general depressed mood (inflammation-induced depression) [ 184 , 214 , 219 ] but also postpartum depression [ 120 ]. When the kynurenine metabolism pathway is activated, this results in metabolites, which are neurotoxic.

A review by Jeon et al. notes a link between the impairment of the kynurenine pathway and inflammation-induced depression (triggered by treatment for various physical diseases, such as malignancy). The authors note that this could represent an important opportunity for immunopharmacology [ 214 ]. Another review by Danzer et al. suggests links between the inflammation-induced activation of indolamine 2,3-dioxegenase (the enzyme that converts tryptophan to kynurenine), the kynurenine metabolism pathway, and depression, and also remarks about the “opportunities for treatment of inflammation-induced depression” [ 184 ].

3.1.7. Cognition

Studies on cognition and the brain—key points:

• Cognitive decline and cognitive deficits are linked to increased depression risk
• Cognitive reserve is important in the disability/depression relationship
• Family history of cognitive impairment is linked to depression

A number of studies have focused on the theme of cognition and the brain. The results show that factors, such as low cognitive ability/function, cognitive vulnerability, cognitive impairment or deficits, subjective cognitive decline, regression of dendritic branching and hippocampal atrophy/death of hippocampal cells, impaired neuroplasticity, and neurogenesis-related aspects, have been linked to depression [ 131 , 212 , 222 , 223 , 224 , 225 , 226 , 227 , 228 , 229 , 230 , 231 , 232 , 233 , 234 , 235 , 236 , 237 , 238 , 239 ]. The cognitive reserve appears to act as a moderator and can magnify the impact of certain determinants on poor mental health. For example, in a study in which participants with multiple sclerosis also had low cognitive reserve, disability was shown to increase the risk for depression [ 63 ]. Cognitive deficits can be both causal and resultant in depression. A study on individuals attending outpatient stroke clinics showed that lower scores in cognition were related to depression; thus, cognitive impairment appears to be associated with depressive symptomatology [ 226 ]. Further, Halahakoon et al. [ 222 ] note a meta-analysis [ 240 ] that shows that a family history of cognitive impairment (in first degree relatives) is also linked to depression.

In addition to cognitive deficits, low-level cognitive ability [ 231 ] and cognitive vulnerability [ 232 ] have also been linked to depression. While cognitive impairment may be implicated in the pathogenesis of depressive symptoms [ 222 ], negative information processing biases are also important; according to the ‘cognitive neuropsychological’ model of depression, negative affective biases play a central part in the development of depression [ 222 , 241 ]. Nevertheless, the evidence on this topic is mixed and further work is needed to determine the underpinning mechanisms between these states.

3.2. Psychological Factors

Studies on psychological factors—key points:

• There are many affective risk factors linked to depression
• Determinants of depression include negative self-concept, sensitivity to rejection, neuroticism, rumination, negative emotionality, and others

A number of studies have been undertaken on the psychological factors linked to depression (including mastery, self-esteem, optimism, negative self-image, current or past mental health conditions, and various other aspects, including neuroticism, brooding, conflict, negative thinking, insight, cognitive fusion, emotional clarity, rumination, dysfunctional attitudes, interpretation bias, and attachment style) [ 66 , 128 , 140 , 205 , 210 , 228 , 235 , 242 , 243 , 244 , 245 , 246 , 247 , 248 , 249 , 250 , 251 , 252 , 253 , 254 , 255 , 256 , 257 , 258 , 259 , 260 , 261 , 262 , 263 , 264 , 265 , 266 , 267 , 268 , 269 , 270 , 271 , 272 , 273 , 274 , 275 , 276 , 277 , 278 , 279 , 280 , 281 , 282 , 283 , 284 , 285 , 286 , 287 , 288 , 289 , 290 ]. Determinants related to this condition include low self-esteem and shame, among other factors [ 269 , 270 , 275 , 278 ]. Several emotional states and traits, such as neuroticism [ 235 , 260 , 271 , 278 ], negative self-concept (with self-perceptions of worthlessness and uselessness), and negative interpretation or attention biases have been linked to depression [ 261 , 271 , 282 , 283 , 286 ]. Moreover, low emotional clarity has been associated with depression [ 267 ]. When it comes to the severity of the disorder, it appears that meta-emotions (“emotions that occur in response to other emotions (e.g., guilt about anger)” [ 268 ]) have a role to play in depression [ 268 ].

A determinant that has received much attention in mental health research concerns rumination. Rumination has been presented as a mediator but also as a risk factor for depression [ 57 , 210 , 259 ]. When studied as a risk factor, it appears that the relationship of rumination with depression is mediated by variables that include limited problem-solving ability and insufficient social support [ 259 ]. However, rumination also appears to act as a mediator: for example, this variable (particularly brooding rumination) lies on the causal pathway between poor attention control and depression [ 265 ]. This shows that determinants may present in several forms: as moderators or mediators, risk factors or outcomes, and this is why disentangling the relationships between the various factors linked to depression is a complex task.

The psychological determinants are commonly researched variables in the mental health literature. A wide range of factors have been linked to depression, such as the aforementioned determinants, but also: (low) optimism levels, maladaptive coping (such as avoidance), body image issues, and maladaptive perfectionism, among others [ 269 , 270 , 272 , 273 , 275 , 276 , 279 , 285 , 286 ]. Various mechanisms have been proposed to explain the way these determinants increase the risk for depression. One of the underpinning mechanisms linking the determinants and depression concerns coping. For example, positive fantasy engagement, cognitive biases, or personality dispositions may lead to emotion-focused coping, such as brooding, and subsequently increase the risk for depression [ 272 , 284 , 287 ]. Knowing the causal mechanisms linking the determinants to outcomes provides insight for the development of targeted interventions.

3.3. Social Determinants

Studies on social determinants—key points:

• Social determinants are the conditions in the environments where people are born, live, learn, work, play, etc.; these influence (mental) health [ 291 ]
• There are many social determinants linked to depression, such as sociodemographics, social support, adverse childhood experiences
• Determinants can be at the individual, social network, community, and societal levels

Studies also focused on the social determinants of (mental) health; these are the conditions in which people are born, live, learn, work, play, and age, and have a significant influence on wellbeing [ 291 ]. Factors such as age, social or socioeconomic status, social support, financial strain and deprivation, food insecurity, education, employment status, living arrangements, marital status, race, childhood conflict and bullying, violent crime exposure, abuse, discrimination, (self)-stigma, ethnicity and migrant status, working conditions, adverse or significant life events, illiteracy or health literacy, environmental events, job strain, and the built environment have been linked to depression, among others [ 52 , 133 , 235 , 236 , 239 , 252 , 269 , 280 , 292 , 293 , 294 , 295 , 296 , 297 , 298 , 299 , 300 , 301 , 302 , 303 , 304 , 305 , 306 , 307 , 308 , 309 , 310 , 311 , 312 , 313 , 314 , 315 , 316 , 317 , 318 , 319 , 320 , 321 , 322 , 323 , 324 , 325 , 326 , 327 , 328 , 329 , 330 , 331 , 332 , 333 , 334 , 335 , 336 , 337 , 338 , 339 , 340 , 341 , 342 , 343 , 344 , 345 , 346 , 347 , 348 , 349 , 350 , 351 , 352 , 353 , 354 , 355 , 356 , 357 , 358 , 359 , 360 , 361 , 362 , 363 , 364 , 365 , 366 , 367 , 368 , 369 , 370 , 371 ]. Social support and cohesion, as well as structural social capital, have also been identified as determinants [ 140 , 228 , 239 , 269 , 293 , 372 , 373 , 374 , 375 , 376 , 377 , 378 , 379 ]. In a study, part of the findings showed that low levels of education have been shown to be linked to post-stroke depression (but not severe or clinical depression outcomes) [ 299 ]. A study within a systematic review indicated that having only primary education was associated with a higher risk of depression compared to having secondary or higher education (although another study contrasted this finding) [ 296 ]. Various studies on socioeconomic status-related factors have been undertaken [ 239 , 297 ]; the research has shown that a low level of education is linked to depression [ 297 ]. Low income is also related to depressive disorders [ 312 ]. By contrast, high levels of education and income are protective [ 335 ].

A group of determinants touched upon by several studies included adverse childhood or early life experiences: ex. conflict with parents, early exposure to traumatic life events, bullying and childhood trauma were found to increase the risk of depression (ex. through pathways, such as inflammation, interaction effects, or cognitive biases) [ 161 , 182 , 258 , 358 , 362 , 380 ].

Gender-related factors were also found to play an important role with respect to mental health [ 235 , 381 , 382 , 383 , 384 , 385 ]. Gender inequalities can start early on in the lifecourse, and women were found to be twice as likely to have depression as men. Gender-related factors were linked to cognitive biases, resilience and vulnerabilities [ 362 , 384 ].

Determinants can impact mental health outcomes through underpinning mechanisms. For example, harmful determinants can influence the uptake of risk behaviours. Risk behaviours, such as sedentary behaviour, substance abuse and smoking/nicotine exposure, have been linked to depression [ 226 , 335 , 355 , 385 , 386 , 387 , 388 , 389 , 390 , 391 , 392 , 393 , 394 , 395 , 396 , 397 , 398 , 399 , 400 , 401 ]. Harmful determinants can also have an impact on diet. Indeed, dietary aspects and diet components (ex. vitamin D, folate, selenium intake, iron, vitamin B12, vitamin K, fiber intake, zinc) as well as diet-related inflammatory potential have been linked to depression outcomes [ 161 , 208 , 236 , 312 , 396 , 402 , 403 , 404 , 405 , 406 , 407 , 408 , 409 , 410 , 411 , 412 , 413 , 414 , 415 , 416 , 417 , 418 , 419 , 420 , 421 , 422 , 423 , 424 , 425 , 426 , 427 , 428 ]. A poor diet has been linked to depression through mechanisms such as inflammation [ 428 ].

Again, it is difficult to constrict diet to the ‘social determinants of health’ category as it also relates to inflammation (biological determinants) and could even stand alone as its own category. Nevertheless, all of these factors are interlinked and influence one another in a complex web of causation, as mentioned elsewhere in the paper.

Supplementary Figure S1 contains a representation of key determinants acting at various levels: the individual, social network, community, and societal levels. The determinants have an influence on risk behaviours, and this, in turn, can affect the mood (i.e., depression), body processes (ex. can increase inflammation), and may negatively influence brain structure and function.

3.4. Others

Studies on ‘other’ determinants—key points:

• A number of factors are related to depression
• These may not be as easily categorized as the other determinants in this paper

A number of factors arose in this review that were related to depression; it was difficult to place these under a specific heading above, so this ‘other’ category was created. A number of these could be sorted under the ‘social determinants of depression’ category. For example, being exposed to deprivation, hardship, or adversity may increase the risk for air pollution exposure and nighttime shift work, among others, and the latter determinants have been found to increase the risk for depression. Air pollution could also be regarded as an ecologic-level (environmental) determinant of mental health.

Nevertheless, we have decided to leave these factors in a separate category (because their categorization may not be as immediately clear-cut as others), and these factors include: low-level light [ 429 ], weight cycling [ 430 ], water contaminants [ 431 ], trade [ 432 ], air pollution [ 433 , 434 ], program-level variables (ex. feedback and learning experience) [ 435 ], TV viewing [ 436 ], falls [ 437 ], various other biological factors [ 116 , 136 , 141 , 151 , 164 , 182 , 363 , 364 , 438 , 439 , 440 , 441 , 442 , 443 , 444 , 445 , 446 , 447 , 448 , 449 , 450 , 451 , 452 , 453 , 454 , 455 , 456 , 457 , 458 , 459 , 460 , 461 , 462 , 463 , 464 , 465 , 466 , 467 , 468 , 469 ], mobile phone use [ 470 ], ultrasound chronic exposure [ 471 ], nighttime shift work [ 472 ], work accidents [ 473 ], therapy enrollment [ 226 ], and exposure to light at night [ 474 ].

4. Cross-Cutting Themes

4.1. lifecourse perspective.

Studies on the lifecourse perspective—key points:

• Early life has an importance on mental health
• Stress has been linked to depression
• In old age, the decline in social capital is important

Trajectories and life events are important when it comes to the lifecourse perspective. Research has touched on the influence of prenatal or early life stress on an individual’s mental health trajectory [ 164 , 199 , 475 ]. Severe stress that occurs in the form of early-life trauma has also been associated with depressive symptoms [ 362 , 380 ]. It may be that some individuals exposed to trauma develop thoughts of personal failure, which then serve as a catalyst of depression [ 380 ].

At the other end of the life trajectory—old age—specific determinants have been linked to an increased risk for depression. Older people are at a heightened risk of losing their social networks, and structural social capital has been identified as important in relation to depression in old age [ 293 ].

4.2. Gene–Environment Interactions

Studies on gene–environment interactions—key points:

• The environment and genetics interact to increase the risk of depression
• The etiology of depression is multifactorial
• Adolescence is a time of vulnerability

A number of studies have touched on gene–environment interactions [ 72 , 77 , 82 , 119 , 381 , 476 , 477 , 478 , 479 , 480 , 481 ]. The interactions between genetic factors and determinants, such as negative life events (ex. relationship and social difficulties, serious illness, unemployment and financial crises) and stressors (ex. death of spouse, minor violations of law, neighbourhood socioeconomic status) have been studied in relation to depression [ 82 , 135 , 298 , 449 , 481 ]. A study reported an interaction of significant life events with functional variation in the serotonin-transporter-linked polymorphic region (5-HTTLPR) allele type (in the context of multiple sclerosis) and linked this to depression [ 361 ], while another reported an interaction between stress and 5-HTTLPR in relation to depression [ 480 ]. Other research reported that the genetic variation of HPA-axis genes has moderating effects on the relationship between stressors and depression [ 198 ]. Another study showed that early-life stress interacts with gene variants to increase the risk for depression [ 77 ].

Adolescence is a time of vulnerability [ 111 , 480 ]. Perceived parental support has been found to interact with genes (GABRR1, GABRR2), and this appears to be associated with depressive symptoms in adolescence [ 480 ]. It is important to pay special attention to critical periods in the lifecourse so that adequate support is provided to those who are most vulnerable.

The etiology of depression is multifactorial, and it is worthwhile to examine the interaction between multiple factors, such as epigenetic, genetic, and environmental factors, in order to truly understand this mental health condition. Finally, taking into account critical periods of life when assessing gene–environment interactions is important for developing targeted interventions.

