research studies on treatment of depression

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• Published: 20 July 2022

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

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

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

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A Correspondence to this article was published on 16 June 2023

A Comment to this article was published on 16 June 2023

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

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Introduction.

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

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

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

Search strategy and selection criteria

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

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

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

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

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

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

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

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

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

Studies published in full in peer reviewed literature.

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

Exclusion criteria consisted of:

Animal studies.

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

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

Data analysis

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

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

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

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

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

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

Search results and quality rating

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

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

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

Serotonin and 5-HIAA

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

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

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

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

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

The serotonin transporter (SERT)

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

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

Depletion studies

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

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

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

SERT gene and gene-stress interactions

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

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

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

Overall results

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

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

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

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

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

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

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

Data availability

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

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

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Joanna Moncrieff & Mark A. Horowitz

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Ruth E. Cooper

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Tom Stockmann

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

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

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

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Clinical Trials

Depression (major depressive disorder).

Displaying 61 studies

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.

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.

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

The 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.

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 ...

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. 

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.

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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Psilocybin Treatment for Major Depression Effective for Up to a Year for Most Patients, Study Shows

New @JHPsychedelics follow-up study on effects of #psilocybin on #MajorDepressiveDisorder in adults finds that 2 doses of the psychedelic compound may ease symptoms for up to 12 months. @HopkinsMedicine ›

Previous studies by Johns Hopkins Medicine researchers showed that psychedelic treatment with psilocybin relieved major depressive disorder symptoms in adults for up to a month. Now, in a follow-up study of those participants, the researchers report that the substantial antidepressant effects of psilocybin-assisted therapy, given with supportive psychotherapy, may last at least a year for some patients.

A report on the new study was published on Feb. 15, 2022 in the Journal of Psychopharmacology .

“Our findings add to evidence that, under carefully controlled conditions, this is a promising therapeutic approach that can lead to significant and durable improvements in depression,” says Natalie Gukasyan, M.D. , assistant professor of psychiatry and behavioral sciences at the Johns Hopkins University School of Medicine. She cautions, however, that “the results we see are in a research setting and require quite a lot of preparation and structured support from trained clinicians and therapists, and people should not attempt to try it on their own.”

Over the last 20 years, there has been a growing of research with classic psychedelics — the pharmacological class of compounds that include psilocybin, an ingredient found in so-called magic mushrooms. According to the National Institute on Drug Abuse, psilocybin can produce perceptual changes, altering a person’s awareness of their surroundings and of their thoughts and feelings. Treatment with psilocybin has shown promise in research settings for treating a range of mental health disorders and addictions.

For this study, the researchers recruited 27 participants with a long-term history of depression, most of whom had been experiencing depressive symptoms for approximately two years before recruitment. The average age of participants was 40, 19 were women, and 25 identified as white, one as African American and one as Asian. Eighty-eight percent of the participants had previously been treated with standard antidepressant medications, and 58% reported using antidepressants in their current depressive episodes.

After screening, participants were randomized into one of two groups in which they received the intervention either immediately, or after an eight-week waiting period. At the time of treatment, all participants were provided with six to eight hours of preparatory meetings with two treatment facilitators. Following preparation, participants received two doses of psilocybin, given approximately two weeks apart between August 2017 and April 2019 at the Behavioral Biology Research Center at Johns Hopkins Bayview Medical Center. Participants returned for follow-up one day and one week after each session, and then at one, three, six and 12 months following the second session; 24 participants completed both psilocybin sessions and all follow-up assessment visits.

The researchers reported that psilocybin treatment in both groups produced large decreases in depression, and that depression severity remained low one, three, six and 12 months after treatment. Depressive symptoms were measured before and after treatment using the GRID-Hamilton Depression Rating Scale, a standard depression assessment tool, in which a score of 24 or more indicates severe depression, 17–23 moderate depression, 8–16 mild depression and 7 or less no depression. For most participants, scores for the overall treatment decreased from 22.8 at pretreatment to 8.7 at one week, 8.9 at four weeks, 9.3 at three months, 7 at six months and 7.7 at 12 months after treatment. Participants had stable rates of response to the treatment and remission of symptoms throughout the follow-up period, with 75% response and 58% remission at 12 months.“Psilocybin not only produces significant and immediate effects, it also has a long duration, which suggests that it may be a uniquely useful new treatment for depression,” says Roland Griffiths, Ph.D., the Oliver Lee McCabe III, Ph.D., Professor in the Neuropsychopharmacology of Consciousness at the Johns Hopkins University School of Medicine, and founding director of the Johns Hopkins Center for Psychedelic and Consciousness Research. “Compared to standard antidepressants, which must be taken for long stretches of time, psilocybin has the potential to enduringly relieve the symptoms of depression with one or two treatments.”

The researchers emphasize that further research is needed to explore the possibility that the efficacy of psilocybin treatment may be substantially longer than 12 months. Johns Hopkins is one of the sites of a national multisite randomized, placebo-controlled trial of psilocybin for major depressive disorder.

Other researchers who contributed to the study are Alan Davis, Frederick Barrett, Mary Cosimano, Nathan Sepeda and Matthew Johnson from the Johns Hopkins University School of Medicine.

The study was funded in part by a crowd-sourced campaign organized by Tim Ferriss and by grants from the Riverstyx Foundation and Dave Morin. Support for Alan Davis and Natalie Gukasyan was provided by a grant from the National Institutes of Health (T32DA07209, National Institute on Drug Abuse). Support for authors was also provided by the Center for Psychedelic and Consciousness Research, which is funded by the Steven and Alexandra Cohen Foundation, Tim Ferriss, Matt Mullenweg, Craig Nerenberg and Blake Mycoskie. The funders had no role in study design, data collection and analysis, or in decision to publish or manuscript preparation.

COI: Alan Davis is a board member of Source Research Foundation. Matthew Johnson has received grant support from the Heffter Research Institute that is unrelated to this study, and he is an advisor to the following companies: AJNA Labs, AWAKN Life Sciences, Beckley Psytech, Entheon Biomedical, Field Trip Psychedelics, Mind Medicine, Otsuka Pharmaceutical Development & Commercialization and Silo Pharma. Roland Griffiths is a board member of the Heffter Research Institute and has received grant support from the institute unrelated to this study. Griffiths is site principal investigator, and Johnson and Gukasyan are co-investigators for a multisite trial of psilocybin-assisted therapy for major depressive disorder sponsored by Usona Institute.

Related Story:

• Psychedelic Treatment with Psilocybin Relieves Major Depression, Study Shows

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New guidelines for depression care emphasize patient-centred approach

Psychiatrists and mental health professionals have a new standard for managing major depression, thanks to refreshed clinical guidelines published today by the Canadian Network for Mood and Anxiety Treatments (CANMAT).

The CANMAT guidelines are the most widely used clinical guidelines for depression in the world. The new version integrates the latest scientific evidence and advances in depression care since the previous guidelines were published in 2016. The update was led by researchers at the University of B.C. and the University of Toronto, alongside a national working group of more than 40 academic clinical experts and patient partners.

"These recommendations not only represent the evidence and broad consensus of leading experts in depression research and care, but, importantly, they also reflect the perspectives of patients with lived experience," says co-lead author Dr. Raymond Lam, professor of psychiatry at UBC and co-director of the Mood Disorders Centre at the Djavad Mowafaghian Centre for Brain Health. "Our hope is that this update will empower clinicians with the latest recommendations that can help achieve better outcomes and improved quality of life for the millions of people affected by depression."

More than one in 10 Canadians will experience depression at some point in their lives, making it one of the largest public health burdens in Canada. However, it is estimated that only 20 per cent of people receive adequate treatment.

The updated guidelines cover eight primary topic areas that map the patient care journey, from assessment and diagnosis through to the selection of treatments and strategies to prevent recurrence. The question-and-answer format is designed to be practical, accessible and easy for clinicians to use.

To develop the refreshed guidelines, the working group conducted a comprehensive literature review of new scientific evidence published since the previous 2016 guidelines. Drafts were revised based on review by patient partners, expert peer review and a defined expert consensus process.

The resulting recommendations are organized by lines of treatment based on the level of evidence supporting each therapy and factors such as safety, tolerability and feasibility. Guidance is provided to aid healthcare professionals in choosing the right treatment option with an emphasis on collaborative decision-making.

"Depression is a complex and highly individualized condition," says Dr. Lam. "The guidelines highlight the importance of collaborating with patients in care decisions and providing a personalized treatment approach that carefully considers a person's needs, preferences and treatment history."

The guidelines underline the strong evidence base for well-established first-line treatments, including a number of medications, as well as psychological treatments such as cognitive behavioural therapy, interpersonal therapy and behavioural activation. Based on recent evidence, a number of new psychological and pharmacological treatments were added to the list of treatment options.

"Notable additions to the new guidelines are a strong emphasis on patient participation in choosing treatment, applying outcome measures throughout care, and an overview of digital mental health tools in the management of depression," says co-lead author Dr. Sidney Kennedy, professor of psychiatry at the University of Toronto and director of the Centre for Depression and Suicide Studies at Unity Health Toronto.

The guidelines include further direction on how healthcare professionals can incorporate lifestyle interventions, such as exercise, nutrition and sleep hygiene. They also explore when neuromodulation treatments should be considered and what should be done when a patient doesn't respond to initial treatments or develops treatment-resistant depression.

"Many well-established psychological and behavioural interventions have accumulated more support for their efficacy across different delivery formats," says co-author Dr. Lena Quilty, associate professor of psychiatry at the University of Toronto and senior scientist at the Centre for Addiction and Mental Health. "We are especially pleased to report on evidence for new interventions that target depression as well as commonly co-occurring challenges such as anxiety or disrupted cognitive processes. We hope that these additional alternatives provide more opportunities for integrated attention to these multi-faceted issues."

CANMAT is a network of academic and clinical experts dedicated to improving clinical care for people with mood and anxiety disorders. The new depression guidelines were published today in The Canadian Journal of Psychiatry . The researchers will be releasing updated versions of the CANMAT Pocket Guide to Depression for clinicians and the CHOICE-D Patient and Family Guide to Depression Treatment.

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Materials provided by University of British Columbia . Note: Content may be edited for style and length.

Journal Reference :

• Raymond W. Lam, Sidney H. Kennedy, Camelia Adams, Anees Bahji, Serge Beaulieu, Venkat Bhat, Pierre Blier, Daniel M. Blumberger, Elisa Brietzke, Trisha Chakrabarty, André Do, Benicio N. Frey, Peter Giacobbe, David Gratzer, Sophie Grigoriadis, Jeffrey Habert, M. Ishrat Husain, Zahinoor Ismail, Alexander McGirr, Roger S. McIntyre, Erin E. Michalak, Daniel J. Müller, Sagar V. Parikh, Lena S. Quilty, Arun V. Ravindran, Nisha Ravindran, Johanne Renaud, Joshua D. Rosenblat, Zainab Samaan, Gayatri Saraf, Kathryn Schade, Ayal Schaffer, Mark Sinyor, Claudio N. Soares, Jennifer Swainson, Valerie H. Taylor, Smadar V. Tourjman, Rudolf Uher, Michael van Ameringen, Gustavo Vazquez, Simone Vigod, Daphne Voineskos, Lakshmi N. Yatham, Roumen V. Milev. Canadian Network for Mood and Anxiety Treatments (CANMAT) 2023 Update on Clinical Guidelines for Management of Major Depressive Disorder in Adults: Réseau canadien pour les traitements de l'humeur et de l'anxiété (CANMAT) 2023 Mise . The Canadian Journal of Psychiatry , 2024; DOI: 10.1177/07067437241245384

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Efficacy of psilocybin for treating symptoms of depression: systematic review and meta-analysis

Linked editorial.

Psilocybin for depression

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• EXPRESSION OF CONCERN: Efficacy of psilocybin for treating symptoms of depression: systematic review and meta-analysis - May 04, 2024
• Athina-Marina Metaxa , masters graduate researcher 1 ,
• Mike Clarke , professor 2
• 1 Nuffield Department of Primary Care Health Sciences, University of Oxford, Oxford OX2 6GG, UK
• 2 Northern Ireland Methodology Hub, Centre for Public Health, ICS-A Royal Hospitals, Belfast, Ireland, UK
• Correspondence to: A-M Metaxa athina.metaxa{at}hmc.ox.ac.uk (or @Athina_Metaxa12 on X)
• Accepted 6 March 2024

Objective To determine the efficacy of psilocybin as an antidepressant compared with placebo or non-psychoactive drugs.

Design Systematic review and meta-analysis.

Data sources Five electronic databases of published literature (Cochrane Central Register of Controlled Trials, Medline, Embase, Science Citation Index and Conference Proceedings Citation Index, and PsycInfo) and four databases of unpublished and international literature (ClinicalTrials.gov, WHO International Clinical Trials Registry Platform, ProQuest Dissertations and Theses Global, and PsycEXTRA), and handsearching of reference lists, conference proceedings, and abstracts.

Data synthesis and study quality Information on potential treatment effect moderators was extracted, including depression type (primary or secondary), previous use of psychedelics, psilocybin dosage, type of outcome measure (clinician rated or self-reported), and personal characteristics (eg, age, sex). Data were synthesised using a random effects meta-analysis model, and observed heterogeneity and the effect of covariates were investigated with subgroup analyses and metaregression. Hedges’ g was used as a measure of treatment effect size, to account for small sample effects and substantial differences between the included studies’ sample sizes. Study quality was appraised using Cochrane’s Risk of Bias 2 tool, and the quality of the aggregated evidence was evaluated using GRADE guidelines.

