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Experimental depression treatment is nearly 80% effective in controlled study

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

October 28, 2021 - By Mandy Erickson

Tommy Van Brocklin

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

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

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

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

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

A lifetime of depression

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

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

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

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

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

Specialized magnetic stimulation

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

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

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

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

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

A hard-to-treat group

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

Nolan Williams and Deirdre Lehman

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

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

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

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

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

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

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

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

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

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

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

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

Mandy Erickson

About Stanford Medicine

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

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Stanford Medicine magazine: Mental health

A digital drawing of DNA strands.

Depression, schizophrenia and bipolar disorder linked with ancient viral DNA in our genome – new research

depression new research

Research Fellow, King's College London

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Professor of Immunology in Medicine, Cornell University

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Senior lecturer, King's College London

Disclosure statement

Rodrigo Duarte received funding from the National Institutes of Health, USA.

Douglas Nixon receives funding from the National Institutes of Health, USA.

Timothy Powell receives funding from the National Institute for Health and Care Research, the National Institutes of Health, and the Medical Research Council.

King's College London provides funding as a member of The Conversation UK.

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Around 8% of human DNA is made up of genetic sequences acquired from ancient viruses . These sequences, known as human endogenous retroviruses (or Hervs), date back hundreds of thousands to millions of years – with some even predating the emergence of Homo sapiens .

Our latest research suggests that some ancient viral DNA sequences in the human genome play a role in susceptibility to psychiatric disorders such as schizophrenia, bipolar disorder and major depressive disorder.

Hervs represent the remnants of these infections with ancient retroviruses. Retroviruses are viruses that insert a copy of their genetic material into the DNA of the cells they infect. Retroviruses probably infected us on multiple occasions during our evolutionary past. When these infections occurred in sperm or egg cells that generated offspring, the genetic material from these retroviruses was passed on to subsequent generations , becoming a permanent part of our lineage.

Initially, scientists considered Hervs to be “junk DNA” – parts of our genome with no discernible function. But as our understanding of the human genome has advanced, it’s become evident that this so-called junk DNA is responsible for more functions than originally hypothesised.

First, researchers found that Hervs can regulate the expression of other human genes. A genetic feature is said to be “expressed” if its DNA segment is used to produce RNA (ribonucleic acid) molecules. These RNA molecules can then serve as intermediaries leading to the production of specific proteins , or help to regulate other parts of the genome .

Initial research suggested that Hervs regulate the expression of neighbouring genes with important biological functions. One example of this is a Herv that regulates the expression of a gene involved in modifying connections between brain cells.

Hervs have also been found to produce RNAs and even proteins in blood and brain samples . These molecules have the potential to exert a wide range of functions, as they can travel across cellular compartments to execute different roles.

Scientists have also found evidence suggesting certain human genes are derived from Hervs. This indicates there were instances during evolution where Hervs were co-opted for specialised biological functions. For example, the human genes syncytins 1 and 2, which are derived from Hervs, play pivotal roles in placental development .

HERVs in psychiatric disorders

Considering the abundance of Hervs in the genome and their potentially numerous functions, we wanted to better understand whether genetic susceptibility to certain psychiatric disorders was associated with differences in Herv expression.

The human brain.

In our study , we profiled Herv expression in nearly 800 autopsy brain samples. This helped us identify DNA variations that influenced Herv expression in the brain.

We then cross-referenced this information with findings from large genetic studies which had compared genetic differences between tens of thousands of people – both with and without mental health conditions. These studies identified variations in DNA associated with different psychiatric conditions.

We found that that the expression of four Hervs was linked with genetic susceptibility to major psychiatric disorders. The expression of two of these Hervs was associated with schizophrenia, one Herv with both schizophrenia and bipolar disorder, and one with depression. These results suggest that Hervs may be playing a more important role in the brain than initially thought.