5. Discussion

Depression is one of the most common mental health conditions, and, if left untreated, it can increase the risk for substance abuse, anxiety disorders, and suicide. In the past 20 years, a large number of studies on the risk and protective factors of depression have been undertaken in various fields, such as genetics, neurology, immunology, and epidemiology. However, there are limitations associated with the extant evidence base. The previous syntheses on depression are limited in scope and focus exclusively on social or biological factors, population sub-groups, or examine depression as a comorbidity (rather than an independent disorder). The research on the determinants and causal pathways of depression is fragmentated and heterogeneous, and this has not helped to stimulate progress when it comes to the prevention and intervention of this condition—specifically unravelling the complexity of the determinants related to this condition and thus refining the prevention and intervention methods.

The scope of this paper was to bring together the heterogeneous, vast, and fragmented literature on depression and paint a picture of the key factors that contribute to this condition. The findings from this review show that there are important themes when it comes to the determinants of depression, such as: the microbiome, dysregulation of the HPA axis, inflammatory reactions, the kynurenine pathway, as well as psychological and social factors. It may be that physical factors are proximal determinants of depression, which, in turn, are acted on by more distal social factors, such as deprivation, environmental events, and social capital.

The Marmot Report [ 291 ], the World Health Organization [ 482 ], and Compton et al. [ 483 ] highlight that the most disadvantaged segments of society are suffering (the socioeconomic context is important), and this inequality in resources has translated to inequality in mental health outcomes [ 483 ]. To tackle the issue of egalitarianism and restore equality in the health between the groups, the social determinants need to be addressed [ 483 ]. A wide range of determinants of mental health have been identified in the literature: age, gender, ethnicity, family upbringing and early attachment patterns, social support, access to food, water and proper nutrition, and community factors. People spiral downwards because of individual- and societal-level circumstances; therefore, these circumstances along with the interactions between the determinants need to be considered.

Another important theme in the mental health literature is the lifecourse perspective. This shows that the timing of events has significance when it comes to mental health. Early life is a critical period during the lifespan at which cognitive processes develop. Exposure to harmful determinants, such as stress, during this period can place an individual on a trajectory of depression in adulthood or later life. When an individual is exposed to harmful determinants during critical periods and is also genetically predisposed to depression, the risk for the disorder can be compounded. This is why aspects such as the lifecourse perspective and gene–environment interactions need to be taken into account. Insight into this can also help to refine targeted interventions.

A number of interventions for depression have been developed or recommended, addressing, for example, the physical factors described here and lifestyle modifications. Interventions targeting various factors, such as education and socioeconomic status, are needed to help prevent and reduce the burden of depression. Further research on the efficacy of various interventions is needed. Additional studies are also needed on each of the themes described in this paper, for example: the biological factors related to postpartum depression [ 134 ], and further work is needed on depression outcomes, such as chronic, recurrent depression [ 452 ]. Previous literature has shown that chronic stress (associated with depression) is also linked to glucocorticoid receptor resistance, as well as problems with the regulation of the inflammatory response [ 484 ]. Further work is needed on this and the underpinning mechanisms between the determinants and outcomes. This review highlighted the myriad ways of measuring depression and its determinants [ 66 , 85 , 281 , 298 , 451 , 485 ]. Thus, the standardization of the measurements of the outcomes (ex. a gold standard for measuring depression) and determinants is essential; this can facilitate comparisons of findings across studies.

5.1. Strengths

This paper has important strengths. It brings together the wide literature on depression and helps to bridge disciplines in relation to one of the most common mental health problems. We identified, selected, and extracted data from studies, and provided concise summaries.

5.2. Limitations

The limitations of the review include missing potentially important studies; however, this is a weakness that cannot be avoided by literature reviews. Nevertheless, the aim of the review was not to identify each study that has been conducted on the risk and protective factors of depression (which a single review is unable to capture) but rather to gain insight into the breadth of literature on this topic, highlight key biological, psychological, and social determinants, and shed light on important themes, such as the lifecourse perspective and gene–environment interactions.

6. Conclusions

We have reviewed the determinants of depression and recognize that there are a multitude of risk and protective factors at the individual and wider ecologic levels. These determinants are interlinked and influence one another. We have attempted to describe the wide literature on this topic, and we have brought to light major factors that are of public mental health significance. This review may be used as an evidence base by those in public health, clinical practice, and research.

This paper discusses key areas in depression research; however, an exhaustive discussion of all the risk factors and determinants linked to depression and their mechanisms is not possible in one journal article—which, by its very nature, a single paper cannot do. We have brought to light overarching factors linked to depression and a workable conceptual framework that may guide clinical and public health practice; however, we encourage other researchers to continue to expand on this timely and relevant work—particularly as depression is a top priority on the policy agenda now.

Acknowledgments

Thank you to Isla Kuhn for the help with the Medline, Scopus, and PsycInfo database searches.

Supplementary Materials

The following are available online at https://www.mdpi.com/article/10.3390/brainsci11121633/s1 , Figure S1: Conceptual framework: Determinants of depression, Table S1: Data charting—A selection of determinants from the literature.

Appendix A.1. Search Strategy

Search: ((((((((((((((((“Gene-Environment Interaction”[Majr]) OR (“Genetics”[Mesh])) OR (“Genome-Wide Association Study”[Majr])) OR (“Microbiota”[Mesh] OR “Gastrointestinal Microbiome”[Mesh])) OR (“Neurogenic Inflammation”[Mesh])) OR (“genetic determinant”)) OR (“gut-brain-axis”)) OR (“Kynurenine”[Majr])) OR (“Cognition”[Mesh])) OR (“Neuronal Plasticity”[Majr])) OR (“Neurogenesis”[Mesh])) OR (“Genes”[Mesh])) OR (“Neurology”[Majr])) OR (“Social Determinants of Health”[Majr])) OR (“Glucocorticoids”[Mesh])) OR (“Tryptophan”[Mesh])) AND (“Depression”[Mesh] OR “Depressive Disorder”[Mesh]) Filters: from 2017—2020.

Ovid MEDLINE(R) and Epub Ahead of Print, In-Process, In-Data-Review & Other Non-Indexed Citations, Daily and Versions(R)

• exp *Depression/
• exp *Depressive Disorder/
• exp *”Social Determinants of Health”/
• exp *Tryptophan/
• exp *Glucocorticoids/
• exp *Neurology/
• exp *Genes/
• exp *Neurogenesis/
• exp *Neuronal Plasticity/
• exp *Kynurenine/
• exp *Genetics/
• exp *Neurogenic Inflammation/
• exp *Gastrointestinal Microbiome/
• exp *Genome-Wide Association Study/
• exp *Gene-Environment Interaction/
• exp *Depression/et [Etiology]
• exp *Depressive Disorder/et
• or/4-16   637368
• limit 22 to yr = “2017–Current”
• “cause* of depression”.mp.
• “cause* of depression”.ti.
• (cause adj3 (depression or depressive)).ti.
• (caus* adj3 (depression or depressive)).ti.

Appendix A.2. PsycInfo

(TITLE ( depression OR “ Depressive Disorder ”) AND TITLE (“ Social Determinants of Health ” OR tryptophan OR glucocorticoids OR neurology OR genes OR neurogenesis OR “ Neuronal Plasticity ” OR kynurenine OR genetics OR “ Neurogenic Inflammation ” OR “ Gastrointestinal Microbiome ” OR “ Genome-Wide Association Study ” OR “ Gene-Environment Interaction ” OR aetiology OR etiology )) OR TITLE ( cause* W/3 ( depression OR depressive )).

Author Contributions

O.R. was responsible for the design of the study and methodology undertaken. Despite P.T.’s involvement in YPMH, he had no role in the design of the study; P.T. was responsible for the conceptualization of the study. Validation was conducted by O.R. and J.F.M. Formal analysis (data charting) was undertaken by O.R. O.R. and P.T. were involved in the investigation, resource acquisition, and data presentation. The original draft preparation was undertaken by O.R. The writing was conducted by O.R., with review and editing by P.T. and J.F.M. Funding acquisition was undertaken by O.R. and P.T. All authors have read and agreed to the published version of the manuscript.

This research was funded by The William Templeton Foundation for Young People’s Mental Health, Cambridge Philosophical Society, and the Aviva Foundation.

Conflicts of Interest

The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results.

Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

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No evidence that depression is caused by low serotonin levels, finds comprehensive review

20 July 2022

After decades of study, there remains no clear evidence that serotonin levels or serotonin activity are responsible for depression, according to a major review of prior research led by UCL scientists.

The new umbrella review – an overview of existing meta-analyses and systematic reviews – published in Molecular Psychiatry , suggests that depression is not likely caused by a chemical imbalance, and calls into question what antidepressants do. Most antidepressants are selective serotonin reuptake inhibitors (SSRIs), which were originally said to work by correcting abnormally low serotonin levels. There is no other accepted pharmacological mechanism by which antidepressants affect the symptoms of depression.

Lead author Professor Joanna Moncrieff, a Professor of Psychiatry at UCL and a consultant psychiatrist at North East London NHS Foundation Trust (NELFT), said: “It is always difficult to prove a negative, but I think we can safely say that after a vast amount of research conducted over several decades, there is no convincing evidence that depression is caused by serotonin abnormalities, particularly by lower levels or reduced activity of serotonin.

“The popularity of the ‘chemical imbalance’ theory of depression has coincided with a huge increase in the use of antidepressants. Prescriptions for antidepressants have risen dramatically since the 1990s, with one in six adults in England and 2% of teenagers now being prescribed an antidepressant in a given year.

“Many people take antidepressants because they have been led to believe their depression has a biochemical cause, but this new research suggests this belief is not grounded in evidence.”

The umbrella review aimed to capture all relevant studies that have been published in the most important fields of research on serotonin and depression. The studies included in the review involved tens of thousands of participants.

Research that compared levels of serotonin and its breakdown products in the blood or brain fluids did not find a difference between people diagnosed with depression and healthy control (comparison) participants.

Research on serotonin receptors and the serotonin transporter, the protein targeted by most antidepressants, found weak and inconsistent evidence suggestive of higher levels of serotonin activity in people with depression. However, the researchers say the findings are likely explained by the use of antidepressants among people diagnosed with depression, since such effects were not reliably ruled out.

The authors also looked at studies where serotonin levels were artificially lowered in hundreds of people by depriving their diets of the amino acid required to make serotonin. These studies have been cited as demonstrating that a serotonin deficiency is linked to depression. A meta-analysis conducted in 2007 and a sample of recent studies found that lowering serotonin in this way did not produce depression in hundreds of healthy volunteers, however. There was very weak evidence in a small subgroup of people with a family history of depression, but this only involved 75 participants, and more recent evidence was inconclusive.

Very large studies involving tens of thousands of patients looked at gene variation, including the gene for the serotonin transporter. They found no difference in these genes between people with depression and healthy controls. These studies also looked at the effects of stressful life events and found that these exerted a strong effect on people’s risk of becoming depressed – the more stressful life events a person had experienced, the more likely they were to be depressed. A famous early study found a relationship between stressful events, the type of serotonin transporter gene a person had and the chance of depression. But larger, more comprehensive studies suggest this was a false finding.

These findings together led the authors to conclude that there is “no support for the hypothesis that depression is caused by lowered serotonin activity or concentrations.”

The researchers say their findings are important as studies show that as many as 85-90% of the public believes that depression is caused by low serotonin or a chemical imbalance. A growing number of scientists and professional bodies are recognising the chemical imbalance framing as an over-simplification.* There is also evidence that believing that low mood is caused by a chemical imbalance leads people to have a pessimistic outlook on the likelihood of recovery, and the possibility of managing moods without medical help. This is important because most people will meet criteria for anxiety or depression at some point in their lives.

The authors also found evidence from a large meta-analysis that people who used antidepressants had lower levels of serotonin in their blood. They concluded that some evidence was consistent with the possibility that long-term antidepressant use reduces serotonin concentrations. The researchers say this may imply that the increase in serotonin that some antidepressants produce in the short term could lead to compensatory changes in the brain that produce the opposite effect in the long term.

While the study did not review the efficacy of antidepressants, the authors encourage further research and advice into treatments that might focus instead on managing stressful or traumatic events in people’s lives, such as with psychotherapy, alongside other practices such as exercise or mindfulness, or addressing underlying contributors such as poverty, stress and loneliness.

Professor Moncrieff said: “Our view is that patients should not be told that depression is caused by low serotonin or by a chemical imbalance, and they should not be led to believe that antidepressants work by targeting these unproven abnormalities. We do not understand what antidepressants are doing to the brain exactly, and giving people this sort of misinformation prevents them from making an informed decision about whether to take antidepressants or not.”

Co-author Dr Mark Horowitz, a training psychiatrist and Clinical Research Fellow in Psychiatry at UCL and NELFT, said: “I had been taught that depression was caused by low serotonin in my psychiatry training and had even taught this to students in my own lectures. Being involved in this research was eye-opening and feels like everything I thought I knew has been flipped upside down.

“One interesting aspect in the studies we examined was how strong an effect adverse life events played in depression, suggesting low mood is a response to people’s lives and cannot be boiled down to a simple chemical equation.”

Professor Moncrieff added: “Thousands of people suffer from side effects of antidepressants, including the severe withdrawal effects that can occur when people try to stop them, yet prescription rates continue to rise. We believe this situation has been driven partly by the false belief that depression is due to a chemical imbalance. It is high time to inform the public that this belief is not grounded in science.”  

The researchers caution that anyone considering withdrawing from antidepressants should seek the advice of a health professional, given the risk of adverse effects following withdrawal. Professor Moncrieff and Dr Horowitz are conducting ongoing research into how best to gradually stop taking antidepressants .

• Research paper in Molecular Psychiatry
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• * For example, the Royal College of Psychiatrists removed all reference to ‘chemical imbalances’ from their website in recent years. They now say in official statements that “the original idea that antidepressants ‘correct a chemical imbalance in the brain’ is an over-simplification.”
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Depression and Serotonin: What the New Review Actually Says

Using but not overusing the evidence presented in this controversial study..

Posted July 26, 2022 | Reviewed by Abigail Fagan

• What Is Depression?
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• A new published review finds no evidence that low serotonin levels cause depression.
• The authors use their data to refute the "chemical imbalance" hypothesis of depression, which is an old and imprecise term.
• Despite the claims of some, the study does not disprove that biological factors are irrelevant to depression.
• The dominant model of depression for decades has been one that recognizes the importance of biological, psychological, and social factors.

Some quite strong feelings and very broad conclusions have come following the recent publication of a review study published in the reputable journal Molecular Psychiatry that found little evidence that low levels of the brain neurotransmitter serotonin are related to the development of depression . The study has received strong media coverage and has spurred intense exchanges on social media . Some see the study as a scientific earthquake and total vindication for those who have been skeptical of the “biological” theory of depression from the start, while others view it as the penultimate dead horse beating that has absolutely no bearing on current practices for understanding or treating depression, now the world’s #1 cause for disability.