Eligibility criteria Randomised trials in which psilocybin was administered as a standalone treatment for adults with clinically significant symptoms of depression and change in symptoms was measured using a validated clinician rated or self-report scale. Studies with directive psychotherapy were included if the psychotherapeutic component was present in both experimental and control conditions. Participants with depression regardless of comorbidities (eg, cancer) were eligible.

Results Meta-analysis on 436 participants (228 female participants), average age 36-60 years, from seven of the nine included studies showed a significant benefit of psilocybin (Hedges’ g=1.64, 95% confidence interval (CI) 0.55 to 2.73, P<0.001) on change in depression scores compared with comparator treatment. Subgroup analyses and metaregressions indicated that having secondary depression (Hedges’ g=3.25, 95% CI 0.97 to 5.53), being assessed with self-report depression scales such as the Beck depression inventory (3.25, 0.97 to 5.53), and older age and previous use of psychedelics (metaregression coefficient 0.16, 95% CI 0.08 to 0.24 and 4.2, 1.5 to 6.9, respectively) were correlated with greater improvements in symptoms. All studies had a low risk of bias, but the change from baseline metric was associated with high heterogeneity and a statistically significant risk of small study bias, resulting in a low certainty of evidence rating.

Conclusion Treatment effects of psilocybin were significantly larger among patients with secondary depression, when self-report scales were used to measure symptoms of depression, and when participants had previously used psychedelics. Further research is thus required to delineate the influence of expectancy effects, moderating factors, and treatment delivery on the efficacy of psilocybin as an antidepressant.

Systematic review registration PROSPERO CRD42023388065.

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Introduction

Depression affects an estimated 300 million people around the world, an increase of nearly 20% over the past decade. 1 Worldwide, depression is also the leading cause of disability. 2

Drugs for depression are widely available but these seem to have limited efficacy, can have serious adverse effects, and are associated with low patient adherence. 3 4 Importantly, the treatment effects of antidepressant drugs do not appear until 4-7 weeks after the start of treatment, and remission of symptoms can take months. 4 5 Additionally, the likelihood of relapse is high, with 40-60% of people with depression experiencing a further depressive episode, and the chance of relapse increasing with each subsequent episode. 6 7

Since the early 2000s, the naturally occurring serotonergic hallucinogen psilocybin, found in several species of mushrooms, has been widely discussed as a potential treatment for depression. 8 9 Psilocybin’s mechanism of action differs from that of classic selective serotonin reuptake inhibitors (SSRIs) and might improve the treatment response rate, decrease time to improvement of symptoms, and prevent relapse post-remission. Moreover, more recent assessments of harm have consistently reported that psilocybin generally has low addictive potential and toxicity and that it can be administered safely under clinical supervision. 10

The renewed interest in psilocybin’s antidepressive effects led to several clinical trials on treatment resistant depression, 11 12 major depressive disorder, 13 and depression related to physical illness. 14 15 16 17 These trials mostly reported positive efficacy findings, showing reductions in symptoms of depression within a few hours to a few days after one dose or two doses of psilocybin. 11 12 13 16 17 18 These studies reported only minimal adverse effects, however, and drug harm assessments in healthy volunteers indicated that psilocybin does not induce physiological toxicity, is not addictive, and does not lead to withdrawal. 19 20 Nevertheless, these findings should be interpreted with caution owing to the small sample sizes and open label design of some of these studies. 11 21

Several systematic reviews and meta-analyses since the early 2000s have investigated the use of psilocybin to treat symptoms of depression. Most found encouraging results, but as well as people with depression some included healthy volunteers, 22 and most combined data from studies of multiple serotonergic psychedelics, 23 24 25 even though each compound has unique neurobiological effects and mechanisms of action. 26 27 28 Furthermore, many systematic reviews included non-randomised studies and studies in which psilocybin was tested in conjunction with psychotherapeutic interventions, 25 29 30 31 32 which made it difficult to distinguish psilocybin’s treatment effects. Most systematic reviews and meta-analyses did not consider the impact of factors that could act as moderators to psilocybin’s effects, such as type of depression (primary or secondary), previous use of psychedelics, psilocybin dosage, type of outcome measure (clinician rated or self-reported), and personal characteristics (eg, age, sex). 25 26 29 30 31 32 Lastly, systematic reviews did not consider grey literature, 33 34 which might have led to a substantial overestimation of psilocybin’s efficacy as a treatment for depression. In this review we focused on randomised trials that contained an unconfounded evaluation of psilocybin in adults with symptoms of depression, regardless of country and language of publication.

In this systematic review and meta-analysis of indexed and non-indexed randomised trials we investigated the efficacy of psilocybin to treat symptoms of depression compared with placebo or non-psychoactive drugs. The protocol was registered in the International Prospective Register of Systematic Reviews (see supplementary Appendix A). The study overall did not deviate from the pre-registered protocol; one clarification was made to highlight that any non-psychedelic comparator was eligible for inclusion, including placebo, niacin, micro doses of psychedelics, and drugs that are considered the standard of care in depression (eg, SSRIs).

Inclusion and exclusion criteria

Double blind and open label randomised trials with a crossover or parallel design were eligible for inclusion. We considered only studies in humans and with a control condition, which could include any type of non -active comparator, such as placebo, niacin, or micro doses of psychedelics.

Eligible studies were those that included adults (≥18 years) with clinically significant symptoms of depression, evaluated using a clinically validated tool for depression and mood disorder outcomes. Such tools included the Beck depression inventory, Hamilton depression rating scale, Montgomery-Åsberg depression rating scale, profile of mood states, and quick inventory of depressive symptomatology. Studies of participants with symptoms of depression and comorbidities (eg, cancer) were also eligible. We excluded studies of healthy participants (without depressive symptomatology).

Eligible studies investigated the effect of psilocybin as a standalone treatment on symptoms of depression. Studies with an active psilocybin condition that involved micro dosing (ie, psilocybin <100 μg/kg, according to the commonly accepted convention 22 35 ) were excluded. We included studies with directive psychotherapy if the psychotherapeutic component was present in both the experimental and the control conditions, so that the effects of psilocybin could be distinguished from those of psychotherapy. Studies involving group therapy were also excluded. Any non-psychedelic comparator was eligible for inclusion, including placebo, niacin, and micro doses of psychedelics.

Changes in symptoms, measured by validated clinician rated or self-report scales, such as the Beck depression inventory, Hamilton depression rating scale, Montgomery-Åsberg depression rating scale, profile of mood states, and quick inventory of depressive symptomatology were considered. We excluded outcomes that were measured less than three hours after psilocybin had been administered because any reported changes could be attributed to the transient cognitive and affective effects of the substance being administered. Aside from this, outcomes were included irrespective of the time point at which measurements were taken.

Search strategy

We searched major electronic databases and trial registries of psychological and medical research, with no limits on the publication date. Databases were the Cochrane Central Register of Controlled Trials via the Cochrane Library, Embase via Ovid, Medline via Ovid, Science Citation Index and Conference Proceedings Citation Index-Science via Web of Science, and PsycInfo via Ovid. A search through multiple databases was necessary because each database includes unique journals. Supplementary Appendix B shows the search syntax used for the Cochrane Central Register of Controlled Trials, which was slightly modified to comply with the syntactic rules of the other databases.

Unpublished and grey literature were sought through registries of past and ongoing trials, databases of conference proceedings, government reports, theses, dissertations, and grant registries (eg, ClinicalTrials.gov, WHO International Clinical Trials Registry Platform, ProQuest Dissertations and Theses Global, and PsycEXTRA). The references and bibliographies of eligible studies were checked for relevant publications. The original search was done in January 2023 and updated search was performed on 10 August 2023.

Data collection, extraction, and management

The results of the literature search were imported to the Endnote X9 reference management software, and the references were imported to the Covidence platform after removal of duplicates. Two reviewers (AM and DT) independently screened the title and abstract of each reference and then screened the full text of potentially eligible references. Any disagreements about eligibility were resolved through discussion. If information was insufficient to determine eligibility, the study’s authors were contacted. The reviewers were not blinded to the studies’ authors, institutions, or journal of publication.

The PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) flow diagram shows the study selection process and reasons for excluding studies that were considered eligible for full text screening. 36

Critical appraisal of individual studies and of aggregated evidence

The methodological quality of eligible studies was assessed using the Cochrane Risk of Bias 2 tool (RoB 2) for assessing risk of bias in randomised trials. 37 In addition to the criteria specified by RoB 2, we considered the potential impact of industry funding and conflicts of interest. The overall methodological quality of the aggregated evidence was evaluated using GRADE (Grading of Recommendations, Assessment, Development and Evaluation). 38

If we found evidence of heterogeneity among the trials, then small study biases, such as publication bias, were assessed using a funnel plot and asymmetry tests (eg, Egger’s test). 39

We used a template for data extraction (see supplementary Appendix C) and summarised the extracted data in tabular form, outlining personal characteristics (age, sex, previous use of psychedelics), methodology (study design, dosage), and outcome related characteristics (mean change from baseline score on a depression questionnaire, response rates, and remission rates) of the included studies. Response conventionally refers to a 50% decrease in symptom severity based on scores on a depression rating scale, whereas remission scores are specific to a questionnaire (eg, score of ≤5 on the quick inventory of depressive symptomatology, score of ≤10 on the Montgomery-Åsberg depression rating scale, 50% or greater reduction in symptoms, score of ≤7 on the Hamilton depression rating scale, or score of ≤12 on the Beck depression inventory). Across depression scales, higher scores signify more severe symptoms of depression.

Continuous data synthesis

From each study we extracted the baseline and post-intervention means and standard deviations (SDs) of the scores between comparison groups for the depression questionnaires and calculated the mean differences and SDs of change. If means and SDs were not available for the included studies, we extracted the values from available graphs and charts using the Web Plot Digitizer application ( https://automeris.io/WebPlotDigitizer/ ). If it was not possible to calculate SDs from the graphs or charts, we generated values by converting standard errors (SEs) or confidence intervals (CIs), depending on availability, using formulas in the Cochrane Handbook (section 7.7.3.2). 40

Standardised mean differences were calculated for each study. We chose these rather than weighted mean differences because, although all the studies measured depression as the primary outcome, they did so with different questionnaires that score depression based on slightly different items. 41 If we had used weighted mean differences, any variability among studies would be assumed to reflect actual methodological or population differences and not differences in how the outcome was measured, which could be misleading. 40

The Hedges’ g effect size estimate was used because it tends to produce less biased results for studies with smaller samples (<20 participants) and when sample sizes differ substantially between studies, in contrast with Cohen’s d. 42 According to the Cochrane Handbook, the Hedges’ g effect size measure is synonymous with the standardised mean difference, 40 and the terms may be used interchangeably. Thus, a Hedges’ g of 0.2, 0.5, 0.8, or 1.2 corresponds to a small, medium, large, or very large effect, respectively. 40

Owing to variation in the participants’ personal characteristics, psilocybin dosage, type of depression investigated (primary or secondary), and type of comparators, we used a random effects model with a Hartung-Knapp-Sidik-Jonkman modification. 43 This model also allowed for heterogeneity and within study variability to be incorporated into the weighting of the results of the included studies. 44 Lastly, this model could help to generalise the findings beyond the studies and patient populations included, making the meta-analysis more clinically useful. 45 We chose the Hartung-Knapp-Sidik-Jonkman adjustment in favour of more widely used random effects models (eg, DerSimonian and Laird) because it allows for better control of type 1 errors, especially for studies with smaller samples, and provides a better estimation of between study variance by accounting for small sample sizes. 46 47

For studies in which multiple treatment groups were compared with a single placebo group, we split the placebo group to avoid multiplicity. 48 Similarly, if studies included multiple primary outcomes (eg, change in depression at three weeks and at six weeks), we split the treatment groups to account for overlapping participants. 40

Prediction intervals (PIs) were calculated and reported to show the expected effect range of a similar future study, in a different setting. In a random effects model, within study measures of variability, such as CIs, can only show the range in which the average effect size could lie, but they are not informative about the range of potential treatment effects given the heterogeneity between studies. 49 Thus, we used PIs as an indication of variation between studies.

Heterogeneity and sensitivity analysis

Statistical heterogeneity was tested using the χ 2 test (significance level P<0.1) and I 2 statistic, and heterogeneity among included studies was evaluated visually and displayed graphically using a forest plot. If substantial or considerable heterogeneity was found (I 2 ≥50% or P<0.1), 50 we considered the study design and characteristics of the included studies. Sources of heterogeneity were explored by subgroup analysis, and the potential effects on the results are discussed.

Planned sensitivity analyses to assess the effect of unpublished studies and studies at high risk of bias were not done because all included studies had been published and none were assessed as high risk of bias. Exclusion sensitivity plots were used to display graphically the impact of individual studies and to determine which studies had a particularly large influence on the results of the meta-analysis. All sensitivity analyses were carried out with Stata 16 software.

Subgroup analysis

To reduce the risk of errors caused by multiplicity and to avoid data fishing, we planned subgroup analyses a priori and limited to: (1) patient characteristics, including age and sex; (2) comorbidities, such as a serious physical condition (previous research indicates that the effects of psilocybin may be less strong for such participants, compared with participants with no comorbidities) 33 ; (3) number of doses and amount of psilocybin administered, because some previous meta-analyses found that a higher number of doses and a higher dose of psilocybin both predicted a greater reduction in symptoms of depression, 34 whereas others reported the opposite 33 ; (4) psilocybin administered alongside psychotherapeutic guidance or as a standalone treatment; (5) severity of depressive symptoms (clinical v subclinical symptomatology); (6) clinician versus patient rated scales; and (7) high versus low quality studies, as determined by RoB 2 assessment scores.