Read more: Discovering how genetic 'dark matter' plays a role in mental illness is just the tip of the iceberg for human health

There are many genes involved in psychiatric disorders – and Hervs are only a part of this puzzle. Although the precise impact of these Hervs on brain cells and on a person’s susceptibility to certain psychiatric disorders requires further research, our study is the first to show that genetic susceptibility for a psychiatric disorder also acts through these ancient viral DNA sequences.

It’s still too early to determine the practical applications of our findings – and whether they might be used to develop new treatments. But we’re optimistic about this line of research. By linking Herv expression in the brain with psychiatric disorders, our research recognises the importance of these mysterious sequences in the human genome, which have been ignored for years.

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

Olivia remes.

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

João Francisco Mendes

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

Peter Templeton

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

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

Associated Data

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

1. Introduction

Depression is one of the most common mental health issues, with an estimated prevalence of 5% among adults [ 1 , 2 ]. Symptoms may include anhedonia, feelings of worthlessness, concentration and sleep difficulties, and suicidal ideation. According to the World Health Organization, depression is a leading cause of disability; research shows that it is a burdensome condition with a negative impact on educational trajectories, work performance, and other areas of life [ 1 , 3 ]. Depression can start early in the lifecourse and, if it remains unmanaged, may increase the risk for substance abuse, chronic conditions, such as cardiovascular disease, and premature mortality [ 4 , 5 , 6 , 7 , 8 ].

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

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

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

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

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

2. Materials and Methods

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

The inclusion and exclusion criteria are the following:

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

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

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

3.1. Biological Factors

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

3.1.1. Physical Health Conditions

Studies on physical health conditions—key points:

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

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

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

3.1.2. Genetics

Studies on genetics—key points:

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

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

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

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

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

3.1.3. Microbiome

Studies on the microbiome—key points:

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

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

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

3.1.4. Inflammation

Studies on inflammation—key points:

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

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

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

3.1.5. Stress and HPA Axis Dysfunction

Studies on stress and HPA axis dysfunction—key points:

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

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

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

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

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

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

3.1.6. Kynurenine Pathway

Studies on the kynurenine pathway—key points:

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

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

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

3.1.7. Cognition

Studies on cognition and the brain—key points:

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

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

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

3.2. Psychological Factors

Studies on psychological factors—key points:

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

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

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

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

3.3. Social Determinants

Studies on social determinants—key points:

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

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

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

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

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

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

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

3.4. Others

Studies on ‘other’ determinants—key points:

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

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

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

4. Cross-Cutting Themes

4.1. lifecourse perspective.

Studies on the lifecourse perspective—key points:

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

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

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

4.2. Gene–Environment Interactions

Studies on gene–environment interactions—key points:

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

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

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

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

5. Discussion

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

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

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

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

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

5.1. Strengths

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

5.2. Limitations

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

6. Conclusions

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

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

Acknowledgments

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

Supplementary Materials

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

Appendix A.1. Search Strategy

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

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

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

Appendix A.2. PsycInfo

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

Author Contributions

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

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

Conflicts of Interest

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

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

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

20 July 2022

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

Image of brain

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

  • Research paper in Molecular Psychiatry
  • Professor Joanna Moncrieff’s academic profile
  • UCL Psychiatry
  • * For example, the Royal College of Psychiatrists removed all reference to ‘chemical imbalances’ from their website in recent years. They now say in official statements that “the original idea that antidepressants ‘correct a chemical imbalance in the brain’ is an over-simplification.”
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Personal Health

The Devastating Ways Depression and Anxiety Impact the Body

Mind and body form a two-way street.

depression new research

By Jane E. Brody

It’s no surprise that when a person gets a diagnosis of heart disease, cancer or some other life-limiting or life-threatening physical ailment, they become anxious or depressed. But the reverse can also be true: Undue anxiety or depression can foster the development of a serious physical disease, and even impede the ability to withstand or recover from one. The potential consequences are particularly timely, as the ongoing stress and disruptions of the pandemic continue to take a toll on mental health .