The study is what is called an “umbrella” review, which means that no new data are presented and the authors are reviewing and summarizing studies that themselves reviewed and summarized individual research studies. They focus on studies that have used various lines of investigation to link depression with low serotonin levels. This includes research (in people only) that compare levels of serotonin in the blood or cerebrospinal fluid between people who are depressed and not-depressed, studies of how well certain protein receptors are able to bind serotonin when depressed, and studies examining the role of a single but very famous gene , the serotonin transporter. The bottom line is that they find little to no evidence from the types of studies they examined that low serotonin levels or activity play a significant role in the development of depression.

These kinds of studies often put people to sleep, but in this case the reaction has been intense and personal. Much of this has to do with the authors pulling in the term “chemical imbalance” as implications of their work. This poorly-chosen term is actually one of psychiatry’s creation and now it’s being thrown back in our face imbued with even broader meaning.

While originally employed as a shortcut term for the monoamine hypothesis (briefly, the idea that some kind of deficiency in a few brain neurotransmitters, including serotonin, was a key contributor to depression), it was quickly incorporated by the pharmaceutical industry as a catch phrase for marketing purposes to depict depression as a biological illness requiring biological treatments.

The monoamine hypothesis faded as a dominant model with further research and was supplanted decades ago by the “biopsychosocial” model of psychiatric disorders which continues to prevail today. Nevertheless, the old chemical imbalance lingo remains a lightening rod to critics of psychiatry. More recently, the term has begun to be the punching bag for people who don’t believe that biological factors (also a squishy term) of any sort play a role in causing depression.

Unfortunately, the current review makes little distinction between the narrower serotonin deficit theory of depression they actually address and this ever expanding but still ill-defined “chemical imbalance” view of mental illness. This has predictably pushed the door wide open for those who want to take this review as proof that neurobiology doesn’t matter at all when it comes to depression, a claim which isn’t supported by this review or wider research whatsoever.

There is some middle ground here. While many of us in psychiatry are a little embarrassed by what now looks like some over simplistic and naïve ideas about the development of depression, there’s no denying that many of these individual studies supporting a straightforward role of serotonin and depression created quite a lot of enthusiasm in their day among the psychiatric community when first published.

These notions were then imparted to students and patients in an attempt to explain what depression was. I remember some of my own Powerpoint slides I previously used in teaching related to a very influential study that the onset of depression was related to the combination of having a particular version of the serotonin transporter gene combined with the presence of an adverse environment. There’s also no denying that selected studies supporting serotonin’s role were heavily leveraged by the pharmaceutical industry to market more antidepressants . For most of us, however, the attractiveness of these simple theories wasn’t in their advertising value but in their ability to help patients see their struggles as something that wasn’t their fault at a time when feelings of guilt and worthlessness were already sky high. Overall, then, this study is an uncomfortable reminder that we did indeed learn and repeat ideas that today look a little foolish.

At the same time, it is important not to let people take this extremely limited study to wild and sweeping conclusions and to prevent the portrayal of the psychiatric community in archaic and stereotypical forms. Depression experts have well moved on from the low serotonin theory years if not decades ago, and although they could have announced this shift better, there certainly is no organized effort to suppress this information. Over two years ago I published a post here on Psychology Today called The Rise and Fall of the Depression Gene which cited some of the same research as this review. Personally, I don’t think I’ve used the term “chemical imbalance” to explain depression in 20 years and current textbooks and information sources provide much more nuance and balance (and vagueness) when describing the origin of depression. Yes, you can still hear people occasionally drop the chemical imbalance term when trying to turn complicated processes into quick soundbites, but that’s a long way from it being an organized and accepted theory promoted by the proverbial psychiatry establishment.

The review also has a number of real problems, which is a little ironic for a study which is one of the few not to have a “limitations” section as part of the manuscript. I’ll blame the editorial staff of the journal for that one, as well as for letting the authors use studies that examine simple depression versus controls differences in serotonin levels to conclude that serotonin, let alone all biological factors, have no role in depression at all.

Reading this study, one would never know that there are animal studies, neuroimaging studies, twin and adoption studies, inflammation research, and many other lines of evidence suggesting that depression is a very complex condition that people can arrive at from multiple pathways. Interestingly, if you look directly at some of the source studies for this review, you will see some of this evidence. For example, the meta-analysis by Ogawa cited in the review did indeed find no evidence of a link between serotonin and depression but did find evidence of a link between dopamine and depression. This statement should not be interpreted as a pitch to trade one overly simplistic view of depression for another but to point out the hazards of making conclusions that far overstep your data.

Another poor choice in this review is that while the authors don’t quite tell readers to stop taking antidepressants, they walk right up to that edge with their claim that the old chemical imbalance theory is one of the primary justifications for why people take them (rather than something like wanting to feel better). This, in my view, is careless and problematic for people who take antidepressants and for those who care for them. Just as many rightly point out that the fact that antidepressants' help shouldn’t be used as evidence of a serotonin deficit in depression, the lack of a clear serotonin deficit in depression shouldn’t be used as evidence to abandon the use of these important medications, any more than (as been said previously) a lack of an “acetaminophen deficit” should be used as evidence not to use Tylenol when you have a headache. Admittedly, we don’t know very well how antidepressants work, but for millions of people, they do.

In the end, it seems best to welcome this study for what it does say while being quite clear about what it doesn’t. Depression is complicated. Different people get there from different paths and find their way out through different means. Ascribing all depression as due to low serotonin, or poor diet , or trauma , or smartphones, or poverty will just end with a study like this.

Moncrieff J, Cooper RE, Stockmann T, et al. The serotonin theory of depression: A systematic umbrella review of the evidence. Mol Psychiatry. 2022; Jul 20. doi: 10.1038/s41380-022-01661-0. Online ahead of print.

Ogawa S, Tsuchimine S, Kunugi H. Cerebrospinal fluid monoamine metabolite concentrations in depressive disorder: A meta-analysis of historic evidence. J Psychiatr Res. 2018; 105:137–46.

David Rettew, M.D. , is a child and adolescent psychiatrist and faculty at the Oregon Health and Science University.

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• Exercise Cuts Stress-Related Brain Activity
• Teen Stress and Depression in Adults

Earlier Headlines

Tuesday, april 23, 2024.

• Social Media Affects People's Views on Mental Illness

Wednesday, April 10, 2024

• Brain Stimulation Treatment May Improve Depression, Anxiety in Older Adults

Monday, April 8, 2024

• Heart Disease, Depression Linked by Inflammation

Thursday, April 4, 2024

• Prairie Voles Display Signs of Human-Like Depression
• Feeding the Lonely Brain

Thursday, March 28, 2024

• Positive Associations Between Premenstrual Disorders and Perinatal Depression
• For Younger Women, Mental Health Now May Predict Heart Health Later

Wednesday, March 27, 2024

• People With Depression See No Immediate Change from Common GP Assessment, Study Shows

Tuesday, March 26, 2024

• Large-Scale Animal Study Links Brain pH Changes to Wide-Ranging Cognitive Issues

Wednesday, March 20, 2024

• Treating Anxiety, Depression in People With Heart Disease Reduced ER Visits, Hospitalizations

Friday, March 1, 2024

• Link Between Adversity, Psychiatric and Cognitive Decline

Monday, February 26, 2024

• Gut-Brain Communication Turned on Its Axis
• Intervention Reduces Likelihood of Developing Postpartum Anxiety and Depression by More Than 70%
• People in Urban Areas With More Green Space Have Better Mental Health

Wednesday, February 21, 2024

• Maternal Mental Conditions Drive Climbing Death Rate in U.S., Evidence Review Finds

Tuesday, February 20, 2024

• Modifying Brain Molecule Relaxin-3 Can Potentially Reduce Side Effects in Treating Anxiety, Depression and More
• Wildfires Linked to Surge in Mental Health-Related Emergency Department Visits

Monday, February 19, 2024

• Understanding the Relationship Between Our Sleep, Body Clock and Mental Health

Tuesday, February 13, 2024

• A Closer Look at Cannabis Use and Binge Eating

Thursday, February 8, 2024

• Benefits of Resistance Exercise Training in Treatment of Anxiety and Depression
• Ketamine's Promise for Severe Depression Grows, but Major Questions Remain

Wednesday, February 7, 2024

• Researchers Make Progress Toward Developing Blood Tests for Psychiatric and Neurological Disorders
• Stress Influences Brain and Psyche Via Immune System

Monday, February 5, 2024

• Are Body Temperature and Depression Linked? Science Says, Yes

Thursday, February 1, 2024

• Psychological Care Delivered Over the Phone Is an Effective Way to Combat Loneliness and Depression, According to a Major New Study
• When a Stressful Situation Is Perceived as a Threat, Health and Wellbeing Suffer

Wednesday, January 24, 2024

• 'Furry Fruit' Improves Mental Health -- Fast
• Can We Predict When a Migraine Attack Will Occur?

Thursday, January 18, 2024

• Relationships With Caring Adults Provide a Buffer Against Depression, Anxiety, Regardless of Adverse Childhood Experiences

Wednesday, January 17, 2024

• Therapy Versus Medication: Comparing Treatments for Depression in Heart Disease

Wednesday, January 10, 2024

• Newly Identified Genes for Depression May Lead to New Treatments
• Reduced Drug Use Is a Meaningful Treatment Outcome for People With Stimulant Use Disorders, Study Shows

Monday, January 8, 2024

• Clear Link Between Autoimmune Disease and Perinatal Depression

Thursday, January 4, 2024

• Bipolar Disorder Linked to Early Death
• Better Mental, Physical Health in Older People Tied to Living Near Nature

Thursday, December 21, 2023

• Connection Between Light Levels and Mental Health -- Climate Change Could Also Have an Impact in the Future

Thursday, December 14, 2023

• Genetic 'protection' Against Depression Was No Match for Pandemic Stress

Wednesday, December 13, 2023

• Body Dissatisfaction Linked With Depression Risk in Children

Tuesday, December 12, 2023

• Caregiving Can Be Stressful, but It Could Also Lower Risk of Depression

Thursday, December 7, 2023

• Discrimination During Pregnancy May Alter Circuits in Infants' Brains

Tuesday, December 5, 2023

• Depression, Constipation, and Urinary Tract Infections May Precede MS Diagnosis

Monday, December 4, 2023

• New Study Maps Ketamine's Effects on Brain

Tuesday, November 28, 2023

• Heart Over Head? Stages of the Heart's Cycle Affect Neural Responses
• Understanding Subjective Beliefs Could Be Vital to Tailoring More Effective Treatments for Depression and ADHD

Monday, November 27, 2023

• Discrimination During Pregnancy Can Affect Infant's Brain Circuitry

Thursday, November 16, 2023

• A Small Molecule Blocks Aversive Memory Formation, Providing a Potential Treatment Target for Depression
• High Levels of Maternal Stress During Pregnancy Linked to Children's Behavior Problems
• New Studies of Brain Activity Explain Benefits of Electroconvulsive Therapy

Tuesday, November 14, 2023

• Genetic Testing Could Greatly Benefit Patients With Depression, Save Health System Millions

Thursday, November 9, 2023

• Brain Imaging Identifies Biomarkers of Mental Illness

Tuesday, November 7, 2023

• Poetry Can Help People Cope With Loneliness or Isolation
• When Dads Are Feeling a Bit Depressed or Anxious, How Do Kids Fare?

Monday, November 6, 2023

• Location of Strong Sense of Discomfort in Brain Found

Friday, November 3, 2023

• Paid Family Leave Boosted Postpartum Wellbeing, Breastfeeding Rates

Thursday, November 2, 2023

• New Clues to the Mechanism Behind Treatment-Resistant Depression

Wednesday, November 1, 2023

• Contraceptive Pill Users Less Likely to Report Depression

Friday, October 27, 2023

• fMRI Study Finds Correlated Shifts in Brain Connectivity Associated With Overthinking in Adolescents

Wednesday, October 25, 2023

• Simple Blood Test Can Help Diagnose Bipolar Disorder

Monday, October 23, 2023

• Heated Yoga May Reduce Depression Symptoms, According to Recent Clinical Trial

Friday, October 20, 2023

• Pupil Response May Shed Light on Who Responds Best to Transcranial Magnetic Stimulation for Depression
• Consistent Lack of Sleep Is Related to Future Depressive Symptoms

Thursday, October 19, 2023

• Researchers Confirm Postpartum Depression Heritability, Home in on Treatment Mechanism
• Ketamine's Effect on Depression May Hinge on Hope
• Study Finds Men's Antidepressant Use Did Not Negatively Impact IVF Success

Tuesday, October 17, 2023

• Depression, Anxiety Common Among College Students

Thursday, October 5, 2023

• Psychedelics Improve Mental Health, Cognition in Special Ops Veterans

Wednesday, October 4, 2023

• Should Fathers Be Screened for Postpartum Depression? Pilot Study

Monday, October 2, 2023

• Study Indicates Possible Link Between Chronic Stress and Alzheimer's Disease

Friday, September 29, 2023

• Increased Risk of Depression and Anxiety When in Higher Education, Study Finds

Monday, September 25, 2023

• Depression, Anxiety May Be Among Early Signs of MS

Friday, September 22, 2023

• Study Shows Millions of People Live With Co-Occuring Chronic Pain and Mental Health Symptoms

Wednesday, September 20, 2023

• Suppressing Negative Thoughts May Be Good for Mental Health After All, Study Suggests
• Decoding Depression: Researchers Identify Crucial Biomarker That Tracks Recovery from Treatment-Resistant Depression

Monday, September 18, 2023

• Telecare Cuts Costs, Boosts Quality of Life for Dementia Patients

Wednesday, September 13, 2023

• Inflammatory Signs for Adolescent Depression Differ Between Boys and Girls

Tuesday, September 12, 2023

• Older Adults With Digestive Diseases Experience Higher Rates of Loneliness, Depression
• Your Body's Own Cannabinoid Molecules Calm You During Stress
• Targeted Ultrasound Can Change Brain Functions for Up to an Hour After Intervention

Monday, September 11, 2023

• Healthy Lifestyle Can Help Prevent Depression -- And New Research May Explain Why
• Antidepressants May Reduce Negative Memories While Improving Overall Memory

Friday, September 8, 2023

• Sleep-Wake Therapy Gives New Hope for Teens With Depression

Thursday, September 7, 2023

• Antidepressant Use in People With Both Physical Health Problems and Depression

Tuesday, August 29, 2023

• Your Genes Influence Whether Depression Leads to Other Diseases

Monday, August 21, 2023

• Overuse of Social Media and Devices Top Parent Concerns as Kids Head Back to School
• Formerly Depressed Patients Continue to Focus on Negative
• Strict Tech Rules at Boarding School a Bonus for Teens' Sleep

Monday, August 14, 2023

• New Maps Reveal the Individual Brain Changes Linked to Different Mental Illness

Friday, August 11, 2023

• Social Media Use Interventions Alleviate Symptoms of Depression

Tuesday, August 8, 2023

• Mothers Experiencing Depression Can Still Thrive as Parents

Monday, August 7, 2023

• Symptoms of the Body and the Mind Are Frequent Fellow Travelers

Wednesday, August 2, 2023

• Modern Antidepressants May Reduce Risk of Relapse for Patients With Bipolar Depression

Tuesday, August 1, 2023

• Researchers Identify Plasma Biomarkers of Mental Health Risk in Adolescents

Monday, July 31, 2023

• Half the Population to Have a Mental Health Disorder by 75

Friday, July 14, 2023

• Ketamine Effective for Treatment-Resistant Depression, Study Suggests

Thursday, July 13, 2023

• High-Quality Sleep Promotes Resilience to Depression and Anxiety

Wednesday, July 12, 2023

• New Talking Therapy for Depression Could Be More Effective and Cheaper Than CBT

Tuesday, July 11, 2023

• Lower Levels of Physical Activity Can Protect Against Depression Among Older Adults

Wednesday, July 5, 2023

• Depression After Traumatic Brain Injury Could Represent a New, Distinct Disease
• Memories of Childhood Abuse and Neglect Has Greater Impact on Mental Health Than the Experience Itself

Tuesday, June 27, 2023

• Brain Imaging-Based Biomarker of Depression Identified
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Trending Topics

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.