Metaregression

Given that enough studies were identified (≥10 distinct observations according to the Cochrane Handbook’s suggestion 40 ), we performed metaregression to investigate whether covariates, or potential effect modifiers, explained any of the statistical heterogeneity. The metaregression analysis was carried out using Stata 16 software.

Random effects metaregression analyses were used to determine whether continuous variables such as participants’ age, percentage of female participants, and percentage of participants who had previously used psychedelics modified the effect estimate, all of which have been implicated in differentially affecting the efficacy of psychedelics in modifying mood. 51 We chose this approach in favour of converting these continuous variables into categorical variables and conducting subgroup analyses for two primary reasons; firstly, the loss of any data and subsequent loss of statistical power would increase the risk of spurious significant associations, 51 and, secondly, no cut-offs have been agreed for these factors in literature on psychedelic interventions for mood disorders, 52 making any such divisions arbitrary and difficult to reconcile with the findings of other studies. The analyses were based on within study averages, in the absence of individual data points for each participant, with the potential for the results to be affected by aggregate bias, compromising their validity and generalisability. 53 Furthermore, a group level analysis may not be able to detect distinct interactions between the effect modifiers and participant subgroups, resulting in ecological bias. 54 As a result, this analysis should be considered exploratory.

Sensitivity analysis

A sensitivity analysis was performed to determine if choice of analysis method affected the primary findings of meta-analysis. Specifically, we reanalysed the data on change in depression score using a random effects Dersimonian and Laird model without the Hartung-Knapp-Sidik-Jonkman modification and compared the results with those of the originally used model. This comparison is particularly important in the presence of substantial heterogeneity and the potential of small study effects to influence the intervention effect estimate. 55

Patient and public involvement

Research on novel depression treatments is of great interest to both patients and the public. Although patients and members of the public were not directly involved in the planning or writing of this manuscript owing to a lack of available funding for recruitment and researcher training, patients and members of the public read the manuscript after submission.

Figure 1 presents the flow of studies through the systematic review and meta-analysis. 56 A total of 4884 titles were retrieved from the five databases of published literature, and a further 368 titles were identified from the databases of unpublished and international literature in February 2023. After the removal of duplicate records, we screened the abstracts and titles of 875 reports. A further 12 studies were added after handsearching of reference lists and conference proceedings and abstracts. Overall, nine studies totalling 436 participants were eligible. The average age of the participants ranged from 36-60 years. During an updated search on 10 August 2023, no further studies were identified.

Flow of studies in systematic review and meta-analysis

After screening of the title and abstract, 61 titles remained for full text review. Native speakers helped to translate papers in languages other than English. The most common reasons for exclusion were the inclusion of healthy volunteers, absence of control groups, and use of a survey based design rather than an experimental design. After full text screening, nine studies were eligible for inclusion, and 15 clinical trials prospectively registered or underway as of August 2023 were noted for potential future inclusion in an update of this review (see supplementary Appendix D).

We sent requests for further information to the authors of studies by Griffiths et al, 57 Barrett, 58 and Benville et al, 59 because these studies appeared to meet the inclusion criteria but were only provided as summary abstracts online. A potentially eligible poster presentation from the 58th annual meeting of the American College of Neuropsychopharmacology was identified but the lead author (Griffiths) clarified that all information from the presentation was included in the studies by Davis et al 13 and Gukasyan et al 60 ; both of which we had already deemed ineligible.

Barrett 58 reported the effects of psilocybin on the cognitive flexibility and verbal reasoning of a subset of patients with major depressive disorder from Griffith et al’s trial, 61 compared with a waitlist group, but when contacted, Barrett explained that the results were published in the study by Doss et al, 62 which we had already screened and judged ineligible (see supplementary Appendix E). Benville et al’s study 59 presented a follow-up of Ross et al’s study 17 on a subset of patients with cancer and high suicidal ideation and desire for hastened death at baseline. Measures of antidepressant effects of psilocybin treatment compared with niacin were taken before and after treatment crossover, but detailed results are not reported. Table 1 describes the characteristics of the included studies and table 2 lists the main findings of the studies.

Characteristics of included studies

• View inline

Main findings of included studies

Side effects and adverse events

Side effects reported in the included studies were minor and transient (eg, short term increases in blood pressure, headache, and anxiety), and none were coded as serious. Cahart-Harris et al noted one instance of abnormal dreams and insomnia. 63 This side effect profile is consistent with findings from other meta-analyses. 30 68 Owing to the different scales and methods used to catalogue side effects and adverse events across trials, it was not possible to combine these data quantitatively (see supplementary Appendix F).

Risk of bias

The Cochrane RoB 2 tools were used to evaluate the included studies ( table 3 ). RoB 2 for randomised trials was used for the five reports of parallel randomised trials (Carhart-Harris et al 63 and its secondary analysis Barba et al, 64 Goodwin et al 18 and its secondary analysis Goodwin et al, 65 and von Rotz et al 66 ) and RoB 2 for crossover trials was used for the four reports of crossover randomised trials (Griffiths et al, 14 Grob et al, 15 and Ross et al 17 and its follow-up Ross et al 67 ). Supplementary Appendix G provides a detailed explanation of the assessment of the included studies.

Summary risk of bias assessment of included studies, based on domains in Cochrane Risk of Bias 2 tool

Quality of included studies

Confidence in the quality of the evidence for the meta-analysis was assessed using GRADE, 38 through the GRADEpro GDT software program. Figure 2 shows the results of this assessment, along with our summary of findings.

GRADE assessment outputs for outcomes investigated in meta-analysis (change in depression scores and response and remission rates). The risk in the intervention group (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). BDI=Beck depression inventory; CI=confidence interval; GRADE=Grading of Recommendations, Assessment, Development and Evaluation; HADS-D=hospital anxiety and depression scale; HAM-D=Hamilton depression rating scale; MADRS=Montgomery-Åsberg depression rating scale; QIDS=quick inventory of depressive symptomatology; RCT=randomised controlled trial; SD=standard deviation

Meta-analyses

Continuous data, change in depression scores —Using a Hartung-Knapp-Sidik-Jonkman modified random effects meta-analysis, change in depression scores was significantly greater after treatment with psilocybin compared with active placebo. The overall Hedges’ g (1.64, 95% CI 0.55 to 2.73) indicated a large effect size favouring psilocybin ( fig 3 ). PIs were, however, wide and crossed the line of no difference (95% CI −1.72 to 5.03), indicating that there could be settings or populations in which psilocybin intervention would be less efficacious.

Forest plot for overall change in depression scores from before to after treatment. CI=confidence interval; DL=DerSimonian and Laird; HKSJ=Hartung-Knapp-Sidik-Jonkman

Exploring publication bias in continuous data —We used Egger’s test and a funnel plot to examine the possibility of small study biases, such as publication bias. Statistical significance of Egger’s test for small study effects, along with the asymmetry in the funnel plot ( fig 4 ), indicates the presence of bias against smaller studies with non-significant results, suggesting that the pooled intervention effect estimate is likely to be overestimated. 69 An alternative explanation, however, is that smaller studies conducted at the early stages of a new psychotherapeutic intervention tend to include more high risk or responsive participants, and psychotherapeutic interventions tend to be delivered more effectively in smaller trials; both of these factors can exaggerate treatment effects, resulting in funnel plot asymmetry. 70 Also, because of the relatively small number of included studies and the considerable heterogeneity observed, test power may be insufficient to distinguish real asymmetry from chance. 71 Thus, this analysis should be considered exploratory.

Funnel plot assessing publication bias among studies measuring change in depression scores from before to after treatment. CI=confidence interval; θ IV =estimated effect size under inverse variance random effects model

Dichotomous data

We extracted response and remission rates for each group when reported directly, or imputed information when presented graphically. Two studies did not measure response or remission and thus did not contribute data for this part of the analysis. 15 18 The random effects model with a Hartung-Knapp-Sidik-Jonkman modification was used to allow for heterogeneity to be incorporated into the weighting of the included studies’ results, and to provide a better estimation of between study variance accounting for small sample sizes.

Response rate —Overall, the likelihood of psilocybin intervention leading to treatment response was about two times greater (risk ratio 2.02, 95% CI 1.33 to 3.07) than with placebo. Despite the use of different scales to measure response, the heterogeneity between studies was not significant (I 2 =25.7%, P=0.23). PIs were, however, wide and crossed the line of no difference (−0.94 to 3.88), indicating that there could be settings or populations in which psilocybin intervention would be less efficacious.

Remission rate —Overall, the likelihood of psilocybin intervention leading to remission of depression was nearly three times greater than with placebo (risk ratio 2.71, 95% CI 1.75 to 4.20). Despite the use of different scales to measure response, no statistical heterogeneity was found between studies (I 2 =0.0%, P=0.53). PIs were, however, wide and crossed the line of no difference (0.87 to 2.32), indicating that there could be settings or populations in which psilocybin intervention would be less efficacious.

Exploring publication bias in response and remission rates data —We used Egger’s test and a funnel plot to examine whether response and remission estimates were affected by small study biases. The result for Egger’s test was non-significant (P>0.05) for both response and remission estimates, and no substantial asymmetry was observed in the funnel plots, providing no indication for the presence of bias against smaller studies with non-significant results.

Heterogeneity: subgroup analyses and metaregression

Heterogeneity was considerable across studies exploring changes in depression scores (I 2 =89.7%, P<0.005), triggering subgroup analyses to explore contributory factors. Table 4 and table 5 present the results of the heterogeneity analyses (subgroup analyses and metaregression, respectively). Also see supplementary Appendix H for a more detailed description and graphical representation of these results.

Subgroup analyses to explore potential causes of heterogeneity among included studies

Metaregression analyses to explore potential causes of heterogeneity among included studies

Cumulative meta-analyses

We used cumulative meta-analyses to investigate how the overall estimates of the outcomes of interest changed as each study was added in chronological order 72 ; change in depression scores and likelihood of treatment response both increased as the percentage of participants with past use of psychedelics increased across studies, as expected based on the metaregression analysis (see supplementary Appendix I). No other significant time related patterns were found.

We reanalysed the data for change in depression scores using a random effects Dersimonian and Laird model without the Hartung-Knapp-Sidik-Jonkman modification and compared the results with those of the original model. All comparisons found to be significant using the Dersimonian and Laird model with the Hartung-Knapp-Sidik-Jonkman adjustment were also significant without the Hartung-Knapp-Sidik-Jonkman adjustment, and confidence intervals were only slightly narrower. Thus, small study effects do not appear to have played a major role in the treatment effect estimate.

Additionally, to estimate the accuracy and robustness of the estimated treatment effect, we excluded studies from the meta-analysis one by one; no important differences in the treatment effect, significance, and heterogeneity levels were observed after the exclusion of any study (see supplementary Appendix J).

In our meta-analysis we found that psilocybin use showed a significant benefit on change in depression scores compared with placebo. This is consistent with other recent meta-analyses and trials of psilocybin as a standalone treatment for depression 73 74 or in combination with psychological support. 24 25 29 30 31 32 68 75 This review adds to those finding by exploring the considerable heterogeneity across the studies, with subsequent subgroup analyses showing that the type of depression (primary or secondary) and the depression scale used (Montgomery-Åsberg depression rating scale, quick inventory of depressive symptomatology, or Beck depression inventory) had a significant differential effect on the outcome. High between study heterogeneity has been identified by some other meta-analyses of psilocybin (eg, Goldberg et al 29 ), with a higher treatment effect in studies with patients with comorbid life threatening conditions compared with patients with primary depression. 22 Although possible explanations, including personal factors (eg, patients with life threatening conditions being older) or depression related factors (eg, secondary depression being more severe than primary depression) could be considered, these hypotheses are not supported by baseline data (ie, patients with secondary depression do not differ substantially in age or symptom severity from patients with primary depression). The differential effects from assessment scales used have not been examined in other meta-analyses of psilocybin, but this review’s finding that studies using the Beck depression inventory showed a higher treatment effect than those using the Montgomery-Åsberg depression rating scale and quick inventory of depressive symptomatology is consistent with studies in the psychological literature that have shown larger treatment effects when self-report scales are used (eg, Beck depression inventory). 76 77 This finding may be because clinicians tend to overestimate the severity of depression symptoms at baseline assessments, leading to less pronounced differences between before and after treatment identified in clinician assessed scales (eg, Montgomery-Åsberg depression rating scale, quick inventory of depressive symptomatology). 78

Metaregression analyses further showed that a higher average age and a higher percentage of participants with past use of psychedelics both correlated with a greater improvement in depression scores with psilocybin use and explained a substantial amount of between study variability. However, the cumulative meta-analysis showed that the effects of age might be largely an artefact of the inclusion of one specific study, and alternative explanations are worth considering. For instance, Studerus et al 79 identified participants’ age as the only personal variable significantly associated with psilocybin response, with older participants reporting a higher “blissful state” experience. This might be because of older people’s increased experience in managing negative emotions and the decrease in 5-hydroxytryptamine type 2A receptor density associated with older age. 80 Furthermore, Rootman et al 81 reported that the cognitive performance of older participants (>55 years) improved significantly more than that of younger participants after micro dosing with psilocybin. Therefore, the higher decrease in depressive symptoms associated with older age could be attributed to a decrease in cognitive difficulties experienced by older participants.

Interestingly, a clear pattern emerged for past use of psychedelics—the higher the proportion of study participants who had used psychedelics in the past, the higher the post-psilocybin treatment effect observed. Past use of psychedelics has been proposed to create an expectancy bias among participants and amplify the positive effects of psilocybin 82 83 84 ; however, this important finding has not been examined in other meta-analyses and may highlight the role of expectancy in psilocybin research.