The human organism does not recognize the medical profession’s artificial separation of mental and physical ills. Rather, mind and body form a two-way street. What happens inside a person’s head can have damaging effects throughout the body, as well as the other way around. An untreated mental illness can significantly increase the risk of becoming physically ill, and physical disorders may result in behaviors that make mental conditions worse.

In studies that tracked how patients with breast cancer fared, for example, Dr. David Spiegel and his colleagues at Stanford University School of Medicine showed decades ago that women whose depression was easing lived longer than those whose depression was getting worse. His research and other studies have clearly shown that “the brain is intimately connected to the body and the body to the brain,” Dr. Spiegel said in an interview. “The body tends to react to mental stress as if it was a physical stress.”

Despite such evidence, he and other experts say, chronic emotional distress is too often overlooked by doctors. Commonly, a physician will prescribe a therapy for physical ailments like heart disease or diabetes, only to wonder why some patients get worse instead of better.

Many people are reluctant to seek treatment for emotional ills. Some people with anxiety or depression may fear being stigmatized, even if they recognize they have a serious psychological problem. Many attempt to self-treat their emotional distress by adopting behaviors like drinking too much or abusing drugs, which only adds insult to their pre-existing injury.

And sometimes, family and friends inadvertently reinforce a person’s denial of mental distress by labeling it as “that’s just the way he is” and do nothing to encourage them to seek professional help.

How common are anxiety and depression?

Anxiety disorders affect nearly 20 percent of American adults . That means millions are beset by an overabundance of the fight-or-flight response that primes the body for action. When you’re stressed, the brain responds by prompting the release of cortisol, nature’s built-in alarm system. It evolved to help animals facing physical threats by increasing respiration, raising the heart rate and redirecting blood flow from abdominal organs to muscles that assist in confronting or escaping danger.

These protective actions stem from the neurotransmitters epinephrine and norepinephrine, which stimulate the sympathetic nervous system and put the body on high alert. But when they are invoked too often and indiscriminately, the chronic overstimulation can result in all manner of physical ills, including digestive symptoms like indigestion, cramps, diarrhea or constipation, and an increased risk of heart attack or stroke.

Depression, while less common than chronic anxiety, can have even more devastating effects on physical health. While it’s normal to feel depressed from time to time, more than 6 percent of adults have such persistent feelings of depression that it disrupts personal relationships, interferes with work and play, and impairs their ability to cope with the challenges of daily life. Persistent depression can also exacerbate a person’s perception of pain and increase their chances of developing chronic pain.

“Depression diminishes a person’s capacity to analyze and respond rationally to stress,” Dr. Spiegel said. “They end up on a vicious cycle with limited capacity to get out of a negative mental state.”

Potentially making matters worse, undue anxiety and depression often coexist, leaving people vulnerable to a panoply of physical ailments and an inability to adopt and stick with needed therapy.

A study of 1,204 elderly Korean men and women initially evaluated for depression and anxiety found that two years later, these emotional disorders increased their risk of physical disorders and disability. Anxiety alone was linked with heart disease, depression alone was linked with asthma, and the two together were linked with eyesight problems, persistent cough, asthma, hypertension, heart disease and gastrointestinal problems.

Treatment can counter emotional tolls

Although persistent anxiety and depression are highly treatable with medications, cognitive behavioral therapy and talk therapy, without treatment these conditions tend to get worse. According to Dr. John Frownfelter, treatment for any condition works better when doctors understand “the pressures patients face that affect their behavior and result in clinical harm.”

Dr. Frownfelter is an internist and chief medical officer of a start-up called Jvion. The organization uses artificial intelligence to identify not just medical factors but psychological, social and behavioral ones as well that can impact the effectiveness of treatment on patients’ health. Its aim is to foster more holistic approaches to treatment that address the whole patient, body and mind combined.