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.

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.

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.

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. 

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 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.

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 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 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 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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Depression and Suicide Risk Screening: Updated Evidence Report and Systematic Review for the US Preventive Services Task Force

Affiliations.

• 1 Kaiser Permanente Evidence-based Practice Center, Kaiser Permanente Center for Health Research, Portland, Oregon.
• 2 Gillings School of Global Public Health, University of North Carolina School of Medicine, Chapel Hill.
• PMID: 37338873
• DOI: 10.1001/jama.2023.7787

Importance: Depression is common and associated with substantial burden. Suicide rates have increased over the past decade, and both suicide attempts and deaths have devastating effects on individuals and families.

Objective: To review the benefits and harms of screening and treatment for depression and suicide risk and the accuracy of instruments to detect these conditions among primary care patients.

Data sources: MEDLINE, PsychINFO, Cochrane library through September 7, 2022; references of existing reviews; ongoing surveillance for relevant literature through November 25, 2022.

Study selection: English-language studies of screening or treatment compared with control conditions, or test accuracy of screening instruments (for depression, instruments were selected a priori; for suicide risk, all were included). Existing systematic reviews were used for treatment and test accuracy for depression.

Data extraction and synthesis: One investigator abstracted data; a second checked accuracy. Two investigators independently rated study quality. Findings were synthesized qualitatively, including reporting of meta-analysis results from existing systematic reviews; meta-analyses were conducted on original research when evidence was sufficient.

Main outcomes and measures: Depression outcomes; suicidal ideation, attempts, and deaths; sensitivity and specificity of screening tools.

Results: For depression, 105 studies were included: 32 original studies (N=385 607) and 73 systematic reviews (including ≈2138 studies [N ≈ 9.8 million]). Depression screening interventions, many of which included additional components beyond screening, were associated with a lower prevalence of depression or clinically important depressive symptomatology after 6 to 12 months (pooled odds ratio, 0.60 [95% CI, 0.50-0.73]; reported in 8 randomized clinical trials [n=10 244]; I2 = 0%). Several instruments demonstrated adequate test accuracy (eg, for the 9-item Patient Health Questionnaire at a cutoff of 10 or greater, the pooled sensitivity was 0.85 [95% CI, 0.79-0.89] and specificity was 0.85 [95% CI, 0.82-0.88]; reported in 47 studies [n = 11 234]). A large body of evidence supported benefits of psychological and pharmacologic treatment of depression. A pooled estimate from trials used for US Food and Drug Administration approval suggested a very small increase in the absolute risk of a suicide attempt with second-generation antidepressants (odds ratio, 1.53 [95% CI, 1.09-2.15]; n = 40 857; 0.7% of antidepressant users had a suicide attempt vs 0.3% of placebo users; median follow-up, 8 weeks). Twenty-seven studies (n = 24 826) addressed suicide risk. One randomized clinical trial (n=443) of a suicide risk screening intervention found no difference in suicidal ideation after 2 weeks between primary care patients who were and were not screened for suicide risk. Three studies of suicide risk test accuracy were included; none included replication of any instrument. The included suicide prevention studies generally did not demonstrate an improvement over usual care, which typically included specialty mental health treatment.

Conclusions and relevance: Evidence supported depression screening in primary care settings, including during pregnancy and postpartum. There are numerous important gaps in the evidence for suicide risk screening in primary care settings.

Publication types

• Meta-Analysis
• Research Support, U.S. Gov't, P.H.S.
• Systematic Review
• Antidepressive Agents / therapeutic use
• Depression* / diagnosis
• Depression* / therapy
• Mass Screening* / adverse effects
• Mass Screening* / methods
• Meta-Analysis as Topic
• Psychotherapy
• Randomized Controlled Trials as Topic
• Risk Assessment
• Sensitivity and Specificity
• Suicide, Attempted / prevention & control
• United States
• Antidepressive Agents

Depression is probably not caused by a chemical imbalance in the brain – new study

Senior Clinical Lecturer, Critical and Social Psychiatry, UCL

Clinical Research Fellow in Psychiatry, UCL

Disclosure statement

Joanna Moncrieff is a co-investigator on a National Institute of Health Research funded study exploring methods of antidepressant discontinuation. She is co-chair person of the Critical Psychiatry Network, an informal and unfunded group of psychiatrists and an unpaid board member of the voluntary group, the Council for Evidence-based Psychiatry.

Mark Horowitz is co-founder of a company aiming to help people safely stop unnecessary antidepressants in Canada. He is an (unpaid) associate of the International Institute of Psychiatric Drug Withdrawal (IIPDW) and a member of the Critical Psychiatry Network.

University College London provides funding as a founding partner of The Conversation UK.

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For three decades, people have been deluged with information suggesting that depression is caused by a “chemical imbalance” in the brain – namely an imbalance of a brain chemical called serotonin. However, our latest research review shows that the evidence does not support it.

You can listen to more articles from The Conversation, narrated by Noa, here .

Although first proposed in the 1960s , the serotonin theory of depression started to be widely promoted by the pharmaceutical industry in the 1990s in association with its efforts to market a new range of antidepressants, known as selective serotonin-reuptake inhibitors or SSRIs. The idea was also endorsed by official institutions such as the American Psychiatric Association, which still tells the public that “differences in certain chemicals in the brain may contribute to symptoms of depression”.

Countless doctors have repeated the message all over the world, in their private surgeries and in the media. People accepted what they were told. And many started taking antidepressants because they believed they had something wrong with their brain that required an antidepressant to put right. In the period of this marketing push, antidepressant use climbed dramatically, and they are now prescribed to one in six of the adult population in England , for example.

For a long time, certain academics , including some leading psychiatrists , have suggested that there is no satisfactory evidence to support the idea that depression is a result of abnormally low or inactive serotonin. Others continue to endorse the theory . Until now, however, there has been no comprehensive review of the research on serotonin and depression that could enable firm conclusions either way.

At first sight, the fact that SSRI-type antidepressants act on the serotonin system appears to support the serotonin theory of depression. SSRIs temporarily increase the availability of serotonin in the brain, but this does not necessarily imply that depression is caused by the opposite of this effect.

There are other explanations for antidepressants’ effects. In fact, drug trials show that antidepressants are barely distinguishable from a placebo (dummy pill) when it comes to treating depression. Also, antidepressants appear to have a generalised emotion-numbing effect which may influence people’s moods, although we do not know how this effect is produced or much about it.

First comprehensive review

There has been extensive research on the serotonin system since the 1990s, but it has not been collected systematically before. We conducted an “umbrella” review that involved systematically identifying and collating existing overviews of the evidence from each of the main areas of research into serotonin and depression. Although there have been systematic reviews of individual areas in the past, none have combined the evidence from all the different areas taking this approach.

One area of research we included was research comparing levels of serotonin and its breakdown products in the blood or brain fluid. Overall, this research did not show a difference between people with depression and those without depression.

Another area of research has focused on serotonin receptors , which are proteins on the ends of the nerves that serotonin links up with and which can transmit or inhibit serotonin’s effects. Research on the most commonly investigated serotonin receptor suggested either no difference between people with depression and people without depression, or that serotonin activity was actually increased in people with depression – the opposite of the serotonin theory’s prediction.

Research on the serotonin “transporter” , that is the protein which helps to terminate the effect of serotonin (this is the protein that SSRIs act on), also suggested that, if anything, there was increased serotonin activity in people with depression. However, these findings may be explained by the fact that many participants in these studies had used or were currently using antidepressants.

We also looked at research that explored whether depression can be induced in volunteers by artificially lowering levels of serotonin . Two systematic reviews from 2006 and 2007 and a sample of the ten most recent studies (at the time the current research was conducted) found that lowering serotonin did not produce depression in hundreds of healthy volunteers. One of the reviews showed very weak evidence of an effect in a small subgroup of people with a family history of depression, but this only involved 75 participants.

Very large studies involving tens of thousands of patients looked at gene variation, including the gene that has the instructions for making the serotonin transporter . They found no difference in the frequency of varieties of this gene between people with depression and healthy controls.

Although a famous early study found a relationship between the serotonin transporter gene and stressful life events, larger, more comprehensive studies suggest no such relationship exists. Stressful life events in themselves, however, exerted a strong effect on people’s subsequent risk of developing depression.

Some of the studies in our overview that included people who were taking or had previously taken antidepressants showed evidence that antidepressants may actually lower the concentration or activity of serotonin.

Not supported by the evidence

The serotonin theory of depression has been one of the most influential and extensively researched biological theories of the origins of depression. Our study shows that this view is not supported by scientific evidence. It also calls into question the basis for the use of antidepressants.

Most antidepressants now in use are presumed to act via their effects on serotonin. Some also affect the brain chemical noradrenaline. But experts agree that the evidence for the involvement of noradrenaline in depression is weaker than that for serotonin .

There is no other accepted pharmacological mechanism for how antidepressants might affect depression. If antidepressants exert their effects as placebos, or by numbing emotions, then it is not clear that they do more good than harm.

Although viewing depression as a biological disorder may seem like it would reduce stigma, in fact, research has shown the opposite , and also that people who believe their own depression is due to a chemical imbalance are more pessimistic about their chances of recovery.

It is important that people know that the idea that depression results from a “chemical imbalance” is hypothetical. And we do not understand what temporarily elevating serotonin or other biochemical changes produced by antidepressants do to the brain. We conclude that it is impossible to say that taking SSRI antidepressants is worthwhile, or even completely safe.

If you’re taking antidepressants, it’s very important you don’t stop doing so without speaking to your doctor first. But people need all this information to make informed decisions about whether or not to take these drugs.

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Little evidence that chemical imbalance causes depression, UCL scientists find

Researchers question use of antidepressants, prescribed to one in six UK adults

Scientists have called into question the widespread use of antidepressants after a major review found “no clear evidence” that low serotonin levels are responsible for depression.

Prescriptions for antidepressants have risen dramatically since the 1990s, with one in six adults and 2% of teenagers in England now being prescribed them. Millions more people around the world regularly use antidepressants.

“Many people take antidepressants because they have been led to believe their depression has a biochemical cause, but this new research suggests this belief is not grounded in evidence,” said the study’s lead author, Joanna Moncrieff, a professor of psychiatry at University College London and consultant psychiatrist at North East London NHS foundation trust.

“It is always difficult to prove a negative, but I think we can safely say that after a vast amount of research conducted over several decades, there is no convincing evidence that depression is caused by serotonin abnormalities, particularly by lower levels or reduced activity of serotonin.

“Thousands of people suffer from side-effects of antidepressants, including the severe withdrawal effects that can occur when people try to stop them, yet prescription rates continue to rise. We believe this situation has been driven partly by the false belief that depression is due to a chemical imbalance. It is high time to inform the public that this belief is not grounded in science.”

The new review of existing studies found that depression is not likely to be caused by a chemical imbalance and said people should be made aware of other options for treating it.

However, other experts, including from the Royal College of Psychiatrists, questioned the findings and urged people not to stop taking their medication in light of the study, arguing that antidepressants remained effective.

In the new analysis, researchers said 85% to 90% of the public believed depression was caused by low serotonin or a chemical imbalance.

Most antidepressants are selective serotonin reuptake inhibitors (SSRIs), originally said to work by correcting abnormally low serotonin levels.

The review, published in the journal Molecular Psychiatry , looked at studies examining serotonin and depression involving tens of thousands of people. One of the findings was that research comparing levels of serotonin and its breakdown products in the blood or brain fluids did not discover any difference between people diagnosed with depression and healthy people.

The authors also looked at studies where serotonin levels were artificially lowered in hundreds of people and concluded that lowering serotonin in this way did not produce depression in hundreds of healthy volunteers.

Other studies looked at the effects of stressful life events and found that the more stressful life events a person had experienced, the more likely they were to be depressed, showing the importance of external events.

According to the research, there is also evidence from other studies that antidepressants may actually induce low serotonin in the long term.

“Our view is that patients should not be told that depression is caused by low serotonin or by a chemical imbalance, and they should not be led to believe that antidepressants work by targeting these unproven abnormalities,” said Moncrieff.

“We do not understand what antidepressants are doing to the brain exactly, and giving people this sort of misinformation prevents them from making an informed decision about whether to take antidepressants or not.”

A spokesperson for the Royal College of Psychiatrists said: “Antidepressants are an effective, Nice-recommended treatment for depression that can also be prescribed for a range of physical and mental health conditions. We would not recommend for anyone to stop taking their antidepressants based on this review, and encourage anyone with concerns about their medication to contact their GP.”

Dr Michael Bloomfield, a consultant psychiatrist and principal clinical research fellow at University College London, who was not involved in the study, said: “Many of us know that taking paracetamol can be helpful for headaches, and I don’t think anyone believes that headaches are caused by not enough paracetamol in the brain. The same logic applies to depression and medicines used to treat depression.

“There is consistent evidence that antidepressant medicines can be helpful in the treatment of depression and can be life-saving.”

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Basic Research Powers the First Medication for Postpartum Depression

May 14, 2024 • Feature Story • 75th Anniversary

At a Glance

• Postpartum depression (PPD) is a common mental disorder that many women experience after giving birth.
• Onset of PPD coincides with a dramatic drop in levels of a brain-derived steroid (neurosteroid) known as allopregnanolone.
• Decades of research supported by NIMH illuminated the role of neurosteroids like allopregnanolone in mental illnesses.
• In 2019, brexanolone—a medication that acts by mimicking allopregnanolone—became the first approved drug to treat PPD.
• Able to significantly and rapidly reduce PPD symptoms, brexanolone was a major leap forward in depression treatment.