Limitations of this study

Generalisability of the findings of this meta-analysis was limited by the lack of racial and ethnic diversity in the included studies—more than 90% of participants were white across all included trials, resulting in a homogeneous sample that is not representative of the general population. Moreover, it was not possible to distinguish between subgroups of participants who had never used psilocybin and those who had taken psilocybin more than a year before the start of the trial, as these data were not provided in the included studies. Such a distinction would be important, as the effects of psilocybin on mood may wane within a year after being administered. 21 85 Also, how psychological support was conceptualised was inconsistent within studies of psilocybin interventions; many studies failed to clearly describe the type of psychological support participants received, and others used methods ranging from directive guidance throughout the treatment session to passive encouragement or reassurance (eg, Griffiths et al, 14 Carhart-Harris et al 63 ). The included studies also did not gather evidence on participants’ previous experiences with treatment approaches, which could influence their response to the trials’ intervention. Thus, differences between participant subgroups related to past use of psilocybin or psychotherapy may be substantial and could help interpret this study’s findings more accurately. Lastly, the use of graphical extraction software to estimate the findings of studies where exact numerical data were not available (eg, Goodwin et al, 18 Grob et al 15 ), may have affected the robustness of the analyses.

A common limitation in studies of psilocybin is the likelihood of expectancy effects augmenting the treatment effect observed. Although some studies used low dose psychedelics as comparators to deal with this problem (eg, Carhart-Harris et al, 63 Goodwin et al, 18 Griffiths et al 14 ) or used a niacin placebo that can induce effects similar to those of psilocybin (eg, Grob et al, 15 Ross et al 17 ), the extent to which these methods were effective in blinding participants is not known. Other studies have, however, reported that participants can accurately identify the study groups to which they had been assigned 70-85% of the time, 84 86 indicating a high likelihood of insufficient blinding. This is especially likely for studies in which a high proportion of participants had previously used psilocybin and other hallucinogens, making the identification of the drug’s acute effects easier (eg, Griffiths et al, 14 Grob et al, 15 Ross et al 17 ). Patients also have expectations related to the outcome of their treatment, expecting psilocybin to improve their symptoms of depression, and these positive expectancies are strong predictors of actual treatment effects. 87 88 Importantly, the effect of outcome expectations on treatment effect is particularly strong when patient reported measures are used as primary outcomes, 89 which was the case in several of the included studies (eg, Griffiths et al, 14 Grob et al, 15 Ross et al 17 ). Unfortunately, none of the included studies recorded expectations before treatment, so it is not possible to determine the extent to which this factor affected the findings.

Implications for clinical practice

Although this review’s findings are encouraging for psilocybin’s potential as an effective antidepressant, a few areas about its applicability in clinical practice remain unexplored. Firstly, it is unclear whether the protocols for psilocybin interventions in clinical trials can be reliably and safely implemented in clinical practice. In clinical trials, patients receive psilocybin in a non-traditional medical setting, such as a specially designed living room, while they may be listening to curated calming music and are isolated from most external stimuli by wearing eyeshades and external noise-cancelling earphones. A trained therapist closely supervises these sessions, and the patient usually receives one or more preparatory sessions before the treatment commences. Standardising an intervention setting with so many variables is unlikely to be achievable in routine practice, and consensus is considerably lacking on the psychotherapeutic training and accreditations needed for a therapist to deliver such treatment. 90 The combination of these elements makes this a relatively complex and expensive intervention, which could make it challenging to gain approval from regulatory agencies and to gain reimbursement from insurance companies and others. Within publicly funded healthcare systems, the high cost of treatment may make psilocybin treatment inaccessible. The high cost associated with the intervention also increases the risk that unregulated clinics may attempt to cut costs by making alterations to the protocol and the therapeutic process, 91 92 which could have detrimental effects for patients. 92 93 94 Thus, avoiding the conflation of medical and commercial interests is a primary concern that needs to be dealt with before psilocybin enters mainstream practice.

Implications for future research

More large scale randomised trials with long follow-up are needed to fully understand psilocybin’s treatment potential, and future studies should aim to recruit a more diverse population. Another factor that would make clinical trials more representative of routine practice would be to recruit patients who are currently using or have used commonly prescribed serotonergic antidepressants. Clinical trials tend to exclude such participants because many antidepressants that act on the serotonin system modulate the 5-hydroxytryptamine type 2A receptor that psilocybin primarily acts upon, with prolonged use of tricyclic antidepressants associated with more intense psychedelic experiences and use of monoamine oxidase inhibitors or SSRIs inducing weaker responses to psychedelics. 95 96 97 Investigating psilocybin in such patients would, however, provide valuable insight on how psilocybin interacts with commonly prescribed drugs for depression and would help inform clinical practice.

Minimising the influence of expectancy effects is another core problem for future studies. One strategy would be to include expectancy measures and explore the level of expectancy as a covariate in statistical analysis. Researchers should also test the effectiveness of condition masking. Another proposed solution would be to adopt a 2×2 balanced placebo design, where both the drug (psilocybin or placebo) and the instructions given to participants (told they have received psilocybin or told they have received placebo) are crossed. 98 Alternatively, clinical trials could adopt a three arm design that includes both an inactive placebo (eg, saline) and active placebo (eg, niacin, lower psylocibin dose), 98 allowing for the effects of psilocybin to be separated from those of the placebo.

Overall, future studies should explore psilocybin’s exact mechanism of treatment effectiveness and outline how its physiological effects, mystical experiences, dosage, treatment setting, psychological support, and relationship with the therapist all interact to produce a synergistic antidepressant effect. Although this may be difficult to achieve using an explanatory randomised trial design, pragmatic clinical trial designs may be better suited to psilocybin research, as their primary objective is to achieve high external validity and generalisability. Such studies may include multiple alternative treatments rather than simply an active and placebo treatment comparison (eg, psilocybin v SSRI v serotonin-noradrenaline reuptake inhibitor), and participants would be recruited from broader clinical populations. 99 100 Although such studies are usually conducted after a drug’s launch, 100 earlier use of such designs could help assess the clinical effectiveness of psilocybin more robustly and broaden patient access to a novel type of antidepressant treatment.

Conclusions

This review’s findings on psilocybin’s efficacy in reducing symptoms of depression are encouraging for its use in clinical practice as a drug intervention for patients with primary or secondary depression, particularly when combined with psychological support and administered in a supervised clinical environment. However, the highly standardised treatment setting, high cost, and lack of regulatory guidelines and legal safeguards associated with psilocybin treatment need to be dealt with before it can be established in clinical practice.

What is already known on this topic

Recent research on treatments for depression has focused on psychedelic agents that could have strong antidepressant effects without the drawbacks of classic antidepressants; psilocybin being one such substance

Over the past decade, several clinical trials, meta-analyses, and systematic reviews have investigated the use of psilocybin for symptoms of depression, and most have found that psilocybin can have antidepressant effects

Studies published to date have not investigated factors that may moderate psilocybin’s effects, including type of depression, past use of psychedelics, dosage, outcome measures, and publication biases

What this study adds

This review showed a significantly greater efficacy of psilocybin among patients with secondary depression, patients with past use of psychedelics, older patients, and studies using self-report measures for symptoms of depression

Efficacy did not appear to be homogeneous across patient types—for example, those with depression and a life threatening illness appeared to benefit more from treatment

Further research is needed to clarify the factors that maximise psilocybin’s treatment potential for symptoms of depression

Ethics statements

Ethical approval.

This study was approved by the ethics committee of the University of Oxford Nuffield Department of Medicine, which waived the need for ethical approval and the need to obtain consent for the collection, analysis, and publication of the retrospectively obtained anonymised data for this non-interventional study.

Data availability statement

The relevant aggregated data and statistical code will be made available on reasonable request to the corresponding author.

Acknowledgments

We thank DT who acted as an independent secondary reviewer during the study selection and data review process.

Contributors: AMM contributed to the design and implementation of the research, analysis of the results, and writing of the manuscript. MC was involved in planning and supervising the work and contributed to the writing of the manuscript. AMM and MC are the guarantors. 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 https://www.icmje.org/disclosure-of-interest/ and declare: no support from any organisation for the submitted work; AMM is employed by IDEA Pharma, which does consultancy work for pharmaceutical companies developing drugs for physical and mental health conditions; MC was the supervisor for AMM’s University of Oxford MSc dissertation, which forms the basis for this paper; no other relationships or activities that could appear to have influenced the submitted work.

Transparency: The corresponding author (AMM) 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 registered have been explained.

Dissemination to participants and related patient and public communities: To disseminate our findings and increase the impact of our research, we plan on writing several social media posts and blog posts outlining the main conclusions of our paper. These will include blog posts on the websites of the University of Oxford’s Department of Primary Care Health Sciences and Department for Continuing Education, as well as print publications, which are likely to reach a wider audience. Furthermore, we plan to present our findings and discuss them with the public in local mental health related events and conferences, which are routinely attended by patient groups and advocacy organisations.

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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Open Access

Peer-reviewed

Research Article

Impact of depression on self-efficacy, illness perceptions and self-management among people with type 2 diabetes: A systematic review of longitudinal studies

Roles Conceptualization, Formal analysis, Methodology, Writing – original draft, Writing – review & editing

* E-mail: [email protected]

Affiliations School of Public Health, College of Health and Medical Sciences, Haramaya University, Harar, Ethiopia, Department of Psychiatry, School of Medicine, College of Health Sciences, Addis Ababa University, Addis Ababa, Ethiopia

Roles Data curation, Methodology, Validation

Affiliations Department of Psychiatry, School of Medicine, College of Health Sciences, Addis Ababa University, Addis Ababa, Ethiopia, Department of Nursing, College of Health Sciences, Debre Berhan University, Debre Berhan, Ethiopia

Roles Formal analysis, Writing – review & editing

Affiliation Aklilu Lemma Institute of Pathobiology, Addis Ababa University, Addis Ababa, Ethiopia

Roles Conceptualization, Supervision, Writing – review & editing

Affiliation Department of Internal Medicine, St. Paul’s Hospital Millennium Medical College, Addis Ababa, Ethiopia

Roles Conceptualization, Formal analysis, Methodology, Supervision, Writing – review & editing

Affiliations Department of Psychiatry, School of Medicine, College of Health Sciences, Addis Ababa University, Addis Ababa, Ethiopia, Health Service and Population Research Department and WHO Collaborating Centre for Mental Health Research and Training, Institute of Psychiatry, Psychology and Neuroscience, Centre for Global Mental Health, King’s College London, London, United Kingdom, Centre for Innovative Drug Development and Therapeutic Trials for Africa (CDT-Africa), College of Health Sciences, Addis Ababa University, Addis Ababa, Ethiopia

• Andualem Derese, 
• Yohannes Gebreegzhiabhere, 
• Girmay Medhin, 
• Sisay Sirgu, 
• Charlotte Hanlon

• Published: May 6, 2024
• https://doi.org/10.1371/journal.pone.0302635
• Reader Comments

Treating comorbid depression does not always improve outcomes for people with type 2 diabetes. Evidence is lacking on potential psychological and behavioural intermediaries of the impact of depression on diabetes outcomes.

To synthesise evidence on the impact of comorbid depression on self-efficacy, illness perceptions, and self-management in people with type 2 diabetes.

Data sources

We searched PubMed, Embase, PsycINFO, and Global Health databases from inception up to 29 th March 2023.

Study eligibility criteria

Only prospective studies (cohort or intervention studies) were included, with no restrictions on language. The outcomes were self-efficacy, illness perceptions, and self-management.

Participants

People with type 2 diabetes in community or health settings.

Comorbid depression or depressive symptoms in people with type 2 diabetes.

Synthesis of results

A narrative review of heterogeneous studies.

Risk of bias

The risk of bias was assessed using the Effective Public Health Practice Project (EPHPP) quality assessment tool for quantitative studies.

Twenty-five studies were included, all from high-income countries. Depression was associated with lower self-efficacy (2 studies), poor illness perception (1 study), and poor self-management practices (17 studies) in people with type 2 diabetes. In 6/7 studies, depressive symptoms predicted less adherence to dietary recommendations, 8/10 studies found depressive symptoms were associated with poor medication adherence, 1/3 study found that depressive symptoms were associated with poor weight control, 3/4 with less physical exercise, and 2/3 with general self-care practices.

Limitations

There were no studies from low- and middle-income countries and non-Western settings, and we cannot assume the mechanisms linking comorbid depression with diabetes outcomes are similar.

Conclusions

Comorbid depression was associated with lower self-efficacy, poorer self-management, and less adaptive illness perceptions among people with diabetes.

Citation: Derese A, Gebreegzhiabhere Y, Medhin G, Sirgu S, Hanlon C (2024) Impact of depression on self-efficacy, illness perceptions and self-management among people with type 2 diabetes: A systematic review of longitudinal studies. PLoS ONE 19(5): e0302635. https://doi.org/10.1371/journal.pone.0302635

Editor: Dickens Akena, Makerere University CHS: Makerere University College of Health Sciences, UGANDA

Received: October 18, 2023; Accepted: April 9, 2024; Published: May 6, 2024

Copyright: © 2024 Derese et al. This is an open access article distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Data Availability: All relevant data are within the paper and its Supporting Information files.

Funding: CH receives support from the National Institute of Health Research through grant NIHR200842 and the NIHR Global Health Research Unit on Health System Strengthening in Sub-Saharan Africa, King's College London (GHRU 16/136/54) using UK aid from the UK Government. The views expressed in this publication are those of the authors and not necessarily those of the NHS, the National Institute for Health Research, or the Department of Health and Social Care, England. CH, AD, and YG also receive support from AMARI as part of the DELTAS Africa Initiative [DEL- [15-01].