The analyses used by Jvion, a Hindi word meaning life-giving, could alert a doctor when underlying depression might be hindering the effectiveness of prescribed treatments for another condition. For example, patients being treated for diabetes who are feeling hopeless may fail to improve because they take their prescribed medication only sporadically and don’t follow a proper diet, Dr. Frownfelter said.

“We often talk about depression as a complication of chronic illness,” Dr. Frownfelter wrote in Medpage Today in July . “But what we don’t talk about enough is how depression can lead to chronic disease. Patients with depression may not have the motivation to exercise regularly or cook healthy meals. Many also have trouble getting adequate sleep.”

Some changes to medical care during the pandemic have greatly increased patient access to depression and anxiety treatment. The expansion of telehealth has enabled patients to access treatment by psychotherapists who may be as far as a continent away.

Patients may also be able to treat themselves without the direct help of a therapist. For example, Dr. Spiegel and his co-workers created an app called Reveri that teaches people self-hypnosis techniques designed to help reduce stress and anxiety, improve sleep, reduce pain and suppress or quit smoking.

Improving sleep is especially helpful, Dr. Spiegel said, because “it enhances a person’s ability to regulate the stress response system and not get stuck in a mental rut.” Data demonstrating the effectiveness of the Reveri app has been collected but not yet published, he said.

Jane Brody is the Personal Health columnist, a position she has held since 1976. She has written more than a dozen books including the best sellers “Jane Brody’s Nutrition Book” and “Jane Brody’s Good Food Book.” More about Jane E. Brody

Managing Anxiety and Stress

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

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

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

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

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

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  • Systematic Review
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  • Published: 20 July 2022

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

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

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

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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 ).

figure 1

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

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

Serotonin and 5-HIAA

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

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

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

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

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

The serotonin transporter (SERT)

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

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

Depletion studies

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

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

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

SERT gene and gene-stress interactions

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

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

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

Overall results

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

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

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

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

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

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

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

Data availability

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

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

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

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

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

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depression new research

David Rettew M.D.

Depression and Serotonin: What the New Review Actually Says

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

Posted July 26, 2022 | Reviewed by Abigail Fagan

  • What Is Depression?
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  • A new published review finds no evidence that low serotonin levels cause depression.
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  • Despite the claims of some, the study does not disprove that biological factors are irrelevant to depression.
  • The dominant model of depression for decades has been one that recognizes the importance of biological, psychological, and social factors.

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

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

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

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

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

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

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

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

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

depression new research

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

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

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

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

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

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

David Rettew M.D.

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

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What is depression?

Depression (also known as major depression, major depressive disorder, or clinical depression) is a common but serious mood disorder. It causes severe symptoms that affect how a person feels, thinks, and handles daily activities, such as sleeping, eating, or working.

To be diagnosed with depression, the symptoms must be present for at least 2 weeks.

There are different types of depression, some of which develop due to specific circumstances.

  • Major depression includes symptoms of depressed mood or loss of interest, most of the time for at least 2 weeks, that interfere with daily activities.
  • Persistent depressive disorder (also called dysthymia or dysthymic disorder) consists of less severe symptoms of depression that last much longer, usually for at least 2 years.
  • Perinatal depression is depression that occurs during pregnancy or after childbirth. Depression that begins during pregnancy is prenatal depression, and depression that begins after the baby is born is postpartum depression.
  • Seasonal affective disorder is depression that comes and goes with the seasons, with symptoms typically starting in the late fall or early winter and going away during the spring and summer.
  • Depression with symptoms of psychosis is a severe form of depression in which a person experiences psychosis symptoms, such as delusions (disturbing, false fixed beliefs) or hallucinations (hearing or seeing things others do not hear or see).

People with  bipolar disorder  (formerly called manic depression or manic-depressive illness) also experience depressive episodes, during which they feel sad, indifferent, or hopeless, combined with a very low activity level. But a person with bipolar disorder also experiences manic (or less severe hypomanic) episodes, or unusually elevated moods, in which they might feel very happy, irritable, or “up,” with a marked increase in activity level.