Joshua A. Gordon, M.D., Ph.D., a practicing psychiatrist at the time, would never forget the call he received one night from a distraught mother.

“She was plagued with a deep, inescapable hopelessness—so depressed she was afraid she was going to hurt her month-old daughter. I helped her get to the hospital, where she spent the next 2 months in an in-patient program trying every available treatment to recover,” said Dr. Gordon, now the Director of the National Institute of Mental Health (NIMH).

Unfortunately, this experience is not uncommon among women and other postpartum people who may feel intense sadness, anxiety, and loss of interest after giving birth. These symptoms can be signs of a clinical disorder known as postpartum depression (PPD) . Unlike the "baby blues" or feelings of sadness many new mothers experience in the days after delivery, PPD is more intense and long-lasting, with damaging impacts on health and well-being.

More than the blues: Impacts of PPD on women's mental health

Depression is a common but serious mood disorder. According to the Centers for Disease Control and Prevention (CDC), rates of depression are high—and rising—among postpartum women. Using data from the 2018 Pregnancy Risk Assessment Monitoring System  , the CDC found that about 1 in 8 postpartum women had symptoms of depression, while another CDC study  showed rates of PPD that were seven times higher in 2015 compared to 2000.

Depression can happen to anyone, and it's especially tough for new moms dealing with the physical challenges of childbirth and the stresses of caring for a young child. When women experience PPD, they often have strong feelings of sadness, anxiety, worthlessness, and guilt. Their sleep, eating, thoughts, and actions can all change noticeably. These mood and behavior changes can be highly distressing and even life-threatening, making it difficult for a woman to do everyday things and take care of herself or her child. In extreme cases, women with PPD may be at risk of hurting themselves or their child or attempting suicide.

Fast-acting, effective treatment for PPD can be life-changing and potentially lifesaving. However, for too long, such care was hard to reach, leaving many women to struggle with depression at a pivotal point in life. Despite some similarities, PPD is not the same as major depression at other times in life. Because of this, usual depression treatments are much less effective in managing the symptoms of PPD.

“PPD is very difficult to treat,” said Mi Hillefors, M.D., Ph.D., Deputy Director of the NIMH Division of Translational Research. “It is usually treated with medications originally approved for major depression—despite limited evidence that they are effective in treating PPD. Standard depression treatments, including antidepressants, psychotherapy, and brain stimulation therapy, can also take weeks or longer to work.”

PPD’s unique risk factors reflect the physical changes of pregnancy and the postpartum period, which include dramatic changes in levels of many hormones and other molecules.

These biological changes had long been seen as a possible source of postpartum mood disorders like depression. But could they also be a solution?

Unlocking the power of allopregnanolone through basic research

Some psychiatric medications owe their discovery to chance. Not so with brexanolone, the first-ever medication to specifically treat PPD. Brexanolone culminated a long series of research studies, much of it funded by NIMH as part of its commitment to understand and support women’s mental health .

Thanks to NIMH-supported basic research, brexanolone was developed by design—a design centered around a molecule called allopregnanolone  .

Allopregnanolone is a steroid naturally produced in the brain and with important actions there, such as regulating neurotransmitter activity and protecting neurons from damage. Its impact extends to mental health, with higher levels linked to better mood, lower anxiety, and reduced depression  .

Allopregnanolone is also important to pregnancy  , during which its levels are extremely high. This happens because of the enhanced production of a hormone called progesterone, which prepares the body for pregnancy and childbirth.

In the last few months of pregnancy, the ovaries and placenta make more progesterone, causing a huge rise in allopregnanolone levels. These levels then drop rapidly after birth. Because allopregnanolone plays a crucial role in mood, these ups and downs can impact a woman’s mental health during and after pregnancy.

Researchers had been aware of brain-derived steroids like allopregnanolone as far back as the 1940s. But the journey to a new PPD treatment began within NIMH's Intramural Research Program (IRP) . At the helm was the NIMH Scientific Director at that time, Steven Paul, M.D., who collaborated with researchers in the NIMH Clinical Neuroscience Branch and at other NIH institutes, including the National Institute of Neurological Disorders and Stroke (NINDS). The researchers sought to understand how the steroids work, change over time, respond to stress, and ultimately relate to health and disease.

Early discoveries came in the 1980s. Paul, working with Maria Majewska, Ph.D., Jacqueline Crawley, Ph.D., A. Leslie Morrow, Ph.D., and other researchers showed that hormones such as progesterone and molecules derived from them have calming and anxiety-reducing effects  . Extensive research by Paul’s lab showed that these anxiolytic effects come from enhancing the activity of GABA  by binding to specific sites on its receptor. As the main inhibitory neurotransmitter (chemical messenger), GABA reduces the activity of neurons, making them less likely to fire. When molecules bind to its receptor, GABA becomes more potent at inhibiting electrical activity  in the brain, with calming effects on behavior.

Paul and IRP colleague Robert Purdy, Ph.D., used the term “ neuroactive steroids  ,” or neurosteroids, to describe these molecules able to bind to receptors in the brain to rapidly alter neuronal excitability. Their work in animals confirmed that allopregnanolone is synthesized in the brain  . They also showed the effects of allopregnanolone on GABA receptors in humans. Moreover, they found that allopregnanolone affects the response to stress  , with acute stress leading the neurosteroid to increase to levels that alter GABA activity. These findings suggested that neurosteroids play an important role in helping animals “reset” and adaptively respond to stressful life events.

Together, this IRP-conducted research established the importance of neurosteroids via their presence in the brain, ability to reduce neuronal activity, and release during stress. Although much of this work was conducted in animals, it would spotlight neurosteroids—and allopregnanolone in particular—as promising targets for treating mental disorders, eventually opening the door to their therapeutic use in humans.

Bridging the gap to advance clinical intervention

While NIMH intramural researchers were making remarkable strides, researchers at other institutions were also conducting work bolstered by funding from NIMH. Among them were Alessandro Guidotti, M.D., at the University of Illinois at Chicago; Istvan Mody, Ph.D., at the University of California, Los Angeles; and Charles Zorumski, M.D., at Washington University in St. Louis. Their NIMH-funded research propelled understanding of inhibitory neurosteroids and their importance in reducing the adverse effects of stress. This work would be the impetus for homing in on allopregnanolone as a treatment for PPD.

Guidotti and colleagues conducted several NIMH-funded studies. Their research in rodents confirmed that allopregnanolone is produced in the brain  and helps regulate neuronal excitability  by acting on GABA receptors. They also built on the knowledge that neurosteroids are affected by stress. However, unlike acute stress, a stressor lasting multiple weeks led to a decrease in allopregnanolone  in brain areas involved in anxiety- and depression-like behaviors.

Importantly, their NIMH-funded work offered some of the earliest evidence that allopregnanolone contributes to depression by showing significantly lower levels  in people with depression compared to people without the disorder, a rise in levels (but not that of other neurosteroids) after treatment with antidepressant medication  , and a link between increased levels and reduced depression symptoms  .

NIMH and NINDS funded multiple studies by Mody and colleagues on interactions of neurosteroids, stress, and GABA receptors. This research was integral to understanding a mechanism in the brains of mice  that might explain why some people become depressed after childbirth. Their NIMH-supported research  showed changes in GABA receptors in the brain, where neurosteroids are active, that impaired the body’s ability to adapt to hormonal fluctuations. Animals with an irregular GABA receptor component lacking sensitivity to neurosteroids showed depression-like behaviors and reduced maternal care; treating them with a drug that restored the receptor’s function reversed those changes.

Another study by Mody and colleagues  revealed changes in GABA expression during pregnancy that led to greater neuronal activity in the brain—but could be brought down by allopregnanolone. This finding opened the door to future studies exploring whether a postpartum drop in the neurosteroid contributed to the risk for mood disorders after birth.

Zorumski led a team in extensively studying neurosteroids as well. Among their seminal findings was identifying the mechanisms by which inhibitory neurosteroids like allopregnanolone affect GABA receptor activity  . Their NIMH-funded work dramatically augmented knowledge of how neurosteroids alter GABA receptors to contribute to the risk for mental disorders like PPD.

“The accumulated evidence from these studies established the necessary bridges to justify examining a potential therapeutic role for allopregnanolone in women with PPD,” said Peter Schmidt, M.D., Chief of the NIMH Behavioral Endocrinology Branch.

By the 2010s, researchers had a much better understanding of how allopregnanolone is linked to PPD. Studies showed decreased allopregnanolone in pregnant  and postpartum  women with symptoms of depression and higher allopregnanolone associated with a lower risk of PPD  . The possibility that PPD might be caused by the downregulation of GABA receptors in response to low levels of allopregnanolone after birth inspired researchers to put that theory to the test in clinical studies with human participants.

Taking allopregnanolone from bench to bedside

Extensive research, supported by NIMH and other NIH institutes, found that neurosteroids play a key role in how people deal with stress. They also contribute to the development of mood disorders like anxiety and depression. For allopregnanolone, evidence that it sharply decreases after pregnancy and regulates GABA activity gave rise to the notion that it contributes to PPD—and inspired hope it could be used to treat the disorder.

The biopharmaceutical company Sage Therapeutics utilized this basic research to develop brexanolone. Administered intravenously by a health care professional in a doctor’s office or clinic, brexanolone mimics the effects of allopregnanolone, increasing the inhibitory actions of GABA receptors.

Stephen Kanes, M.D., Ph.D., at Sage Therapeutics and Samantha Meltzer-Brody, M.D., MPH, at the University of North Carolina led several randomized clinical trials to measure the effectiveness of the medication in treating PPD and evaluate its safety and tolerability. The studies, which recruited adult women with PPD from hospitals, research centers, and psychiatric clinics across the United States, measured the effects of brexanolone compared to a placebo over 4 weeks.

The trials were a success. Brexanolone significantly and meaningfully reduced PPD symptoms  , and it had only mild side effects. Compared to usual depression treatments, brexanolone brought about a faster response and greater improvement  . Whereas most antidepressants take weeks to work, brexanolone improved symptoms and functioning in women with PPD within a few hours to days. And the effects lasted up to a month after the treatment stopped. Not only was brexanolone more effective, but it also worked faster than other depression medications.

“The dramatic impact of basic research on real-world health outcomes has been inspiring. The fact that NIMH-supported studies contributed to successful drug development in a matter of decades is a remarkable feat and a powerful demonstration of the potential of this foundational research,” said Dr. Gordon.

Based on this promising evidence, the U.S. Food and Drug Administration (FDA) gave brexanolone priority review and breakthrough therapy designation in September 2016. Then, in March 2019, the FDA approved brexanolone  , making it the first drug to treat PPD.

Brightening the future for women with PPD

For women with PPD, brexanolone was a long-awaited reason to celebrate. For NIMH, it was a testament to discoveries made through the decades of research it supported. Although some barriers to treatment persisted, women now had greater hope for treating depression symptoms after pregnancy.

“The approval of brexanolone was an important milestone. Finally, an effective, fast-acting medication specifically to treat PPD,” said Dr. Hillefors. “It was also a victory for psychiatric neuroscience because basic and translational research—by design, not chance—led to a truly novel and effective treatment for a psychiatric disorder.”

Without NIMH-supported studies providing the foundational knowledge of neurosteroids, researchers may have never made the connection between allopregnanolone and treating PPD. “That’s why the approval of brexanolone is such a cause for celebration for mental health research: It represents a true bench-to-bedside success,” said Dr. Gordon.

The success of brexanolone has continued to open the door to exciting advancements in mental health care. For instance, researchers and clinicians are investigating ways to make brexanolone work better for all postpartum people. Researchers are also testing how neurosteroids can be used to treat other forms of depression and other mental health conditions.

Just the beginning of treatment advances for PPD

Brexanolone is only the start of what will hopefully be a new future for PPD treatment. In August 2023, the FDA approved zuranolone  as the first oral medication for PPD. Zuranolone acts via similar biological mechanisms as brexanolone. Its approval reflects the next step in NIMH-supported basic research being translated into clinical practice with real-world benefits.

The success of the drug, which is taken in pill form, was shown in two randomized multicenter clinical trials  . Women with severe PPD who received zuranolone showed statistically significant and clinically meaningful improvements in depression symptoms compared to women who received a placebo. These effects were rapid, sustained through 45 days, and seen across a range of clinical measures. The benefits were mirrored in patients’ self-assessment of their depression symptoms.

According to Dr. Schmidt, “The approval of zuranolone to treat PPD provides women with a rapid and effective treatment that avoids some of the limitations of the original intravenous medication.”

And the journey is far from over. Researchers, clinicians, and industry are continuing to innovate new treatments for PPD to increase access and availability to ensure all people can receive help for their postpartum symptoms.

“While I will never forget that phone call from my patient, the development of these effective medications brings us hope for helping people with PPD and for the overall impact of basic research to truly make a difference in people’s lives,” concluded Dr. Gordon.