Competing interests: The authors have declared that no competing interests exist.

Introduction

Non-communicable diseases (NCDs) are among the leading causes of death globally, accounting for 71% of all deaths worldwide [ 1 ]. Diabetes mellitus (DM) is one of the five priority diseases targeted for action by world leaders at the United Nations General Assembly [ 2 ]. Diabetes is a chronic metabolic disorder characterised by persistent hyperglycemia [ 3 ]. Individuals with type 2 diabetes account for 90% of diabetes cases and have insulin resistance, usually accompanied by relative insulin deficiency [ 3 ]. Poorly controlled DM leads to severe complications, including stroke, blindness, kidney failure, and limb amputation [ 4 ].

Good glycemic control is crucial in avoiding diabetes complications. It can be achieved through practical diabetes self-management activities, such as regular plasma glucose monitoring, medication adherence, and diet and lifestyle modifications [ 5 ]. However, these self-care management activities are often complex, and many people with diabetes do not perform them as recommended [ 5 , 6 ].

People with diabetes are at a higher risk of mental health problems due to biological, environmental, social, behavioral, and emotional factors [ 7 – 9 ]. Depression often co-occurs with diabetes and has been found to adversely affect diabetes outcomes directly and indirectly [ 10 – 13 ]. A systematic review and meta-analysis of observational studies found that depression in people with diabetes mellitus ranged from 2% to 88%, with a pooled prevalence of 28% [ 14 ]. However, the nature of the relationship between depression and diabetes outcomes may be affected by intermediate factors [ 15 – 17 ], including psychosocial and behavioural factors such as self-efficacy [ 17 , 18 ], self-management [ 15 , 16 , 18 ], illness perception [ 19 , 20 ] and social support [ 21 ].

In systematic reviews and meta-analyses of comorbid depression and diabetes, interventions targeting depression have been found to reduce depressive symptom severity, but treating depression does not consistently improve glycemic control [ 22 – 25 ]. The reason might be that intermediate psychosocial and behavioural factors, specifically self-efficacy, illness perceptions, and self-care management, are negatively affected by depression but do not necessarily improve with interventions specific to depressive symptoms [ 15 , 18 ]. Systematic reviews have been published on the impact of comorbid depression on medication adherence in diabetes [ 26 ] and commitment to lifestyle changes [ 27 ], but not on the broader range of psychosocial and behavioural factors that may mediate the impact of depression on diabetes outcomes. Furthermore, these reviews are now outdated.

The objective of this review was to synthesise the evidence on the impact of comorbid depression on self-efficacy, illness perceptions, and self-management in people with diabetes.

Materials and methods

Registration and protocol.

We followed the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines [ 28 ] for reporting this review. The review protocol was registered on the PROSPERO International Register of Systematic Reviews [CRD42019136249].

Search strategy

We searched PubMed, Embase, PsycINFO, and Global Health databases from inception to 29 th March 2023 without language restriction. We did forward and backward searches of the citations of included studies using Google Scholar and hand-searched for unpublished literature from University repositories. The search terms comprised key terms, MeSH terms, and Emtree terms for depression, diabetes mellitus, self-efficacy, illness perception, and self-management. The detailed search strategy is available in ( S1 File ).

Eligibility criteria

The following criteria were used to include studies in the review:

Study design: Prospective cohort studies or intervention studies.

Study setting: Community, primary care, general and/or specialist medical outpatient settings. Studies conducted in in-patient settings were not eligible for this review.

Participants: Adults (age ≥ 18 years) with a clinical diagnosis (using HbA1C or plasma glucose) of type 2 diabetes mellitus. Studies that were restricted to special populations, including pregnant women, people with dementia or, psychosis, or HIV, were not eligible for this review.

Exposure/intervention: For observational studies, the exposure was the presence of depression assessed with either [A] diagnostic categories of depressive disorder based on the International Classification of Diseases (ICD-11 or earlier versions) or Diagnostic and Statistical Manual of Mental Disorders (DSM-V or earlier versions) criteria or [B] depressive symptoms identified using standardised scales like the Patient Health Questionnaire (PHQ-9) or Centre for epidemiologic studies depression scale (CES-D).

Intervention studies were included if they evaluated any intervention for participants with comorbid depression (diagnosed by a standardised tool or meeting diagnostic criteria). These interventions could be psychological, pharmacological, or a combination of both. For the intervention studies, our interest was in how changes in the exposure of depression (through intervention) affected the outcomes of self-efficacy, illness perceptions or self-management.

Comparator: People with a clinical diagnosis of type 2 diabetes mellitus without depression or elevated depressive symptoms.

Outcomes: The effect of depression on the constructs of self-efficacy, illness perceptions, or self-management, measured using standardised scales and defined as follows:

Self-efficacy is confidence in one’s ability to achieve intended results, according to Albert Bandura [ 29 , 30 ]. People differ in their efficacy across different domains of functioning. In the case of diabetes, self-efficacy is the judgment of one’s capabilities to monitor, plan, and perform self-management activities [ 31 ].

Self-management or self-care refers to daily activities that people with chronic diseases carry out to control their illnesses and cope with their illness’s psychosocial consequences [ 32 ]. Self-management comprises activities related to diet, exercise, blood glucose monitoring, medication adherence, and foot care [ 33 ].

Illness perceptions and cognitions are terms used to describe a range of cognitive processes underlying attention, interpretation, and behavior in response to illness-related information [ 34 ]. A positive perception of diabetes controllability, coupled with good knowledge about the disease, empowers individuals to adhere to treatment regimens and self-management practices like diet and exercise20].

The identified references were first exported into Endnote reference management software [ 35 ], and duplicates were removed. The titles and abstracts were then independently screened for eligibility by two reviewers (AD and YG). The article was included for full-text review if screened in by either reviewer. Full manuscripts were checked independently against inclusion criteria by two authors, and any differences were reconciled through discussions. Excluded articles and reasons for exclusions were documented.

Data extraction

Data were extracted by AD and YG independently into a custom-designed Excel spreadsheet with the following domains: author, publication year, country, study design, sample size, outcomes, measures, and critical findings. As before, any discrepancies were reconciled through discussions.

Assessment of bias

Two of the co-authors (AD and YG) assessed the risk of bias independently using the Effective Public Health Practice Project (EPHPP) quality assessment tool for quantitative studies [ 36 ]. This tool has eight sections, of which six (selection bias, allocation bias, control of confounders, blinding of outcome assessors, data collection methods, and withdrawals and dropouts) were used in the global rating of the study. The global rating provides an overall methodological rating of strong, moderate, or weak [ 36 ]. While EPHPP dictionary provides detailed guidance for rating initial six components, it does not offer specific criteria for component ratings of intervention integrity and analysis appropriateness. For this study, we focused on evaluating each domain individually, to provide comprehensive understanding of the potential for bias. The issue was solved by discussion among the two authors (AD and YG) in case of discrepancies.

Synthesis method

We used narrative synthesis. The included studies were critically appraised to assess their quality and relevance. Key findings were extracted from each study. Then, the studies were grouped together based on study design. The findings are then summarised in a narrative format, considering each study’s strengths and limitations.

Study selection

A total of 7272 records were obtained from four databases. After removing 1269 duplicates, 6003 records underwent title and abstract screening. Of these, 118 were included for full-text review, and 97 were excluded as they did not fulfill the inclusion criteria. Three further articles were identified from the forward and backward citation search, and one study was added through a hand search of unpublished databases. A total of 25 articles from 21 studies were included in the final analysis, as shown in the PRISMA diagram ( Fig 1 ).

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https://doi.org/10.1371/journal.pone.0302635.g001

Characteristics of the studies

All studies were from high-income countries (HIC) and were published from 2004 to 2022. Among the 25 included studies, the majority (17/25) were from the USA. The remaining studies were conducted in Canada (n = 4), Denmark, Germany, Japan, and the UK (one from each country).

Regarding study design, 18 were cohort studies, and seven were randomised controlled trials (RCTs). The sample size of each study ranged from 85 to 87,650. Most (n = 21) of the studies were facility-based, and only four were community-based.

The reviewed studies assessed the impact of comorbid depression on self-efficacy (n = 2), illness perceptions (n = 1), and different aspects of self-management (total n = 23), including medication adherence (n = 13), adherence to dietary recommendations (n = 11), exercise (n = 6), self-monitoring of blood glucose (SMBG)(n = 4), foot care (n = 3), weight change (n = 2), and compliance with regular visits (n = 1). (See Tables 1 – 3 below).

https://doi.org/10.1371/journal.pone.0302635.t001

https://doi.org/10.1371/journal.pone.0302635.t002

https://doi.org/10.1371/journal.pone.0302635.t003

Seven screening tools and four approaches to diagnostic measurement were used to define depression. The screening scales used were the Patient Health Questionnaire (PHQ-9), Center for Epidemiologic Studies Depression Scale (CES-D), Depression, Anxiety and Stress Scale (DASS), Diabetes Wellbeing Questionnaire (DWBQ), ESA-Questionnaire (ESA-Q), Depression Screening Questionnaire (DSQ), Hopkins Symptom Checklist 90 (HSC-90), Harvard Department of Psychiatry/National Depression Screening Day Scale (HANDS) and 5-item mental health sub-scale from Medical Outcomes Study (MOS-36 items). The diagnostic instruments for depression were the Composite International Diagnostic Interview (CIDI), Emotional Self-Awareness Questionnaire, and Structured Clinical Interview for DSM (SCID) or trained clinicians applying international diagnostic criteria.

The studies used diverse measures, methods, and analytic approaches, meaning a meta-analysis could not be carried out.

Risk of bias within studies

Most studies received “strong” ratings for data collection methods and handling of confounders. Withdrawals and dropouts led to weak ratings and a risk of attrition bias. (See S2 File ).

Effect of depression on self-efficacy

Two studies reported the effect of depression on self-efficacy [ 37 , 38 ]. Both studies were from the USA and were longitudinal analyses nested within a trial. The studies reported either change in depressive symptoms or baseline depression being negatively and significantly associated with self-efficacy at follow-up after adjusting for relevant covariates.

Effect of depression on illness perception

Only one cohort study reported the impact of depression on illness perceptions after six months of follow-up. In the study by Hudson et al. [ 39 ], depression and anxiety symptoms at baseline were prospectively associated with specific diabetes illness perceptions. Participants with higher depression scores and who were more anxious at baseline were more likely to perceive that diabetes was an unpredictable condition at six months follow-up [ 39 ].

Effect of depression on diabetes self-management

Twenty-two articles assessed the effect of depression on adherence to medication, dietary recommendations, physical exercise, health behaviors, glucose testing, weight loss, foot care, and reducing substance use. The findings are described as follows:

Effect of depression on adherence to medication

Ten studies (eight cohort studies and two RCTs) assessed the effect of depression on medication adherence. Baseline depressive symptoms were significant predictors of poor adherence to diabetes control medications [ 44 , 50 , 59 – 61 ], anti-hypertensive medications [ 59 ], and low-density lipoproteins (LDL) control medications [ 59 ]. Another study found that having depressive symptoms at baseline predicted problems with medication adherence at consecutive follow-ups [ 54 ]. A study in Denmark found that the presence of depression or treatment with an anti-depressant was associated with an increase in diabetes medication initiation and adherence when compared to those without depression treatment [ 49 ]. Another study also found that people who started anti-depressant therapy were less likely to have poor adherence compared with controls who did not take anti-depressants [ 48 ].

On the contrary, two studies found no longitudinal association between depressive symptoms and adherence to oral hypoglycemic agents [ 45 , 51 ]. In a randomised, controlled trial that assessed the effectiveness of depression care management to improve affective and diabetes outcomes in older adults, enhanced care was associated with reduced severity of depression but no impact on medication adherence [ 45 ].

Effect of depression on dietary recommendations

In six studies, baseline depressive symptoms significantly predicted poor adherence to general dietary recommendations [ 42 , 52 – 54 , 56 , 60 ], decreased spacing of carbohydrates [ 53 , 60 ], and lower consumption of fruits and vegetables [ 53 , 60 ] at follow-up, after controlling for baseline levels of self-care. Similarly, participants with moderate-to-severe depressive symptoms at baseline had significant improvements in dietary quality when their depressive symptoms decreased over time [ 43 ]. In contrast, depression care interventions in three studies did not affect adherence to dietary recommendations [ 44 , 45 , 47 ].

Effect of depression on physical exercise

In six studies, depressive symptoms were significantly associated with less physical exercise or weight loss [ 52 – 54 , 56 , 58 , 60 ]. In another study, depression care interventions increased the frequency of exercise [ 45 ], but a 12-month enhanced depression care intervention was not associated with improvement in physical activity [ 44 ].

Effect on substance use

In a cohort study, depression and sub-threshold depression at baseline significantly predicted increased use of substances, like cigarette smoking and alcohol consumption, at follow-up [ 54 ]. Lin et al. assessed the impact of a 12-month enhanced depression care intervention, which was not associated with improvement in smoking cessation [ 44 ].

Effect on health behaviors

In eight studies, depression longitudinally predicted less frequent self-monitoring of blood glucose [ 60 ], poorer compliance with regular visits [ 57 ], and worse foot care [ 42 , 60 , 62 ] at follow-up, controlling for baseline levels of self-care. In three studies, baseline depressive symptoms had a direct negative effect on overall self-care at follow-up [ 46 , 54 , 55 ]. In an RCT, a physical exercise intervention for depression significantly improved diabetes distress, diabetes self-care, and quality of life in individuals with diabetes. Additionally, the program led to reductions in triglycerides, total cholesterol and LDL-cholesterol [ 63 ]. However, depression care interventions in another trial did not affect glucose testing or glycemic control [ 45 ]. Similarly, one study demonstrated no significant relationship between depression and self-care activities [ 47 ].