Other depressive disorders found in the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5-TR)   include disruptive mood dysregulation disorder (diagnosed in children and adolescents) and premenstrual dysphoric disorder (that affects women around the time of their period).

Who gets depression?

Depression can affect people of all ages, races, ethnicities, and genders.

Women are diagnosed with depression more often than men, but men can also be depressed. Because men may be less likely to recognize, talk about, and seek help for their feelings or emotional problems, they are at greater risk of their depression symptoms being undiagnosed or undertreated.

Studies also show higher rates of depression and an increased risk for the disorder among members of the LGBTQI+ community.

What are the signs and symptoms of depression?

If you have been experiencing some of the following signs and symptoms, most of the day, nearly every day, for at least 2 weeks, you may have depression:

  • Persistent sad, anxious, or “empty” mood
  • Feelings of hopelessness or pessimism
  • Feelings of irritability, frustration, or restlessness
  • Feelings of guilt, worthlessness, or helplessness
  • Loss of interest or pleasure in hobbies and activities
  • Fatigue, lack of energy, or feeling slowed down
  • Difficulty concentrating, remembering, or making decisions
  • Difficulty sleeping, waking too early in the morning, or oversleeping
  • Changes in appetite or unplanned weight changes
  • Physical aches or pains, headaches, cramps, or digestive problems without a clear physical cause that do not go away with treatment
  • Thoughts of death or suicide or suicide attempts

Not everyone who is depressed experiences all these symptoms. Some people experience only a few symptoms, while others experience many. Symptoms associated with depression interfere with day-to-day functioning and cause significant distress for the person experiencing them.

Depression can also involve other changes in mood or behavior that include:

  • Increased anger or irritability
  • Feeling restless or on edge
  • Becoming withdrawn, negative, or detached
  • Increased engagement in high-risk activities
  • Greater impulsivity
  • Increased use of alcohol or drugs
  • Isolating from family and friends
  • Inability to meet the responsibilities of work and family or ignoring other important roles
  • Problems with sexual desire and performance

Depression can look different in men and women. Although people of all genders can feel depressed, how they express those symptoms and the behaviors they use to cope with them may differ. For example, men (as well as women) may show symptoms other than sadness, instead seeming angry or irritable. And although increased use of alcohol or drugs can be a sign of depression in anyone, men are more likely to use these substances as a coping strategy.

In some cases, mental health symptoms appear as physical problems (for example, a racing heart, tightened chest, ongoing headaches, or digestive issues). Men are often more likely to see a health care provider about these physical symptoms than their emotional ones.

Because depression tends to make people think more negatively about themselves and the world, some people may also have thoughts of suicide or self-harm.

Several persistent symptoms, in addition to low mood, are required for a diagnosis of depression, but people with only a few symptoms may benefit from treatment. The severity and frequency of symptoms and how long they last will vary depending on the person, the illness, and the stage of the illness.

If you experience signs or symptoms of depression and they persist or do not go away, talk to a health care provider. If you see signs or symptoms of depression in someone you know, encourage them to seek help from a mental health professional.

If you or someone you know is struggling or having thoughts of suicide, call or text the 988 Suicide and Crisis Lifeline   at 988 or chat at 988lifeline.org   . In life-threatening situations, call 911 .

What are the risk factors for depression?

Depression is one of the most common mental disorders in the United States . Research suggests that genetic, biological, environmental, and psychological factors play a role in depression.

Risk factors for depression can include:

  • Personal or family history of depression
  • Major negative life changes, trauma, or stress

Depression can happen at any age, but it often begins in adulthood. Depression is now recognized as occurring in children and adolescents, although children may express more irritability or anxiety than sadness. Many chronic mood and anxiety disorders in adults begin as high levels of anxiety in childhood.