Publications

Burval, J., Kerns, R., & Reed, K. (2020). Treating postpartum depression with brexanolone. Nursing , 50 (5), 48−53. https://doi.org/10.1097/01.NURSE.0000657072.85990.5a  

Cornett, E. M., Rando, L., Labbé, A. M., Perkins, W., Kaye, A. M., Kaye, A. D., Viswanath, O., & Urits, I. (2021). Brexanolone to treat postpartum depression in adult women. Psychopharmacology Bulletin , 51 (2), 115–130. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8146562/pdf/PB-51-2-115.pdf 

Deligiannidis, K. M., Meltzer-Brody, S., Maximos, B., Peeper, E. Q., Freeman, M., Lasser, R., Bullock, A., Kotecha, M., Li, S., Forrestal, F., Rana, N., Garcia, M., Leclair, B., & Doherty, J. (2023). Zuranolone for the treatment of postpartum depression. American Journal of Psychiatry , 180 (9), 668−675. https://doi.org/10.1176/appi.ajp.20220785  

Deligiannidis, K. M., Kroll-Desrosiers, A. R., Mo, S., Nguyen, H. P., Svenson, A., Jaitly, N., ... & Shaffer, S. A. (2016). Peripartum neuroactive steroid and γ-aminobutyric acid profiles in women at-risk for postpartum depression. Psychoneuroendocrinology , 70 , 98−107. https://doi.org/10.1016/j.psyneuen.2016.05.010  

Edinoff, A. N., Odisho, A. S., Lewis, K., Kaskas, A., Hunt, G., Cornett, E. M., Kaye, A. D., Kaye, A., Morgan, J., Barrilleaux, P. S., Lewis, D., Viswanath, O., & Urits, I. (2021). Brexanolone, a GABAA modulator, in the treatment of postpartum depression in adults: A comprehensive review. Frontiers in Psychiatry , 12 , Article 699740. https://doi.org/10.3389/fpsyt.2021.699740  

Epperson, C. N., Rubinow, D. R., Meltzer-Brody, S., Deligiannidis, K. M., Riesenberg, R., Krystal, A.D., Bankole, K., Huang, M. Y., Li, H., Brown, C., Kanes, S. J., & Lasser R. (2023). Effect of brexanolone on depressive symptoms, anxiety, and insomnia in women with postpartum depression: Pooled analyses from 3 double-blind, randomized, placebo-controlled clinical trials in the HUMMINGBIRD clinical program. Journal of Affective Disorders , 320 , 353−359. https://doi.org/10.1016/j.jad.2022.09.143  

Gilbert Evans, S. E., Ross, L. E., Sellers, E. M., Purdy, R. H., & Romach, M. K. (2005). 3α-reduced neuroactive steroids and their precursors during pregnancy and the postpartum period. Gynecological Endocrinology , 21 (5), 268−279. https://doi.org/10.1080/09513590500361747  

Guintivano, J., Manuck, T., & Meltzer-Brody, S. (2018). Predictors of postpartum depression: A comprehensive review of the last decade of evidence. Clinical Obstetrics and Gynecology , 61 (3), 591−603. https://doi.org/10.1097/GRF.0000000000000368  

Gunduz-Bruce, H., Koji, K., & Huang, M.-Y. (2022). Development of neuroactive steroids for the treatment of postpartum depression. Journal of Neuroendocrinology , 34 (2), Article e13019. https://doi.org/10.1111/jne.13019  

Haight, S. C., Byatt, N., Moore Simas, T. A., Robbins, C. L., & Ko, J. Y. (2019). Recorded diagnoses of depression during delivery hospitalizations in the United States, 2000-2015. Obstetrics and Gynecology , 133 (6), 1216−1223. https://doi.org/10.1097/AOG.0000000000003291  

Hellgren, C., Åkerud, H., Skalkidou, A., Bäckström, T., & Sundström-Poromaa, I. (2014). Low serum allopregnanolone is associated with symptoms of depression in late pregnancy. Neuropsychobiology , 69 (3), 147–153. https://doi.org/10.1159/000358838  

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Study says depression not caused by chemical imbalance, raising questions about antidepressants

University college london research says depression is not a serotonin imbalance and drugs that target it may not be the answer.

By Lois M. Collins

Millions of Americans take antidepressants, but a new study suggests the theory underpinning their use may be entirely wrong. Research from the University College London raises doubt that chemical imbalance in the brain is responsible for depression .

A major review of previous studies on serotonin’s role in depression, just published in the journal Molecular Psychiatry, concluded that serotonin level — the target of antidepressants — is not responsible for depression.

The researchers found “no support for the hypothesis that depression is caused by lowered serotonin activity or concentrations.”

They found stronger evidence that stressful life events can lead to depression.

The question is, do antidepressants help, and if so, how? If not, could they be doing harm?

Experts are divided and the study has drawn some pushback.

“Some of the studies in our overview that included people who were taking or had previously taken antidepressants showed evidence that antidepressants may actually lower the concentration or activity of serotonin,” according to an article in The Conversation by the study’s authors, Joanna Moncrieff, professor of psychiatry, and Mark Horowitz, clinical research fellow in psychiatry, both of University College London.

“Most antidepressants are selective serotonin reuptake inhibitors, which were originally said to work by correcting abnormally low serotonin levels. There is no other accepted pharmacological mechanism by which antidepressants affect the symptoms of depression,” the researchers said in a news release . 

The research suggests depression is not biochemical and questions how, given that, a biochemical solution would work. Horowitz and Moncrieff also question whether that kind of treatment, which acts on brain chemistry, does more harm than good.

“Our view is that patients should not be told that depression is caused by low serotonin or by a chemical imbalance, and they should not be led to believe that antidepressants work by targeting these unproven abnormalities. We do not understand what antidepressants are doing to the brain exactly, and giving people this sort of misinformation prevents them from making an informed decision about whether to take antidepressants or not,” Moncrieff said.

Targeting serotonin

The “chemical imbalance” theory has dominated the thinking about depression for several decades, according to the researchers.

“It is always difficult to prove a negative, but I think we can safely say that after a vast amount of research conducted over several decades, there is no convincing evidence that depression is caused by serotonin abnormalities, particularly by lower levels or reduced activity of serotonin,” Moncrieff said.

In the United States between 2015 and 2018, 13.9% of adults took antidepressants for depression, according to the National Center for Health Statistics in the Centers for Disease Control and Prevention.

As many as 1 in 6 adults in England are now prescribed antidepressants every year, according to the study.

“I had been taught that depression was caused by low serotonin in my psychiatry training and had even taught this to students in my own lectures. Being involved in this research was eye-opening and feels like everything I thought I knew has been flipped upside down,” said Horowitz in background material.

As Mike McRae wrote for ScienceAlert , “This doesn’t necessarily mean serotonin-based treatments aren’t working on some other mechanism we don’t yet understand. And  no one should consider ditching their meds  without consulting their doctors. But given so many people are relying on these drugs, it is important to figure out what’s really going on.”

Study nuts and bolts

In all, studies in the review included tens of thousands of participants. Among the serotonin mechanisms studied and the findings:

• No difference was seen between people with depression and healthy control subjects in levels of serotonin and breakdown products in the blood or brain fluids.
• In studies of serotonin receptors and the serotonin transporter protein most antidepressants target, they found “weak and inconsistent evidence” suggesting higher levels of serotonin activity in those who are depressed. They believe that was caused by use of antidepressants.
• Studies that lowered serotonin levels in hundreds of healthy volunteers did not produce depression. The researchers saw “very weak evidence” in a small 75-person subgroup of people with a family history of depression. A study after that was inconclusive.
• No evidence of variation in the serotonin transporter gene was found between those with depression and healthy control subjects. 

On the other hand, stressful life events had a “strong effect” on the risk of becoming depressed. And the more one experienced stress or trauma, the greater the likelihood of depression. 

“A famous early study found a relationship between stressful events, the type of serotonin transporter gene a person had and the chance of depression. But larger, more comprehensive studies suggest this was a false finding,” the release said.

In the piece from The Conversation , Moncrieff and Horowitz wrote, “It is important that people know that the idea that depression results from a ‘chemical imbalance’ is hypothetical. And we do not understand what temporarily elevating serotonin or other biochemical changes produced by antidepressants do to the brain. We conclude that it is impossible to say that taking SSRI antidepressants is worthwhile, or even completely safe.”

Public perception

Surveys suggest as many as 90% of people believe depression is caused by low serotonin or chemical imbalance. There’s evidence believing that creates a “pessimistic outlook on the likelihood of recovery” and the hope of managing depression without medical help, the study said.

Doubts about brain chemistry’s role in depression have been around a while.

“If you’re among those who are hearing all of this for the first time, the hypothesis has been on shaky ground practically since it took off in the 1990s, with study after study failing to support the idea,” wrote ScienceAlert’s McRae . He noted the Moncrieff and Horowitz limited their research to high-quality, peer-evaluated studies.

“Just 17 studies made the cut, which included a genetic association study, another umbrella review, and a dozen systematic reviews and meta-analyses,” he wrote.

The impact is huge, given most people will have diagnosable levels of anxiety or depression at some point, the researchers said.

The researchers also said one large meta-analysis found people using antidepressants had less serotonin in their blood, which could mean that antidepressants designed to raise levels of serotonin may do the opposite over time.

The researchers note they didn’t look at the efficacy of antidepressants. Their hope, they said, is that more research and treatment will focus on helping people manage stressful or traumatic events, “such as with psychotherapy, alongside other practices such as exercise or mindfulness, or addressing underlying contributors such as poverty, stress and loneliness.”

Some experts disagree

The research has attracted some pushback.

The Guardian quoted Dr. Michael Bloomfield, a consultant psychiatrist and principal clinical research fellow at University College London, who was not involved in the study: “Many of us know that taking paracetamol can be helpful for headaches, and I don’t think anyone believes that headaches are caused by not enough paracetamol in the brain. The same logic applies to depression and medicines used to treat depression.”

He added, “There is consistent evidence that antidepressant medicines can be helpful in the treatment of depression and can be life-saving.”

Johan Lundberg  at the Karolinska Institute in Sweden told New Scientist that one limitation of the study is failure to distinguish between those with long-term depression and those having episodes of depression, because their state during the study could be different in terms of serotonin. “It is key to separately analyze data from studies that examine the same patients when ill and when in remission, to have optimal conditions to examine the hypothesis,” he said.

The same article quoted a spokesperson for the Royal College of Psychiatrists who was talking about treatment guidelines from public health officials in England, who said antidepressants are an effective treatment for depression and some other physical and mental health conditions.

The spokesperson noted that “antidepressants will vary in effectiveness for different people, and the reasons for this are complex. We would not recommend for anyone to stop taking their antidepressants based on this review, and encourage anyone with concerns about their medication to contact their (family doctor).”

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May 15, 2024, treatment-resistant depression linked to body mass index: study.

Genetic factors are a small but significant contributor to severe depression that does not respond to standard therapy, according to researchers at Vanderbilt University Medical Center and Massachusetts General Hospital.

The heritability of treatment-resistant depression (TRD) was found to have significant genetic overlap with schizophrenia, attention deficit disorder, cognitive, alcohol and smoking traits, and body mass index (BMI), suggesting a shared biology and, potentially, new treatment avenues.

The report, published May 15 in The American Journal of Psychiatry , provides insights into the genetics and biology underlying TRD, supports the utility of estimating disease probabilities from clinical data for genomic investigations, and “lays the groundwork for future efforts to apply genomic data for biomarker and drug development.”

“Despite the large proportion of patients with TRD, the biology has remained poorly understood. Our work here provides genetic support for new biological directions to explore in addressing this gap,” said Douglas Ruderfer , PhD, associate professor of Medicine (Genetic Medicine), Psychiatry, and Biomedical Informatics.

“This work finally gives us some new leads, rather than reinventing the same antidepressants over and over again, for a condition that is extremely common,” said Roy Perlis , MD, professor of Psychiatry at Harvard Medical School and director of the MGH Center for Experimental Drugs and Diagnostics.

Nearly 2 out of every 10 people in the United States experience severe depression, and roughly a third of them do not respond to antidepressant treatments and therapies. TRD is associated with a significantly increased risk for suicide.

Despite evidence that treatment resistance may be a heritable trait, the “genetic architecture” of this condition remains unclear, largely because of the lack of a consistent and rigorous definition of treatment resistance, and the challenge of recruiting enough research subjects to study.

To overcome these barriers, the researchers selected a surrogate for the condition — whether an individual diagnosed with major depressive disorder had received electroconvulsive therapy (ECT).

ECT applies a low voltage applied to the head to induce a generalized seizure without muscle convulsions. Approximately half of patients with TRD respond to ECT, which is thought to improve symptoms by stimulating “rewiring” of brain circuits after they are disrupted by the electrical current.

To ensure the study was sufficiently “powered,” or had enough patients from which valid results could be obtained, the researchers developed a machine-learning model to predict, from clinical information recorded in the electronic health record (EHR), which patients were most likely to receive ECT.

The researchers applied this model to EHRs and biobanks from Mass General Brigham and VUMC and validated the results by comparing the predicted cases to actual ECT cases identified through the Geisinger Health System in Pennsylvania, and the Million Veteran Program of the U.S. Department of Veterans Affairs.

More than 154,000 patients from the four health systems with medical records and genotypes, or sequences of their DNA samples, were included in a genome-wide association study, which can identify genetic associations with health conditions (in this case, a marker for TRD).

The study identified genes clustered in two locations, or loci, on different chromosomes that correlated significantly the likelihood of ECT predicted by the model. The first locus overlapped with a previously reported chromosomal location associated with body mass index (BMI).

The ECT-BMI relationship was inverse—patients with lower body weight tended to be at higher risk for treatment resistance.

This finding is supported by studies that found patients with anorexia nervosa, an eating disorder characterized by extremely low body weight, are more likely than those with a higher BMI to be resistant to treatment of coinciding depression.

The other locus associated with ECT points to a gene that is highly expressed in brain regions that regulate body weight and appetite. Recently this gene also has been implicated in bipolar disorder, a major psychiatric illness.

Large studies are currently underway to collect tens of thousands of ECT cases for a case-control study.

Confirmation of the link between the ECT marker for TRD and the complex metabolic pathways underlying food intake, maintenance of body weight, and energy balance could open the door to new, more effective treatments for treatment of major depressive disorder, the researchers said.

Co-authors from VUMC were JooEun Kang, MD, PhD, Michael Ripperger, Drew Wilimitis, Theodore Morley, Lide Han, PhD, Stephan Heckers, MD, MSc, and Colin G. Walsh, MD, MA; at MGH they included Thomas McCoy, MD, and Victor Castro.

This work was funded by National Institutes of Health grants R01MH116269, R01MH121455, R01MH116270, R01MH123804, 5T32GM007347, K08MH122911, R01MH125246, R01AG067025, U01MH116442, and R01MH109677, the VA, and the Brain & Behavior Research Foundation.

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Are We Talking Too Much About Mental Health?

Recent studies cast doubt on whether large-scale mental health interventions are making young people better. Some even suggest they can have a negative effect.

By Ellen Barry

In recent years, mental health has become a central subject in childhood and adolescence. Teenagers narrate their psychiatric diagnosis and treatment on TikTok and Instagram. School systems, alarmed by rising levels of distress and self-harm, are introducing preventive coursework in emotional self-regulation and mindfulness.

Now, some researchers warn that we are in danger of overdoing it. Mental health awareness campaigns, they argue, help some young people identify disorders that badly need treatment — but they have a negative effect on others, leading them to over-interpret their symptoms and see themselves as more troubled than they are.

The researchers point to unexpected results in trials of school-based mental health interventions in the United Kingdom and Australia: Students who underwent training in the basics of mindfulness , cognitive behavioral therapy and dialectical behavior therapy did not emerge healthier than peers who did not participate, and some were worse off, at least for a while.

And new research from the United States shows that among young people, “self-labeling” as having depression or anxiety is associated with poor coping skills, like avoidance or rumination.

In a paper published last year , two research psychologists at the University of Oxford, Lucy Foulkes and Jack Andrews, coined the term “prevalence inflation” — driven by the reporting of mild or transient symptoms as mental health disorders — and suggested that awareness campaigns were contributing to it.