Problem-solving therapy (PST) for depression was not associated with a change in the frequency of self-care behaviors [ 41 ]. PST intervention and depression remission (assessed using PHQ-9) from the baseline did not result in a significant change in the frequency of self-care behaviors in two prospective models (from baseline to 18 months and from baseline to 24 months) [ 41 ]. However, depression remission status assessed by SCL-20 significantly predicted a more regular healthy diet and exercise at follow-up [ 41 ].

In this systematic review, we synthesised findings from studies on the impact of comorbid depression in people with type 2 diabetes mellitus on self-efficacy, illness perceptions, and self-management. All included studies were longitudinal, with either interventional or observational cohort designs, and were of good quality; however, none were conducted in LMICs. Comorbid depression in people with type 2 diabetes mellitus (T2DM) predicted low self-efficacy, pessimistic illness perception, poorer adherence to medication, and greater difficulty in following dietary recommendations in most, but not all, studies. Interventions for depression resulted in improvement in depressive symptoms. However, improvement in depressive symptoms did not consistently lead to improvements in DM self-management.

The two studies that assessed the impact of depression on diabetes self-efficacy indicated that depression at baseline was negatively associated with self-efficacy at follow-up. This is in keeping with the predictions of self-efficacy theory and highlights that emotional states can boost or undermine self-efficacy [ 64 ]. A reciprocal relationship between depression and specific diabetes cognitions over time, with those who were depressed more likely to perceive DM as unpredictable [ 39 ], is consistent with the Common Sense Self-Regulation Model (CS-SRM) [ 65 ]. This could be because a higher level of depression is associated with lower perceived personal and treatment control and more severe consequences of chronic disease [ 66 ]. However, a study from the UK that used structural equation modeling to investigate potential mechanisms found that depression was directly associated with specific diabetes cognitions over time but that these cognition domains did not mediate the effect of emotion on diabetes self-care [ 39 ]. Further prospective studies are needed to investigate how self-efficacy relates to depression and self-management activities.

The review findings indicated that depressive symptoms generally predicted lower engagement with self-management behaviors, but the evidence was stronger for some types of self-management behaviors than others. For example, depressive symptoms were consistently associated with lower adherence to medication, exercise and diet, compared to the association with weight control. This is in line with Beck’s cognitive model, which hypothesises that people’s emotions and behaviors are influenced by their perceptions of events [ 67 ]. According to the cognitive model, individuals’ perceptions are often distorted and dysfunctional when distressed or depressed, affecting their physiological and behavioral actions, including motivation to carry out self-care activities [ 67 ].

However, the review findings indicate that not all interventions targeting depression improved self-management behaviors. The pathway through which depression affects diabetes outcomes may not only be directly through its effect on self-management; other indirect mechanisms might also be involved through diabetes distress or self-efficacy [ 68 ]. The other explanation might be that the intensity of these interventions might not be sufficient to increase optimism sustainably and the DM-specific motivation required to bring change related to self-management behaviors, even if depressive symptoms have reduced.

There were different interventions targeting either depression alone or both depression and diabetes management. In an RCT by Lin et al., a collaborative depression intervention (pharmacotherapy, problem-solving treatment, or combination) was used. The intervention resulted in less severe depression over time but did not result in improved diabetes self-care behaviors when compared to the usual care [ 44 ]. On the contrary, Oh et al. found that Problem Solving Therapy (PST) for depression did not result in depression remission. Furthermore, depression remission and receiving PST were not associated with changes in self-care behaviors [ 41 ]. Another study using a diabetes self-management intervention resulted in a lower mean CES-D score over time than the usual care, indicating potential bi-directional association [ 43 ].

Williams et al. used enhanced care (that included education, PST, or support for anti-depressant management) for depression. They found that the intervention resulted in less severe depression and improved overall functioning compared to the usual care. Moreover, the intervention increased weekly exercise days but did not affect other aspects of self-care [ 45 ].

In this review, we focused on individual psychological constructs, which may be less salient in other sociocultural settings, particularly those more collectivistic. In such settings, self-management may rely more on others and available resources than just the individual, as seen in managing other chronic conditions [ 69 ]. General illness perceptions about diabetes mellitus may be more externalised in some non-Western settings (i.e., less in the control of the individual). Therefore, the interaction with depressive symptoms may have different consequences. Nonetheless, a qualitative study in Ethiopia among people with type 2 DM indicated that an individual’s perception of their illness and its treatment could negatively influence their experience and adherence to medication [ 70 ]. Further work is needed to understand salient contextual factors for people with DM and comorbid depression in LMICs and the potential mechanisms linking these constructs to DM outcomes.

Our review identified no studies from LMICs or non-Western countries. There is, therefore, a critical gap in the research evidence. LMIC and non-Western settings are likely to differ in terms of social, cultural, and educational factors, which could influence the interplay between depression, self-efficacy, illness perceptions, and self-management. There were methodological differences in the included studies, which precluded meta-analysis and limited the conclusions that could be drawn from the review. There were very few studies on the impact of depression on illness perception and self-efficacy. The potential for selection bias, specifically attrition bias, also limited the review, as only studies published in English were included. This could have excluded studies that were published in other languages.

Observational studies generally suggest that depressive symptoms are associated with lower self-efficacy and engagement in self-management behaviours, but the evidence is mixed. Interventions designed to reduce depressive symptoms have also shown mixed results regarding their impact on self-management behaviours. Further research is needed to identify the pathways through which depression affects diabetes outcomes to inform intervention development. There is a particular need for studies from LMICs and non-Western settings where mechanisms linking comorbid depression with diabetes outcomes may differ.

Supporting information

S1 file. search strategy used in the systematic review..

https://doi.org/10.1371/journal.pone.0302635.s001

S2 File. Quality assessment for included studies.

https://doi.org/10.1371/journal.pone.0302635.s002

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A New Study Is Finally Attempting to Pin Down The Root Causes of Depression

Most experts agree that depression is not one thing.

The core experiences of depression — changes in energy, activity, thinking, and mood — have been described for more than 10,000 years. The word “depression” has been used for about 350 years.

Given this long history, it may surprise you that experts don’t agree about what depression is, how to define it, or what causes it.

However, many experts do agree that depression is not one thing . It’s a large family of illnesses with different causes and mechanisms. This makes choosing the best treatment for each person challenging.

Reactive vs endogenous depression

One strategy is to search for sub-types of depression and see whether they might do better with different kinds of treatments. One example is contrasting “reactive” depression with “endogenous” depression.

Reactive depression (also thought of as social or psychological depression) is presented as being triggered by exposure to stressful life events. These might be being assaulted or losing a loved one — an understandable reaction to an outside trigger.

Endogenous depression (also thought of as biological or genetic depression) is proposed to be caused by something inside , such as genes or brain chemistry.

Many people working clinically in mental health accept this sub-typing. You might have read about this online .

But we think this approach is way too simple.

While stressful life events and genes may, individually, contribute to causing depression, they also interact to increase the risk of someone developing depression. And evidence shows that there is a genetic component to being exposed to stressors. Some genes affect things such as personality. Some affect how we interact with our environments.

What we did and what we found

Our team set out to look at the role of genes and stressors to see if classifying depression as reactive or endogenous was valid.

In the Australian Genetics of Depression Study , people with depression answered surveys about exposure to stressful life events. We analyzed DNA from their saliva samples to calculate their genetic risk for mental disorders.

Our question was simple. Does genetic risk for depression, bipolar disorder, schizophrenia, ADHD, anxiety, and neuroticism (a personality trait) influence people’s reported exposure to stressful life events?

You may be wondering why we bothered calculating the genetic risk for mental disorders in people who already have depression. Every person has genetic variants linked to mental disorders. Some people have more, some less. Even people who already have depression might have a low genetic risk for it. These people may have developed their particular depression from some other constellation of causes.

We looked at the genetic risk of conditions other than depression for a couple of reasons. First, genetic variants linked to depression overlap with those linked to other mental disorders. Second, two people with depression may have completely different genetic variants. So, we wanted to cast a wide net to look at a wider spectrum of genetic variants linked to mental disorders.

If reactive and endogenous depression sub-types are valid, we’d expect people with a lower genetic component to their depression (the reactive group) to report more stressful life events. And we’d expect those with a higher genetic component (the endogenous group) would report fewer stressful life events.

But after studying more than 14,000 people with depression, we found the opposite.

We found people at higher genetic risk for depression, anxiety, ADHD, or schizophrenia say they’ve been exposed to more stressors .

Assault with a weapon, sexual assault, accidents, legal and financial troubles, and childhood abuse and neglect were all more common in people with a higher genetic risk of depression, anxiety, ADHD, or schizophrenia.

These associations were not strongly influenced by people’s age, sex, or relationships with family. We didn’t look at other factors that may influence these associations, such as socioeconomic status. We also relied on people’s memory of past events, which may not be accurate.

How do genes play a role?

Genetic risk for mental disorders changes people’s sensitivity to the environment.

Imagine two people, one with a high genetic risk for depression and one with a low risk. They both lose their jobs. The genetically vulnerable person experiences the job loss as a threat to their self-worth and social status. There is a sense of shame and despair. They can’t bring themselves to look for another job for fear of losing it, too. For the other, the job loss feels less about them and more about the company. These two people internalize the event differently and remember it differently.

Genetic risk for mental disorders also might make it more likely people find themselves in environments where bad things happen. For example, a higher genetic risk for depression might affect self-worth, making people more likely to get into dysfunctional relationships, which then go badly.

What does our study mean for depression?

First, it confirms genes and environments are not independent. Genes influence the environments we end up in and what then happens. Genes also influence how we react to those events.

Second, our study doesn’t support a distinction between reactive and endogenous depression. Genes and environments have a complex interplay. Most cases of depression are a mix of genetics, biology, and stressors.

Third, people with depression who appear to have a stronger genetic component to their depression report their lives are punctuated by more serious stressors.

So, clinically, people with higher genetic vulnerability might benefit from learning specific techniques to manage their stress. This might help some people reduce their chance of developing depression in the first place. It might also help some people with depression reduce their ongoing exposure to stressors.

This article was originally published on The Conversation by Jacob Crouse and Ian Hickie at the University of Sydney . Read the original article here .

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A Correction to this article was published on 17 May 2021

This article has been updated

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

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Avoid common mistakes on your manuscript.

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

Current Situation of Research on Depression

Analysis of published papers.

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

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

Analysis of Patented Technology Application

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

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

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

Analysis of Clinical Trial

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

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

New Medicine Development

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

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

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

Epidemiology of Depression

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

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

Neurobiological Pathogenesis of Depressive Disorder

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

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

Stress-Responsive HPA Axis

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

Glutamate Signaling Pathway

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

Gamma-Aminobutyric Acid (GABA)

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

Neurotrophin Family

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

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

Neuroinflammation

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

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

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

Microbiome-Gut-Brain Axis

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

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

Other Systems and Pathways

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

Advances in Various Kinds of Research on Depressive Disorder

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

Genetic Studies

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

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

Brain Imaging and Neuroimaging Studies

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

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

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

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

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

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

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

Objective Index for Diagnosis of MDD

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

Management of Depression

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

Current Antidepressant Treatment

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

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

Neuromodulation Therapy

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

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

Precision Medicine for Depression

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

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

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

Future Perspectives

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

Change history

17 may 2021.

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

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Acknowledgments

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

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Zezhi Li, Jun Chen & Yiru Fang

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

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

Meihua Ruan

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

Shanghai Key Laboratory of Psychotic Disorders, Shanghai, 201108, China

Jun Chen & Yiru Fang

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

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Published : 13 February 2021

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DOI : https://doi.org/10.1007/s12264-021-00638-3

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New wave psychiatry

Rolling back mental illness with electromagnetism

By Kris Newby

Illustration by Juan Bernabeu

During the past century, psychiatry has been stuck in a rut. In the beginning, there was talk therapy to help patients recognize internal conflicts that generated negative thoughts and behaviors. Then there was psychopharmacology, the use of mood-altering drugs. While these approaches worked for some, they left many patients without hope.

Enter a new wave of psychiatric treatments based on an ancient approach to healing the brain — electricity.

Back in A.D. 46, Roman physician Scribonius Largus treated migraines by placing a live electric torpedo fish “on the place which is in pain, until the pain ceases and the part grows numb.” Over the millennia, there have been variations on this theme — shock therapy and deep brain stimulation, to name a few. But none of these treatments have been practical or safe enough to use in mainstream psychiatry — especially the torpedo fish.

Now, a Stanford Medicine research team is developing a noninvasive, more targeted electromagnetic treatment that can improve mental disorders like depression in a week or less with long-lasting relief. Called Stanford neuromodulation therapy, or SNT, it uses a magnetic paddle placed on the scalp to deliver gentle electrical pulses that reset brain circuits that have gone awry.

This next generation in transcranial magnetic stimulation is successfully treating severe depression in people for whom other approaches have failed. In a small double-blind, randomized clinical trial, nearly 80% of the 14 participants went into remission after five days. Follow-up studies have shown similar results, with about half of the participants remaining depression-free four weeks after treatment.

The Stanford University Brain Stimulation Lab has led the charge to refine this technology, incorporating new knowledge about functional brain circuits and learning theory to recalibrate misbehaving brain networks for conditions that include bipolar disorder, addiction, borderline personality disorder and obsessive-compulsive disorder.