Depression, especially in midlife or older age, can co-occur with other serious medical illnesses, such as diabetes, cancer, heart disease, chronic pain, and Parkinson’s disease. These conditions are often worse when depression is present, and research suggests that people with depression and other medical illnesses tend to have more severe symptoms of both illnesses. The Centers for Disease Control and Prevention (CDC)  has also recognized that having certain mental disorders, including depression and schizophrenia, can make people more likely to get severely ill from COVID-19.

Sometimes a physical health problem, such as thyroid disease, or medications taken for an illness cause side effects that contribute to depression. A health care provider experienced in treating these complicated illnesses can help determine the best treatment strategy. 

How is depression treated?

Depression, even the most severe cases, can be treated. The earlier treatment begins, the more effective it is. Depression is usually treated with psychotherapy , medication , or a combination of the two.

Some people experience treatment-resistant depression, which occurs when a person does not get better after trying at least two antidepressant medications. If treatments like psychotherapy and medication do not reduce depressive symptoms or the need for rapid relief from symptoms is urgent, brain stimulation therapy  may be an option to explore.

Quick tip : No two people are affected the same way by depression, and there is no "one-size-fits-all" treatment. Finding the treatment that works best for you may take trial and error.

Psychotherapies

Several types of psychotherapy (also called talk therapy or counseling) can help people with depression by teaching them new ways of thinking and behaving and helping them change habits that contribute to depression. Evidence-based approaches to treating depression include cognitive-behavioral therapy (CBT) and interpersonal therapy (IPT). Learn more about psychotherapy .

The growth of telehealth for mental health services , which offers an alternative to in-person therapy, has made it easier and more convenient for people to access care in some cases. For people who may have been hesitant to look for mental health care in the past, virtual mental health care might be an easier option.

Medications

Antidepressants are medications commonly used to treat depression. They work by changing how the brain produces or uses certain chemicals involved in mood or stress. You may need to try several different antidepressants before finding the one that improves your symptoms and has manageable side effects. A medication that has helped you or a close family member in the past will often be considered first.

Antidepressants take time—usually 4–8 weeks—to work, and problems with sleep, appetite, and concentration often improve before mood lifts. It is important to give a medication a chance to work before deciding whether it’s right for you. Learn more about mental health medications . 

New medications, such as intranasal esketamine , can have rapidly acting antidepressant effects, especially for people with treatment-resistant depression. Esketamine is a medication approved by the U.S. Food and Drug Administration (FDA)  for treatment-resistant depression. Delivered as a nasal spray in a doctor’s office, clinic, or hospital, it acts rapidly, typically within a couple of hours, to relieve depression symptoms. People who use esketamine will usually continue taking an oral antidepressant to maintain the improvement in their symptoms.

Another option for treatment-resistant depression is to take an antidepressant alongside a different type of medication that may make it more effective, such as an antipsychotic or anticonvulsant medication. Further research is needed to identify the role of these newer medications in routine practice.

If you begin taking an antidepressant, do not stop taking it without talking to a health care provider . Sometimes people taking antidepressants feel better and stop taking the medications on their own, and their depression symptoms return. When you and a health care provider have decided it is time to stop a medication, usually after a course of 9–12 months, the provider will help you slowly and safely decrease your dose. Abruptly stopping a medication can cause withdrawal symptoms.

Note : In some cases, children, teenagers, and young adults under 25 years may experience an increase in suicidal thoughts or behavior when taking antidepressants, especially in the first few weeks after starting or when the dose is changed. The FDA advises that patients of all ages taking antidepressants be watched closely, especially during the first few weeks of treatment.

If you are considering taking an antidepressant and are pregnant, planning to become pregnant, or breastfeeding, talk to a health care provider about any health risks to you or your unborn or nursing child and how to weigh those risks against the benefits of available treatment options.

To find the latest information about antidepressants, talk to a health care provider and visit the FDA website  .

Brain stimulation therapies

If psychotherapy and medication do not reduce symptoms of depression, brain stimulation therapy may be an option to explore. There are now several types of brain stimulation therapy, some of which have been authorized by the FDA to treat depression. Other brain stimulation therapies are experimental and still being investigated for mental disorders like depression.