“It’s creating this message that teenagers are vulnerable, they’re likely to have problems, and the solution is to outsource them to a professional,” said Dr. Foulkes, a Prudence Trust Research Fellow in Oxford’s department of experimental psychology, who has written two books on mental health and adolescence.

Until high-quality research has clarified these unexpected negative effects, they argue, school systems should proceed cautiously with large-scale mental health interventions.

“It’s not that we need to go back to square one, but it’s that we need to press pause and reroute potentially,” Dr. Foulkes said. “It’s possible that something very well-intended has overshot a bit and needs to be brought back in.”

This remains a minority view among specialists in adolescent mental health, who mostly agree that the far more urgent problem is lack of access to treatment.

About 60 percent of young Americans with severe depression receive no treatment, according to Mental Health America, a nonprofit research group. In crisis, desperate families fall back on emergency rooms, where teens often remain for days before a psychiatric bed opens up. There is good reason to embrace a preventive approach, teaching schoolchildren basic skills that might forestall crises later, experts say.

Dr. Foulkes said she understood that her argument runs counter to that consensus, and when she began to present it, she braced for a backlash. To her surprise, she said, many educators reached out to express quiet agreement.

“There’s definitely a fear about being the one to say it,” she said.

A deflating result

In the summer of 2022, the results of a landmark study on mindfulness training in British classrooms landed — like a lead balloon.

The trial, My Resilience in Adolescence, or MYRIAD, was ambitious, meticulous and expansive, following about 28,000 teenagers over eight years. It had been launched in a glow of optimism that the practice would pay off, improving the students’ mental health outcomes in later years.

Half of the teenagers were trained by their teachers to direct their attention to the present moment — breathing, physical sensations or everyday activities — in 10 lessons of 30 to 50 minutes apiece.

The results were disappointing . The authors reported “no support for our hypothesis” that mindfulness training would improve students’ mental health. In fact, students at highest risk for mental health problems did somewhat worse after receiving the training, the authors concluded.

But by the end of the eight-year project, “mindfulness is already embedded in a lot of schools, and there are already organizations making money from selling this program to schools,” said Dr. Foulkes, who had assisted on the study as a postdoctoral research associate. “And it’s very difficult to get the scientific message out there.”

Why, one might ask, would a mental health program do harm?

Researchers in the study speculated that the training programs “bring awareness to upsetting thoughts,” encouraging students to sit with darker feelings, but without providing solutions, especially for societal problems like racism or poverty. They also found that the students didn’t enjoy the sessions and didn’t practice at home.

Another explanation is that mindfulness training could encourage “co-rumination,” the kind of long, unresolved group discussion that churns up problems without finding solutions.

As the MYRIAD results were being analyzed, Dr. Andrews led an evaluation of Climate Schools, an Australian intervention based on the principles of cognitive behavioral therapy, in which students observed cartoon characters navigating mental health concerns and then answered questions about practices to improve mental health.

Here, too, he found negative effects. Students who had taken the course reported higher levels of depression and anxiety symptoms six months and 12 months later.

Co-rumination appears to be higher in girls, who tend to come into the program more distressed, as well as more attuned to their friends, he said. “It might be,” he said, “that they kind of get together and make things a little bit worse for each other.”

Dr. Andrews, a Wellcome Trust research fellow, has since joined an effort to improve Climate Schools by addressing negative effects. And he has concluded that schools should slow down until “we know the evidence base a bit more.” Sometimes, he said, “doing nothing is better than doing something.”

The awareness paradox

One problem with mental health awareness, some research suggests, is that it may not help to put a label to your symptoms.

Isaac Ahuvia, a doctoral candidate at Stony Brook University, recently tested this in a study of 1,423 college students . Twenty-two percent “self-labeled” as having depression, telling researchers “I am depressed” or “I have depression,” but 39 percent met the diagnostic criteria for depression.

He found that the students who self-labeled felt that they had less control over depression and were more likely to catastrophize and less likely to respond to distress by putting their difficulties in perspective, compared with peers who had similar depression symptoms.

Jessica L. Schleider, a co-author of the self-labeling study, said this was no surprise. People who self-label “appear to be viewing depression as a biological inevitability,” she said. “People who don’t view emotions as malleable, view them as set and stuck and uncontrollable, tend to cope less well because they don’t see a point to trying.”

But Dr. Schleider, an associate professor of medical social sciences at Northwestern University and the director of the university’s Lab for Scalable Mental Health, pushed back on the prevalence inflation hypothesis. She disagreed with the claim that students are overdiagnosing themselves, noting that Mr. Ahuvia’s findings suggest otherwise.

Awareness campaigns are bound to have multiple effects, helping some students and not others. And ultimately, she argued, the priority for public health should be reaching young people in the most distress.

“The urgency of the mental health crisis is so clear,” she said. “In the partnerships that I have, the emphasis is on the kids truly struggling right now who have nothing — we need to help them — more so than a possible risk for a subset of kids who aren’t really struggling.”

Maybe, she said, we need to look beyond the “universal, school-assembly-style approach,” to targeted, light-touch interventions, which research has shown can be effective at decreasing anxiety and conduct disorders, especially in younger children.

“There is a risk of throwing the baby out with the bathwater,” Dr. Schleider said. “The response can’t be ‘Forget all of it.’ It should be ‘What about this intervention was unhelpful?’”

Other researchers echoed her concern, pointing to studies that show that on average, students benefit from social and emotional learning courses.

One of the largest, a 2023 meta-analysis of 252 classroom programs in 53 countries, found that students who participated performed better academically, displayed better social skills and had lower levels of emotional distress or behavioral problems. In that context, negative effects in a handful of trials appear modest, the researchers said.

“We clearly have not figured out how to do them yet, but I can’t imagine any population-based intervention that the field got right the first time,” said Dr. Andrew J. Gerber, the president and medical director of Silver Hill Hospital and a practicing child and adolescent psychiatrist.

“Really, if you think about almost everything we do in schools, we don’t have great evidence for it working,” he added. “That doesn’t mean we don’t do it. It just means that we’re constantly thinking about ways to improve it.”

‘We want everyone to have it’

These debates are taking place a long way away from classrooms, where mental health curriculums are increasingly commonplace.

Allyson Kangisser, a counselor at Woodsdale Elementary School in Wheeling, W.Va., said the focus in her school is on basic coping skills. In the early grades, students are asked, “What things can you do to take care of yourself when you’re having big feelings?”

Starting in third grade, they take on more complex material, such as watching cartoon characters to distinguish transient stress from chronic conditions like depression. “We’re not trying to have them diagnose themselves,” Ms. Kangisser said. “We are saying, what do you feel — this one? Or this one?”

At the school’s sixth annual mental health fair last month, Woodsdale students walked through a giant inflatable brain, its lobes neatly labeled. They did yoga stretches and talked about regulating their emotions. Ms. Kangisser said the event is valuable precisely because it is universal, so troubled children are not singled out.

“The mental health fair, everybody does it,” she said. “It’s not ‘You need it, and you don’t.’ We want everyone to have it, because you just never know.”

By the time the students reach college, they will have absorbed enormous amounts of information about mental health — from school, but also from social media and from one another.

Dr. Jessica Gold, chief wellness officer for the University of Tennessee system, said the college students she sees are recognizably different — more comfortable speaking about their emotions and more willing to be vulnerable. They also overuse diagnostic terms and have the self-assurance to question a psychiatrist’s judgment.

“It’s sort of a double-edged sword,” she said. “We want people to talk about this more, but we don’t want that to lead to overdiagnosis or incorrect diagnosis or overtreatment. We want it to lead to normalizing of having feelings.”

Lucy Kim, a Yale senior who has lobbied for better mental health support on campus, described the prevalence inflation hypothesis as “disheartening, dismissive and potentially dangerous,” providing another way to discount the experiences of young people.

“As a college student, I see a generation of young people around me impacted by a depth and breadth of loneliness, exhaustion and disillusionment suggestive of a malaise that goes deeper than the general vicissitudes of life,” said Ms. Kim, 23.

Overdiagnosis does happen, she said, and so does glorification of mental health disorders. But stigma and barriers to treatment remain the bigger problem. “I can confidently say I have never heard anyone respond to disclosures of depression with ‘That’s so cool, I wish I had that, too,’” she said.

Ellen Barry is a reporter covering mental health for The Times. More about Ellen Barry

Managing Anxiety and Stress

Stay balanced in the face of stress and anxiety with our collection of tools and advice..

How are you, really? This self-guided check-in will help you take stock of your emotional well-being — and learn how to make changes .

These simple and proven strategies will help you manage stress , support your mental health and find meaning in the new year.

First, bring calm and clarity into your life with these 10 tips . Next, identify what you are dealing with: Is it worry, anxiety or stress ?

Persistent depressive disorder is underdiagnosed, and many who suffer from it have never heard of it. Here is what to know .

New research suggests people tend to be lonelier in young adulthood and late life. But experts say it doesn’t have to be that way .

How much anxiety is too much? Here is how to establish whether you should see a professional about it .

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• Scott J. Russo   ORCID: orcid.org/0000-0002-6470-1805 3 ,
• Dalibor Sames   ORCID: orcid.org/0000-0001-6911-2260 2 , 4 &
• Daniel Wacker   ORCID: orcid.org/0000-0003-4951-7230 1 , 3  

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• Cryoelectron microscopy
• Molecular neuroscience
• Receptor pharmacology
• Stress and resilience

Psychedelic substances such as lysergic acid diethylamide (LSD) and psilocybin show potential for the treatment of various neuropsychiatric disorders 1 , 2 , 3 . These compounds are thought to mediate their hallucinogenic and therapeutic effects through the serotonin (5-hydroxytryptamine (5-HT)) receptor 5-HT 2A (ref. 4 ). However, 5-HT 1A also plays a part in the behavioural effects of tryptamine hallucinogens 5 , particularly 5-methoxy- N,N -dimethyltryptamine (5-MeO-DMT), a psychedelic found in the toxin of Colorado River toads 6 . Although 5-HT 1A is a validated therapeutic target 7 , 8 , little is known about how psychedelics engage 5-HT 1A and which effects are mediated by this receptor. Here we map the molecular underpinnings of 5-MeO-DMT pharmacology through five cryogenic electron microscopy (cryo-EM) structures of 5-HT 1A , systematic medicinal chemistry, receptor mutagenesis and mouse behaviour. Structure–activity relationship analyses of 5-methoxytryptamines at both 5-HT 1A and 5-HT 2A enable the characterization of molecular determinants of 5-HT 1A signalling potency, efficacy and selectivity. Moreover, we contrast the structural interactions and in vitro pharmacology of 5-MeO-DMT and analogues to the pan-serotonergic agonist LSD and clinically used 5-HT 1A agonists. We show that a 5-HT 1A -selective 5-MeO-DMT analogue is devoid of hallucinogenic-like effects while retaining anxiolytic-like and antidepressant-like activity in socially defeated animals. Our studies uncover molecular aspects of 5-HT 1A -targeted psychedelics and therapeutics, which may facilitate the future development of new medications for neuropsychiatric disorders.

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Data availability.

Density maps and structure coordinates have been deposited into the Electron Microscopy Data Bank (EMDB) and the PDB with the following accession identifiers: EMD-29560 and PDB 8FY8 for 5-MeO-DMT–5-HT 1A –Gα i1 –Gβ 1 –Gγ 2 ; EMD-29597 and PDB 8FYT for LSD–5-HT 1A –Gα i1 –Gβ 1 -Gγ 2 ; EMD-29571 and PDB 8FYE for 4-F,5-MeO-PyrT–5-HT 1A –Gα i1 –Gβ 1 –Gγ 2 ; EMD-29585 and PDB 8FYL for vilazodone–5-HT 1A –Gα i1 –Gβ 1 –Gγ 2 ; and EMD-29599 and PDB 8FYX for buspirone–5-HT 1A –Gα i1 –Gβ 1 –Gγ 2 .   Source data are provided with this paper. Additional data from this study are available upon request.

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Acknowledgements

This work was supported by NIH grant R35GM133504, a Sloan Research Fellowship in Neuroscience, an Edward Mallinckrodt, Jr Foundation Grant, a McKnight Foundation Scholars Award, an Irma T. Hirschl/Monique Weill-Caulier Trust Research Award (all to D.W.); an NIH F31 MH132317 (A.L.W), and T32 Training Grant GM062754 and DA053558 (A.L.W and G.Z.); the G. Harold & Leila Y. Mathers Charitable Foundation, the NIH grant R01DA050613, G.L. Freeman, and Columbia University for support of this work (all to D.S.); and the following NIH grants: R01MH127820 and R01MH104559 (S.J.R.). L.F.P is supported by the Leon Levy Foundation and the Brain and Behavior Research Foundation. Some of this work was performed at the National Center for CryoEM Access and Training (NCCAT) and the Simons Electron Microscopy Center located at the New York Structural Biology Center, supported by the NIH Common Fund Transformative High Resolution Cryo-Electron Microscopy program (U24 GM129539) and by grants from the Simons Foundation (SF349247) and NY State Assembly. We further acknowledge cryo-EM resources at the National Resource for Automated Molecular Microscopy located at the New York Structural Biology Center, supported by grants from the Simons Foundation (SF349247), NYSTAR, and the NIH National Institute of General Medical Sciences (GM103310) with additional support from Agouron Institute (F00316) and NIH (OD019994). For additional data collection, we are grateful to staff at the Laboratory for BioMolecular Structure (LBMS), which is supported by the DOE Office of Biological and Environmental Research (KP160711). This work was supported in part through the computational and data resources and staff expertise provided by Scientific Computing and Data at the Icahn School of Medicine at Mount Sinai and supported by the Clinical and Translational Science Awards (CTSA) grant ULTR004419 from the National Center for Advancing Translational Sciences. We thank B. Bechand for early examination of in vivo pharmacology of the described compounds assisted by V. C. Galicia; C. Hwu for assistance with synthesis and purification of several compounds (all at Columbia University); and F. Zandkarimi from the Columbia University Chemistry Department Mass Spectrometry Core Facility for conducting the high-resolution mass spectrometry experiments.