Brain training

The Brain Stimulation lab director, Nolan Williams , MD, didn’t have a roadmap for a career in psychiatry and neurology growing up in Charleston, South Carolina. Both parents were blue-collar workers without college degrees. Though he met some medical professionals while attending the Academic Magnet High School in North Charleston, he attributes most of his success in medicine to early training in martial arts.

“I started taekwondo when I was 8 and was granted a black belt at 15. I won two world championships in college,” said Williams, 41, whose laid-back demeanor and shoulder-length auburn hair project more of a surfer vibe than that of a psychiatrist. (He also kitesurfs.)

Taekwondo taught him that success in life boils down to five principles: courtesy, integrity, perseverance, self-control and indomitable spirit. He believes in the repetitive mind-body drills that both taekwondo and medicine require to build skills and perform at a high level.

“When you step into the ring, you know there’s going to be a fight,” he said. “You have to be fully present in that moment, not thinking about the future or the past.”

Today, Williams is an associate professor of psychiatry and behavioral sciences focused on building better tools for treating mental illness. His research spans a wide range of solutions, from rapid-acting psychedelics to retraining misfiring brain circuits.

“I’m an agnostic psychiatric tool builder. If it’s safe for the patient and the risk-benefit ratio is right, we’ll look at it. My job is to find tools that can help people feel more like themselves.” Nolan Williams, MD, associate professor of psychiatry and behavioral sciences and director of the Brain Stimulation lab

Williams entered the nascent field of electrical brain stimulation in 2006 as a medical student under the mentorship of Mark George, MD, a professor of psychiatry, radiology and neurosciences at the Medical University of South Carolina. George pioneered the use of transcranial magnetic stimulation, TMS, for mapping mood-regulating brain circuits and was the first to identify the cingulate cortex as a brain region that plays a role in depression. He conducted some of the first clinical trials of TMS for treating persistent depression, and his six-week protocol was approved by the U.S. Food and Drug Administration in 2008.

After completing dual residencies in psychiatry and neurology and a research fellowship with George, Williams came to Stanford Medicine as an instructor. It seemed like an excellent place to take TMS to the next level. The chair of the Department of Psychiatry and Behavioral Sciences, Laura Roberts , MD, was supportive of the new frontier of interventional psychiatry and breaking down walls between neurology and psychiatry.

Stanford Medicine’s academic ecosystem fostered collaborations between medicine and engineering, leading to discoveries in brain-circuit mapping, genetics and the use of light to influence brain activity. Another advantage: The campus is located at the epicenter of a thriving biotech community and venture capitalists willing to invest in paradigm-busting ideas. So, Williams stepped into the ring and began building a team to tackle depression — one of the most disabling and costly medical conditions worldwide.

Dream machine

Sergio “Checo” Gonzales left his home in rural Northern New Mexico in 2010 to pursue undergraduate and medical degrees at the University of New Mexico. His driving passion is to improve the health care disparities that he witnessed as a child. His research is focused on mathematical modeling of complex social systems in resource-poor communities.

He loves academic research, and he’s had visiting scholar stints at Harvard, Wharton and Washington University School of Medicine. He even learned Diné Bizaad, the Navajo language, so he could form deeper connections with members of the Navajo Nation for whom he was providing health care. In this culture, he would be called an azee’ííł’íní, one who makes Western medicine.

Today, this work is on hold, as he struggles with depression, specifically anhedonia, a lack of interest, enjoyment or pleasure from life’s experiences.

“The most challenging aspect of it is my inability to feel any kind of emotion,” Gonzales said. “I can intellectualize the importance of my research, my fiancée, my dogs and my family, but I am often paralyzed with the idea that I’m a worthless person who doesn’t want to be on this earth.”

“I was contemplating taking my own life and really struggling to complete daily tasks needed to make progress in my academic career.” Sergio “Checo” Gonzales, a particiant in and SNT trial whose depression led him to take a leave of absence from medical school at University of New Mexico

While he thinks he may have suffered from undiagnosed depression since childhood, severe symptoms emerged during the first year of medical school, when he realized that he needed to find an environment more supportive of all his talents and academic interests. He also faced significant barriers to finding psychotherapy and pharmacotherapy that worked for him.

“I was contemplating taking my own life and really struggling to complete daily tasks needed to make progress in my academic career.”

To survive, he took a leave of absence from medical school and began work toward a PhD in biomedical data science at Stanford Medicine. After a couple of rough years during the COVID-19 shutdown, his psychiatrist enrolled him in the SNT clinical trial, which was transformative.

“It was like magic,” Gonzales said. “Over two days, I went from feeling like death was the only way to end my suffering to my normal self, excited to live the rest of my life. The only side effect was that I felt great.”

The remission enabled him to return to his studies and pick up the pieces of his life. Nearly all his symptoms disappeared. But over the following three months, symptoms crept back. Now he’s in a holding pattern, back in intensive psychotherapy and finding no relief with multiple trials of pharmacotherapy, waiting until he can resume the “magic” SNT treatments when they become available to the public.

The discovery process

One in 5 people suffer from depression in the United States, 322 million worldwide. The economic burden of major depressive disorder among U.S. adults is immense, estimated at $326 billion in 2018 (in 2020 dollars).

But some of the most devastating impacts of depression are immeasurable — broken families, abandoned jobs, hospitalizations and suicides. More than 700,000 adults in the U.S. die by suicide annually, and it is the fourth-leading cause of death among 15- to 29-year-olds.

Before SNT, there were no quick fixes for people who sink into life-threatening despair. Talk therapy takes months to years to be effective. Antidepressant drugs must be taken for four to six weeks before benefits are felt — if those medications work. TMS requires at least six weeks of treatments. But SNT, a type of accelerated TMS, can improve depressive symptoms in less than a week.

Breakthroughs with SNT were twofold. The first was the discovery that electricity flows backward in the sadness-control brain circuit of many people with depression. The second was that dysregulated circuits could be retrained more quickly by administering a more intense pattern of magnetic pulses over a shorter period.

Anish Mitra , MD, PhD, now an assistant professor of psychiatry and behavioral sciences, was instrumental in the lab’s discovery of the backward circuit problem. As a graduate student at Washington University in Saint Louis, Missouri, he developed a mathematical tool to identify active areas of the brain through analysis of brain scans. His tool could measure tiny timing differences in the blood flow to various brain circuits, which, in turn, revealed the direction of electrical flow through these circuits.

“What’s liberating is that it showed me that depression doesn’t have to be my identity — it’s just a function of my brain biochemistry that can be fixed.” SNT trial participant Sergio “Checo” Gonzales

When they used this tool to analyze severely depressed patients, they noticed that electricity flowed through the emotional control brain circuit, the left dorsolateral prefrontal cortex, in the wrong direction from healthy controls. Moreover, if they sent electrical pulses against this current, they could fix it, much as a pacemaker resynchronizes an irregularly beating heart.

Williams thought about this new finding in the context of his martial arts training and new research on optimal learning. He knew that the six-week, low-intensity TMS treatments weren’t fast enough for patients in crisis situations. His hypothesis was that more repetitive, high-intensity bursts would be more effective, using the same learning strategies that people use to study for exams or prepare for a taekwondo competition.

After some trial-and-error studies, he found an optimal pulse pattern for treating major depressive disorder. Next, his team designed a clinical study to assess the efficacy of this approach, and he became the first to treat real-world patients with SNT, targeting the depression brain network of neurons originally discovered by Michael Fox, MD, PhD, at Harvard Medical School.

In 2021, the FDA designated SNT as a “breakthrough therapy,” which put it on a fast track through the regulatory approval process, because of its potential to treat a serious condition much more effectively than existing therapies. Then in 2022, the FDA cleared the SAINT neuromodulation system as a Class II medical device, which combines SNT stimulator hardware and software with a neuronavigation tool for identifying a personalized brain target. It is the first noninvasive, rapid-acting neuromodulation approach to treatment-resistant depression.

Treatments are delivered in 10 50-minute sessions per day, over five consecutive days. It’s painless and noninvasive. Patients can watch movies or read during the sessions. The most common side effect is a headache that dissipates in a few hours.

How it works

SNT magnetically induces electrical flow through the “wiring” of a brain, the neurons, with gamma frequency bursts overlayed on theta waves. Theta waves are natural brainwave oscillations of 4 to 8 hertz (cycles per second) that are believed to be involved in the creative flow state and implicit learning. Gamma brain waves are the fastest brain waves, oscillating at a frequency of 30 to 90 hertz, and have been found to foster receptivity, happiness and the ability to concentrate.

The treatment begins with a resting-state functional magnetic resonance imaging (fMRI) brain scan that determines the exact location of an individual’s emotion-controller center. Next, a wand containing wire-wrapped magnetic rings, called toroids, is precisely positioned on the scalp just above the left side of the forehead. The coils deliver a shallow field of waves that harmlessly travel through the skull and induce a gentle flow of electricity through the brain’s emotional-control network. The objective is to strengthen the dorsolateral cortex’s role in suppressing the sadness region of the brain.

During the first double-blind, randomized clinical trial of SNT, 29 people with treatment-resistant depression were enrolled. Half received the new treatment, and the rest were given a sham treatment to rule out placebo effects. After five days, 78.6% of the treated group were no longer depressed, and some felt their depression lift after only a few days.

Within two weeks, thoughts of suicide improved dramatically in this group. Remission rates in this trial and follow-up studies have yielded similar results, with 46% to 57% of treated participants reporting sustained depression relief four weeks after treatment. Some patients report being in remission for a year.

The study also showed that SNT doesn’t work for everyone with depression, only for those with a malfunctioning sadness-control brain circuit — and researchers discovered that the more severe the depression, the more signals were traveling the wrong way. This observation has opened a tantalizing possibility: Maybe they could use fMRI brain scan flow patterns to help diagnose mental conditions, adding another tool to the psychiatric toolbox.

Fighting the system

Designing innovative new medical hardware is hard. Getting it through the regulatory gauntlet and into clinics is even harder.

Williams’ ally in this effort is Brandon Bentzley, MD, PhD, a psychiatrist, technologist and neuroscientist who first met Williams at the Medical University of South Carolina.

“We were both molded in the incredible neuroscience community at MUSC, a community that framed brain function in terms of circuits,” Bentzley said. “In meeting Nolan, I was struck by our parallel ambitions to create new treatments for mental health based on a mechanistic understanding of the human brain.”

A year after he graduated, Bentzley followed Williams to Stanford Medicine for his psychiatry residency, and they began talking about the potential of TMS and how to get this promising new technology into the medical system.

In the past, treatments for mental illness were almost always the result of accidental findings. Antidepressants were discovered by observing the mood-altering effects of drugs being tested to treat tuberculosis. Antipsychotics were discovered while testing new types of anesthesia. Bentzley and Williams, on the other hand, set out from the beginning to design a treatment for depression rooted in an understanding of the underlying neurocircuitry of the brain.

“In meeting Nolan, I was struck by our parallel ambitions to create new treatments for mental health based on a mechanistic understanding of the human brain.” Brandon Bentzley, MD, PhD, a psychiatrist, technologist and neuroscientist

“Based on the efficacy and speed of the SNT treatment protocol, my hope is that we can use this technology as a generalizable platform where brain mapping is married to neuromodulation to provide effective treatments for many brain illnesses,” Bentzley said.

In 2020, Bentzley co-founded Magnus Medical Inc. to commercialize a system for SNT treatment — the SAINT neuromodulation system — while Williams continues his research on refining neuromodulation and applying it to other disorders. (Williams has equity and stock options in Magnus Medical.)

“Implementing technologies like this requires a shift in health care,” Bentzley said. “Reimbursements for mental health hospitalization haven’t changed in 20 years, and there is no easy way for these institutions to adopt new interventions.”

Mainstreaming SNT requires mental health care providers to have access to fMRI services, to purchase expensive new equipment and to train staff to operate it. To justify these expenditures, the company will have to educate the psychiatric community of its effectiveness and gather enough cost/benefit data to convince the federal Centers for Medicare & Medicaid Services (CMS) and more than 1,000 medical health insurers to reimburse institutions for prescribing these treatments.

Earlier this year, SAINT secured CMS reimbursement approval for treating major depressive disorder under “new technology add-on payments.” Historically, once a treatment receives CMS approval, other medical insurance plans add it to their list of reimbursable procedures.

Bentzley’s strategy is to launch in large institutions for the most urgent cases of major depressive disorder, then move their systems into smaller clinics. Ongoing work will focus on making the integrated software-hardware system easier for staff to learn and use. The company will add protocols for other mental conditions as soon as they receive FDA approval.

What’s next

Williams’ Brain Stimulation Lab has about 15 faculty and postdocs working on fast-acting therapies for psychiatric disorders. Targets include treatment-resistant depression, obsessive-compulsive disorder, mania, addiction, chronic pain, borderline personality disorder, depression associated with Parkinson’s disease and persistent tic disorders. Recently, the researchers in the lab identified a brain circuit that makes people more susceptible to hypnosis, which could be leveraged to make it easier for patients to overcome addictions such as smoking.

Williams’ peers and collaborators said they believe that SNT is the start of something big, though there’s still a lot of work to be done before it is fully implemented into clinical care at scale.

Claudia Padula , PhD, an assistant professor of psychiatry and behavioral sciences and addiction researcher at the Sierra Pacific Mental Illness Research, Education and Clinical Center at the VA Palo Alto Health Care System, thinks TMS and SNT are still in their infancy for treating alcohol abuse disorder: “We have a lot to figure out, in terms of mechanisms of action, optimal sites, and the number of sessions and pulses … but the trajectory is looking really promising.”

Corey Keller , MD, PhD, an assistant professor of psychiatry and behavioral sciences, has been using TMS for years. As a researcher who runs a lab focused on personalized brain stimulation treatments, he is excited about having an FDA-cleared protocol as a launching point for next-generation technologies.

“For the past 15 years, TMS treatments have been largely nonpersonalized and one-size-fits-all,” Keller said. “TMS can apply millions of different patterns of stimulus. We can personalize the treatment target and intensity of stimulation, as is done in SNT. We are also close to being able to update stimulation patterns in real time, or after every treatment, to measure how much of the brain we’re changing and have that guide treatment. SNT represents an exciting next step in moving in this direction of personalized TMS.”

“We are … close to being able to update stimulation patterns in real time, or after every treatment, to measure how much of the brain we’re changing and have that guide treatment.” Corey Keller, MD, PhD, an assistant professor of psychiatry and behavioral sciences

While Keller is enthusiastic about SNT, he also sees some challenges. It is unclear how this new treatment protocol will be adopted in clinics. The fMRI and neuronavigation equipment required to precisely position the magnetic coils may limit uptake in clinics due to the cost and extra staff needed — though Magnus Medical has streamlined the training and brain-targeting processes. And many clinics will have to make adjustments to handle the 10 consecutive hours needed to accommodate the 10 treatments-per-day protocol.

In the meantime, Williams is casting a wide net in looking for new psychiatric tools, some unconventional. For example, in 2022 his lab ran a study to assess the use of ibogaine, a psychoactive drug, to treat 30 special operations veterans who have traumatic brain injuries and post-traumatic stress syndrome. (Ibogaine is derived from root bark and has been used for centuries by Africans in spiritual and healing ceremonies.)

Surprisingly, participants experienced average reductions in anxiety, depression and PTSD symptoms of 81%, 87% and 88%, respectively, with results that lasted throughout the monthlong study that was published in January 2024 in Nature Medicine. According to Williams, to date about 1,000 veterans have traveled to Mexico for this treatment — because this drug is illegal in the United States.

Williams sums up the history of psychiatry in this way: Psychiatry 1.0 focuses on your thinking, behavior and past trauma in a way that might keep you in therapy for the rest of your life. Psychiatry 2.0 affects neurotransmitter levels in your brain that might require you to take drugs forever. Psychiatry 3.0 refocuses the story on recalibrating your brain circuits, an approach that’s correctable with negligible side effects.

“I’m an agnostic psychiatric tool builder. If it’s safe for the patient and the risk-benefit ratio is right, we’ll look at it. My job is to find tools that can help people feel more like themselves.”

Where to get SNT treatments

The SAINT system for the treatment of major depressive disorder became available in April 2024. This integrated hardware/software system will enable medical clinics to set up their own treatment sites and benefit from ongoing research.

In addition, Magnus Medical will lead a four-center inpatient SAINT study of hospitalized patients with major depressive disorder and active suicidal ideation, with funding from the National Institutes of Mental Health. This double-blind study will evaluate how SAINT changes brain circuits and how these changes may affect suicidal thoughts.

The Brain Stimulation Lab is also running clinical trials for adults with major depressive disorder, bipolar disorder, borderline personality disorder and OCD.

For Gonzales, the restart of SNT treatments — and his research career — can’t begin soon enough. Though he’s anxious about how he’ll pay for the treatments, it’s been a life-changing experience for him.

“I spent so many years trying hard to get better with psychiatrists and drugs that didn’t work, but when they put a magnet on the side of my head, it magically made me better,” he said. “What’s liberating is that it showed me that depression doesn’t have to be my identity — it’s just a function of my brain biochemistry that can be fixed.” — Contact Kris Newby at [email protected]

Kris Newby is a freelance science writer. Contact her at [email protected]

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Physical Fitness Linked to Better Mental Health in Young People

A new study bolsters existing research suggesting that exercise can protect against anxiety, depression and attention challenges.

By Matt Richtel

Physical fitness among children and adolescents may protect against developing depressive symptoms, anxiety and attention deficit hyperactivity disorder, according to a study published on Monday in JAMA Pediatrics.

The study also found that better performance in cardiovascular activities, strength and muscular endurance were each associated with greater protection against such mental health conditions. The researchers deemed this linkage “dose-dependent,” suggesting that a child or adolescent who is more fit may be accordingly less likely to experience the onset of a mental health disorder.

These findings come amid a surge of mental health diagnoses among children and adolescents, in the United States and abroad, that have prompted efforts to understand and curb the problem.

The new study, conducted by researchers in Taiwan, compared data from two large data sets: the Taiwan National Student Fitness Tests, which measures student fitness performance in schools, and the National Insurance Research Databases, which records medical claims, diagnoses prescriptions and other medical information. The researchers did not have access to the students’ names but were able to use the anonymized data to compare the students’ physical fitness and mental health results.

The risk of mental health disorder was weighted against three metrics for physical fitness: cardio fitness, as measured by a student’s time in an 800-meter run; muscle endurance, indicated by the number of situps performed; and muscle power, measured by the standing broad jump.

Improved performance in each activity was linked with a lower risk of mental health disorder. For instance, a 30-second decrease in 800-meter time was associated, in girls, with a lower risk of anxiety, depression and A.D.H.D. In boys, it was associated with lower anxiety and risk of the disorder.

An increase of five situps per minute was associated with lower anxiety and risk of the disorder in boys, and with decreased risk of depression and anxiety in girls.

“These findings suggest the potential of cardiorespiratory and muscular fitness as protective factors in mitigating the onset of mental health disorders among children and adolescents,” the researchers wrote in the journal article.

Physical and mental health were already assumed to be linked , they added, but previous research had relied largely on questionnaires and self-reports, whereas the new study drew from independent assessments and objective standards.

The Big Picture

The surgeon general, Dr. Vivek H. Murthy, has called mental health “the defining public health crisis of our time,” and he has made adolescent mental health central to his mission. In 2021 he issued a rare public advisory on the topic. Statistics at the time revealed alarming trends: From 2001 to 2019, the suicide rate for Americans ages 10 to 19 rose 40 percent, and emergency visits related to self-harm rose 88 percent.

Some policymakers and researchers have blamed the sharp increase on the heavy use of social media, but research has been limited and the findings sometimes contradictory. Other experts theorize that heavy screen use has affected adolescent mental health by displacing sleep, exercise and in-person activity, all of which are considered vital to healthy development. The new study appeared to support the link between physical fitness and mental health.

“The finding underscores the need for further research into targeted physical fitness programs,” its authors concluded. Such programs, they added, “hold significant potential as primary preventative interventions against mental disorders in children and adolescents.”

Matt Richtel is a health and science reporter for The Times, based in Boulder, Colo. More about Matt Richtel

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Since a nationwide Adderall shortage started, some people with A.D.H.D. have said their medication no longer helps with their symptoms. But there could be other factors at play .

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Perimenopausal women have 40% higher risk of depression, study suggests

Researchers examined data from seven studies involving more than 9,000 women around the world

Perimenopausal women have a 40% higher risk of experiencing depression than premenopausal women, a global analysis of research suggests.

Experts from University College London (UCL) found women could be vulnerable to depression in the run-up to their periods stopping, with the development of new cases or existing symptoms worsening. The research underlines the need to provide support and screening to effectively address women’s mental health needs.

The perimenopause usually begins about three to five years before the onset of menopause, the researchers said. Women typically go through the menopause aged 49 to 52, which has previously been found to be the point at which women experience the highest rates of depression.

Common mental health symptoms of perimenopause include low mood, anxiety, mood swings, low self-esteem and issues with memory and concentration. Physical symptoms include hot flushes, sleep problems, heart palpitations, muscle aches, joint pains and weight gain.

The new research, published in the Journal of Affective Disorders, examined data from seven studies involving 9,141 women from across the world, including Australia, the US, China, the Netherlands and Switzerland.

It concluded that perimenopausal women were “at a significantly higher risk for depressive symptoms and diagnoses” – about 40% higher – compared with premenopausal women.

Researchers did not find a significantly increased risk for depressive symptoms in postmenopausal women, when compared with those who were premenopausal.

They suggested that one biological reason may be that the drop in oestrogen women experience during menopause triggers the onset of new symptoms or the worsening of pre-existing depressive symptoms.

Oestrogen “has been found to affect the metabolism of neurotransmitters (dopamine, norepinephrine, endorphin, and serotonin), all of which influence emotional states,” they said.

Night sweats can also lead to sleep problems, which may also have an influence, though this was not conclusive, they added.

Having a previous history of depression has also been associated with depression in women with menopause, while other studies have said caring for both ageing parents and children may make women more vulnerable.

The authors said one limitation of their work was that the study was unable to account for whether the women had a previous history of depression.

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Lead author Yasmeen Badawy said: “Combining data from global studies indicates that these findings cannot be attributed to cultural factors or lifestyle changes alone which have been sometimes used to explain the depressive symptoms that women experience during perimenopause.”

Senior author Dr Roopal Desai said: “This study shows that women in the perimenopausal stage are significantly more likely to experience depression than either before or after this stage.

“Our findings emphasise the importance of acknowledging that women in this life-stage are more vulnerable to experiencing depression. It also underlines the need to provide support and screening for women to help address their mental health needs effectively.”

In a previous study, the same researchers found that therapy – such as mindfulness and cognitive behavioural therapy – could be an effective form of treatment for non-physical symptoms of the menopause.

Corresponding author Prof Aimee Spector said: “Women spend years of their lives dealing with menopausal symptoms that can have a huge impact on their wellbeing and quality of life.

“Our findings show just how significantly the mental health of perimenopausal women can suffer during this time. We need greater awareness and support to ensure they receive appropriate help and care both medically, in the workplace and at home.”

• Mental health
• UCL (University College London)
• Human biology

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Psychedelic Toad Venom Shows Promise for New Depression Treatment

A colorado river toad (Incilius alvarius). The rarely seen amphibian is native to parts of Northwestern Mexico and the Southwestern U.S.

A potential depression treatment might someday come from trip-inducing toad venom. In a new study Wednesday, researchers appear to have deciphered the structural workings of a psychedelic compound derived from the Colorado River toad (Incilius alvarius). The team also tested a modified version of the compound in mice, finding it had antidepressant and antianxiety effects, and potentially without the psychedelic reactions that could complicate its safe use in humans.

Lately, psychedelics like LSD and psilocybin (the active ingredient in magic mushrooms) have received plenty of scientific attention as possible treatments for mental illness. Several clinical trials are currently testing these drugs for conditions such as depression, anxiety, and post-traumatic stress disorder. In June, outside experts affiliated with the Food and Drug Administration will evaluate Phase III data on using MDMA-assisted psychotherapy for PTSD, and it’s almost certain that a positive verdict will clear the way for FDA approval later this year.

Exciting as all this is, there’s still a lot that scientists are trying to figure out about how exactly these drugs work in the brain. Studies have found that the mind-altering effects of several popular psychedelics come largely from stimulating a certain class of serotonin receptors found on brain cells known as 5-HT2A receptors, for instance. But there are other types of 5HT receptors out there, as well as less studied psychedelics that seem to activate them.

Researchers at Mount Sinai and Columbia University decided to take a closer look at one of these psychedelics, called 5-MeO-DMT. This compound is found in the poison of the Colorado River toad (the common nickname of toad venom is a misnomer, since venoms are injected into a victim via fangs or other body parts). The drug is best known for its hallucinogenic and dissociative effects, while some surveys of users have also suggested that 5-MeO-DMT can induce a rapid drop in symptoms of depression and anxiety. Unlike some other psychedelics, however, 5-MeO-DMT appears to activate 5-HT1A receptors.

“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,” study author David Lankri, a neuropharmacologist at the Chemistry Department of Columbia University, told Gizmodo in an email.

The team studied 5-MeO-DMT using various methods of analysis, including cryogenic electron microscopy. This allowed them to confirm that 5-MeO-DMT activates both kinds of 5-HT receptors and to detail the exact structure of the compound.

From there, they created modified versions of it to better understand how it interacts with these receptors. They eventually created a variant of 5-MeO-DMT that was much more potent at activating 5-HT1A and tested it on mice made to develop symptoms of depression and anxiety. In these mice, the modified 5-MeO-DMT seemed to reliably induce antidepressant and antianxiety effects, and apparently without causing the typical psychedelic effects seen with the natural form.

“We showed that a selective compound—that almost entirely ‘ignores’ the psychedelic receptor—could be an effective treatment option for depression and anxiety,” Lankri said. The team’s findings were published Wednesday in Nature.

Studies like this one represent just the beginning of our efforts to understand these substances. Moreover, other well-known psychedelics are likely to be approved as mental health aids sooner than any treatments derived from 5-MeO-DMT or toad venom. Fun as tripping out might be, though, the classic psychedelic symptoms of these drugs will likely limit their widespread prescription and use as medical treatments. Similar drugs without these effects, Lankri noted, could likely be taken at home and wouldn’t require the costly supervision of a trained clinician. Simply having more effective depression drugs that work differently from one another is important, too, since some people will inevitably fail to respond to some of them.

So the researchers are hopeful about the potential of their research and where it may lead in the years to come. The team will continue to study 5-MeO-DMT, as well as the related drug ibogaine, which has also shown some promise as a depression and anxiety treatment.

“It is exciting to see detailed snapshots of the intricate dance of the receptor induced by the toad psychedelic and its molecular descendants,” Lankri said. “These new insights may prove useful in the development of the next generations of psychedelic-inspired medicines while revealing the beauty of the molecular world.”

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