Author information

These authors contributed equally: Audrey L. Warren, David Lankri

Authors and Affiliations

Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA

Audrey L. Warren, Michael J. Capper & Daniel Wacker

Department of Chemistry, Columbia University, New York, NY, USA

David Lankri, Michael J. Cunningham, Inis C. Serrano, Andrew C. Kruegel, Priscilla Duggan, Vaclav Havel & Dalibor Sames

Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, USA

Lyonna F. Parise, Scott J. Russo & Daniel Wacker

Zuckerman Institute of Mind, Brain, Behavior, Columbia University, New York, NY, USA

Gregory Zilberg & Dalibor Sames

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Contributions

D.S., A.C.K, M. J. Cunningham and D.L. conceived and initiated the project. A.L.W. designed experiments, expressed and purified protein for grid freezing, collected data, refined structures with help from M. J. Capper, performed signalling and uptake assays, and co-wrote the manuscript. D.L. designed, synthesized, purified and characterized compounds with assistance from V.H., and co-wrote the manuscript. M. J. Cunningham designed, synthesized, purified and characterized compounds. D.L., V.H. and D.S. designed and supervised the pharmacokinetics study. L.F.P. performed the chronic SD stress assay and subsequent behavioural analyses supervised by S.J.R. I.C.S. designed and performed in vivo pharmacology assays, including the open-field and HTR assays, with assistance from P.D. G.Z. prepared grids for structure determination and assisted with data collection. D.S. and D.W. conceptualized the overall project and designed experiments, analysed the data, supervised the project and management, and wrote the manuscript.

Corresponding authors

Correspondence to Dalibor Sames or Daniel Wacker .

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Competing interests.

The authors declare the following competing financial interests: D.S. and A.C.K. are co-founders of Gilgamesh Pharmaceuticals and Kures. M. J. Cunningham is a co-founder of Gilgamesh Pharmaceuticals. A.L.W., D.L., I.C.S., L.F.P., S.J.R., D.S. and D.W. are inventors on a patent application related to the featured compound class. D.W. has consulted for Otsuka Pharmaceutical, Longboard Pharmaceuticals and Ocean Bio on the design of psychedelic-based therapeutics. None of the companies listed herein contributed to the funding or experimental design. All other authors declare no competing interests.

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Extended data figures and tables

Extended data fig. 1 cryo-em structure determination of drug-bound 5-ht 1a -gαi1/gβ1/gγ2 complexes..

a , Representative structure determination of 5-MeO-DMT-bound 5-HT 1A signalling complex. Top Left , Analytical size exclusion chromatography and SDS-PAGE show monodisperse and pure protein of intact complex and its components. Right , representative Cryo-EM micrograph (white bar indicates scale) of 4680 total micrographs and data processing schematic exemplified by 5-MeO-DMT-bound 5-HT 1A -Gi1 structure: After particle picking, 2D classification and multiple rounds of 3D classification, the final particle stack was refined using non-uniform refinement. A final map was obtained and resolutions were estimated applying the 0.143 cutoff in GS-FSC. Initial models were built in COOT, and then further refined in PHENIX for the generation of final coordinates shown in this manuscript. b , Local resolution map of a 5-MeO-DMT-bound 5-HT 1A -Gi1 complex ( left ) and FSC curves ( right ) calculated based on the final reconstruction in cryoSPARC. c , 5-MeO-DMT (yellow) in the orthosteric binding pocket from the side ( left ) and rotated 45° towards the top of the receptor ( right ) with the map of ligand and surround residue densities shown at 5σ.

Source data

Extended data fig. 2 comparison of different 5-ht 1a structures and differences in binding of lsd to 5-ht 1a and 5-ht 2a ..

a , Superposition of herein reported 5-MeO-DMT-bound 5-HT 1A -Gi complex with the previously reported 5-HT-bound 5-HT 1A -Gi structure (PDB ID: 7E2Y ) shows similar conformations. Additional residues in 5-HT 1A ’s EL2 and G proteins not observed in previous structures are highlighted in red. b , Lipids (blue) and cholesterol hemisuccinate (dark blue) are bound to similar sites as observed before. c , Local resolution map of a LSD-bound 5-HT 1A -Gi1 complex ( left ) and FSC curves ( right ) calculated the final reconstruction in cryoSPARC. d , LSD (grey) in the orthosteric binding pocket from the side ( top ) and rotated 45° towards the top of the receptor ( bottom ) with the map of ligand and surround residue densities shown at 5σ. e , LSD shows distinct binding modes bound to 5-HT 1A -Gi signalling complex and 5-HT 2A (PDB ID: 6WGT ). Left , 5-HT 1A -bound LSD (grey) sits deeper in the binding pocket compared to 5-HT 2A -bound LSD (orange). Zoom in of LSD in 5-HT 1A -Gi structure ( middle ) and 5-HT 2A structure ( right ) highlights differential stereochemistry and receptor-specific interactions of diethylamide moiety. Hydrogen bonds are indicated as grey dashed lines.

Extended Data Fig. 3 Global structure-activity landscape of tryptamine psychedelics at 5-HT 1A and 5-HT 2A receptors and their synthesis.

a , Overview of the cryo-EM structure of the 5HT 1A receptor-Gi signalling complex bound to 5-MeO-DMT ( center ). Classic psychedelics such as the prototypical compounds DMT and LSD are agonists of both 5-HT 1A and 5-HT 2A receptors ( left semi-circle ). 5-MeO-DMT ( top of the circle ), a major psychoactive compound found in toad secretions, shows comparable potency and efficacy at both 5-HT 1A and 5-HT 2A receptors. Systematic structural mapping via elaboration of the core 5-MeO-DMT structure identifies a class of 5-MeO-tryptamines with increasing 5-HT 1A selectivity ( right hemi-circle ). 5-MeO-DMT can be viewed as a deconstruction of ibogaine, a oneirogen with a complex polycyclic tryptamine structure ( bottom of the circle ). Iboga compounds show no activity at 5-HT 1A and 5-HT 2A receptors, but this activity re-emerges by deconstruction of the isoquinuclidine core to simple mono-cyclic tryptamines such as 5-MeO-PipT (5-methoxypiperidinyl-tryptamine) and 4-F,5-MeO-PyrT (4-fluoro, 5-methoxypyrrolidinyl-tryptamine, right hemi-circle). Images of peyote, mushrooms, ayahuasca, and toad are from iStock and ShutterStock, and Tabernanthe iboga schematic is adapted from previous work 65 .  b , General synthesis methodology of tryptamines. a. oxalyl chloride, b. MeOH, LAH, c. PPh3, CBr4, d. Amine, TEA, e. Amine, f. LAH.

Extended Data Fig. 4 Structural comparison of 5-MeO-DMT 5-HT1A-selective analog 4-F, 5-MeO-PyrT bound to 5-HT 1A .

a , Local resolution map of a 4-F,5-MeO-PyrT-bound 5-HT 1A -Gi1 complex ( left ) and FSC curves ( right ) calculated from the final reconstruction in cryoSPARC. b , 4-F,5-MeO-PyrT (dark blue) in the orthosteric binding pocket from the side ( left ) and rotated 45° towards the top of the receptor ( right ) with the map of ligand and surrounding residue densities shown at 5σ. c , structural side-by-side comparison of 5-HT 1A orthosteric site bound to 5-MeO-DMT (yellow) and 4-F,5-MeO-PyrT (dark blue). d , cAMP accumulation assays using wildtype and mutant 5-HT 1A , and different drugs. Concentration-response experiments reveal different sensitivities of distinct drugs to F361L mutation. All signalling studies were performed in triplicates and are averaged from two to three independent experiments. Data have been normalized against 5-HT and errors bars denote s.e.m.

Extended Data Fig. 5 Comparison of 4-F,5-MeO-PyrT binding pose to that of different clinical 5-HT 1A drugs.

a , b , Local resolution maps of vilazodone-bound ( a ) and buspirone-bound ( b ) 5-HT 1A -Gi1 complexes and corresponding FSC curves calculated from the final reconstructions in cryoSPARC. c , d , Vilazodone ( c , green) and buspirone ( d , teal) in the orthosteric binding pocket from the side ( left ) and rotated 45° towards the top of the receptor ( right ) with the density map of ligand and surrounding residues shown at 5σ. e-h , Extracellular view of 4-F,5-MeO-PyrT ( e , dark blue), Vilazodone ( f , green), Aripiprazole ( g , magenta, PDB ID: 7E2Z ), and Buspirone ( h , teal) binding poses in 5-HT 1A ’s orthosteric site.

Extended Data Fig. 6 Selectivity of different 5-MeO-DMT analogs and off-target activity of 4-F,5-MeO-PyrT.

a , 5-HT 1A -Gi and 5-HT 2A -Gq BRET of 5-HT, 5-MeO-DMT, 5-MeO-MET, and 4-F,5-MeO-PyrT with respective potencies and 5-HT 1A  > 5-HT 2A selectivities. b , Off-target inhibition of transporters SERT, PMAT, OCT1, and OCT2 by 4-F,5-MeO-PyrT and known inhibitors. SERT uptake was performed in triplicates and data was averaged from two independent experiments showing data as mean+s.e.m. PMAT, OCT1, and OCT2 uptake was performed once in quadruplicate. c, Arrestin-recruitment of 5-HT and 4-F,5-MeO-PyrT at all human 5-HT receptor subtypes except for 5-HT 7A , whose activation was measured via cAMP stimulation. All functional studies were performed in triplicates and are averaged from two to three independent experiments. Data have been normalized against 5-HT, Citalopram, and Decynium-22, and errors bars denote the s.e.m.

Extended Data Fig. 7 Effects of 5-MeO-DMT derivatives on rodent behavior.

a , Evaluation of 4-F,5-MeO-PyrT in open field for two hours (n = 3-4/group). b , Exemplary traces of the ambulatory distance traveled in open field following 4-F,5-MeO-PyrT (1 mg/kg, s.c.) administration and with and without WAY-100635 pre-treatment (1 mg/kg, s.c., 15 min prior). Panel was created with BioRender.com. c , Effect of WAY-100635 (1 mg/kg, s.c., 15 min prior) on 4-F,5-MeO-PyrT’s and 5-MeO-MET’s effect on total locomotion (n = 7 - 8/group, 30 min). d , Determination of optimal inhibitory WAY-100635 dose via administration of 1 mg/kg and 2 mg/kg WAY-100635 prior to studying 4-F,5-MeO-PyrT’s effects on total locomotion (n = 7 - 8 /group) and HTR (n = 6/group). Analysis was done using one-way ANOVA with multiple comparisons with Tukey’s post hoc test, and exact p values have been denoted in the Figure. e-g , Effects of saline or 4-F,5-MeO-PyrT administration on control (Control) or chronically defeated mice (Stress). Determination of e , distance moved as a measure of locomotor activity, f , social interaction as a measure of anxiety- and depression-related phenotype, g , corner time as a measure of anxiety-like behavior. Analysis was done in a sub-cohort of the animals reported in Fig. 5d . Number of mice for each group is indicated below the data for each respective cohort. Differences were determined by two-way ANOVA with multiple comparisons using Fisher’s LSD post hoc test, and exact p values have been denoted in the Figure. h , Vehicle- and drug-treated stressed mice shown in Fig. 5d were divided into susceptible (SI ratio<1) and resilient (SI ratio>1) populations. Significance in the population shift was determined by a two-sided Fisher’s exact test and p value and number of mice have been denoted in the Figure. Error bars denote the s.e.m.

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Warren, A.L., Lankri, D., Cunningham, M.J. et al. Structural pharmacology and therapeutic potential of 5-methoxytryptamines. Nature (2024). https://doi.org/10.1038/s41586-024-07403-2

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A Modified Psychedelic Toad Toxin Reduces Signs of Depression and Anxiety in Mice, Study Suggests

Colorado River toads produce a psychoactive toxin that some have claimed has medical benefits. The new research suggests these benefits could be achieved without hallucinations

Christian Thorsberg

Daily Correspondent

The Colorado River toad , a species native to Arizona’s Sonoran Desert and parts of northwest Mexico, has gained fame for its production of a toxin with psychoactive properties—and, some say, medicinal benefits.

Now, new research from Mount Sinai Hospital and Columbia University has put that toxin to the test. In a study published Wednesday in the journal Nature ,   scientists found that a modified analog of the toad’s secretion reduces symptoms of depression and anxiety in mice.

“We became intrigued by numerous reports of powerful, unique and life-changing experiences associated with its ritualistic or experimental clinical use, which made us wonder about its therapeutic potential and the underlying mechanisms,” David Lankri , a neuropharmacologist at Columbia University and a co-author of the study, tells Gizmodo ’s Ed Cara.

When threatened or startled, the Colorado River toad (also called the Sonoran desert toad) exudes 5-MeO-DMT, a hallucinogenic compound that discourages predators, from glands in its skin. Similar in structure to psilocybin, the psychedelic component of “magic mushrooms,” the toxin—which people ingest either by licking toads directly or extracting and smoking it—has been said to have dissociative effects and benefits as an antidepressant and anti-anxiety agent.

Most well-known psychedelic molecules (such as LSD) bind to serotonin receptors in the brain called 5-HT2A, which leads to the hallucinations typical of psychedelic experiences.

But by slightly modifying the 5-MeO-DMT toad toxin compound, the researchers created another compound, called 4-F,5-MeO-PyrT. This new molecule interacts primarily with similar yet lesser-studied serotonin receptors called 5-HT1A, a pathway that appears to offer the same antidepressant and anti-anxiety effects without inducing hallucinogenic trips.

Testing this new compound in mice, the team observed how their modified toxin did not produce the head-twitching effects attributed to the hallucinogenic properties of the toad toxin. They gave the newly created molecule to stressed mice—and the animals subsequently spent more time with peers and drank more sugary water, evidence of lowered anxiety and depression levels.

“It’s our hope that down the line, someone could use the findings of our study to help design novel antidepressants for humans, but that’s certainly a long way out,” Audrey Warren , a biochemist at Mount Sinai Hospital and a co-author of the study, says to New Scientist ’s Corryn Wetzel.

But Warren adds that the research is still in its infancy, and ingesting the toads’ toxin comes with significant risks—including side effects of vomiting, seizures, anxiety and death. And experts have cautioned that the toxin’s popularity is threatening the health of the toad in the wild. In California, the species is believed to be locally extinct, while in New Mexico, the toad is listed as threatened .

“There’s a perception of abundance, but when you begin to remove large numbers of a species, their numbers are going to collapse like a house of cards at some point,” Robert Villa , the president of the Tucson Herpetological Society, told the New York Times ’ Simon Romero in 2022.

Psychedelics are gaining popularity for potential medical uses. Researchers and legislators alike have recently looked at MDMA , psilocybin and the lesser-known ibogaine for their potential to treat conditions such as PTSD, anxiety and depression. As this intersection continues to be explored, the new paper raises the possibility that such medical benefits could be achieved without the hallucinations.

The research is “a really nice example of how structural biology can shed light on medicinal chemistry results,” David E. Olson , the director of the University of California Davis Institute for Psychedelics and Neurotherapeutics who was not involved in the study, tells Chemical and Engineering News ’ Bethany Halford.

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Christian Thorsberg | READ MORE

Christian Thorsberg is an environmental writer and photographer from Chicago. His work, which often centers on freshwater issues, climate change and subsistence, has appeared in Circle of Blue , Sierra  magazine, Discover  magazine and Alaska Sporting Journal .