Although brain stimulation therapies are less frequently used than psychotherapy and medication, they can play an important role in treating mental disorders in people who do not respond to other treatments. These therapies are used for most mental disorders only after psychotherapy and medication have been tried and usually continue to be used alongside these treatments.

Brain stimulation therapies act by activating or inhibiting the brain with electricity. The electricity is given directly through electrodes implanted in the brain or indirectly through electrodes placed on the scalp. The electricity can also be induced by applying magnetic fields to the head.

The brain stimulation therapies with the largest bodies of evidence include:

  • Electroconvulsive therapy (ECT)
  • Repetitive transcranial magnetic stimulation (rTMS)
  • Vagus nerve stimulation (VNS)
  • Magnetic seizure therapy (MST)
  • Deep brain stimulation (DBS)

ECT and rTMS are the most widely used brain stimulation therapies, with ECT having the longest history of use. The other therapies are newer and, in some cases, still considered experimental. Other brain stimulation therapies may also hold promise for treating specific mental disorders.

ECT, rTMS, and VNS have authorization from the FDA to treat severe, treatment-resistant depression. They can be effective for people who have not been able to feel better with other treatments; people for whom medications cannot be used safely; and in severe cases where a rapid response is needed, such as when a person is catatonic, suicidal, or malnourished.

Additional types of brain stimulation therapy are being investigated for treating depression and other mental disorders. Talk to a health care provider and make sure you understand the potential benefits and risks before undergoing brain stimulation therapy. Learn more about these brain stimulation therapies .

Natural products

The FDA has not approved any natural products for treating depression. Although research is ongoing and findings are inconsistent, some people use natural products, including vitamin D and the herbal dietary supplement St. John’s wort, for depression. However, these products can come with risks. For instance, dietary supplements and natural products can limit the effectiveness of some medications or interact in dangerous or even life-threatening ways with them.

Do not use vitamin D, St. John’s wort, or other dietary supplements or natural products without talking to a health care provider. Rigorous studies must be conducted to test whether these and other natural products are safe and effective.

Daily morning light therapy is a common treatment choice for people with seasonal affective disorder (SAD). Light therapy devices are much brighter than ordinary indoor lighting and considered safe, except for people with certain eye diseases or taking medications that increase sensitivity to sunlight. As with all interventions for depression, evaluation, treatment, and follow-up by a health care provider are strongly recommended. Research into the potential role of light therapy in treating non-seasonal depression is ongoing.

How can I find help for depression?

A primary care provider is a good place to start if you’re looking for help. They can refer you to a qualified mental health professional, such as a psychologist, psychiatrist, or clinical social worker, who can help you figure out next steps. Find tips for talking with a health care provider about your mental health.

You can learn more about getting help on the NIMH website. You can also learn about finding support  and locating mental health services  in your area on the Substance Abuse and Mental Health Services Administration (SAMHSA) website. 

Once you enter treatment, you should gradually start to feel better. Here are some other things you can do outside of treatment that may help you or a loved one feel better:

  • Try to get physical activity. Just 30 minutes a day of walking can boost your mood.
  • Try to maintain a regular bedtime and wake-up time.
  • Eat regular, healthy meals.
  • Break up large tasks into small ones; do what you can as you can. Decide what must get done and what can wait.
  • Try to connect with people. Talk with people you trust about how you are feeling.
  • Delay making important decisions, such as getting married or divorced, or changing jobs until you feel better. Discuss decisions with people who know you well.
  • Avoid using alcohol, nicotine, or drugs, including medications not prescribed for you.

How can I find a clinical trial for depression?

Clinical trials are research studies that look at new ways to prevent, detect, or treat diseases and conditions, including depression. The goal of a clinical trial is to determine if a new test or treatment works and is safe. Although people may benefit from being part of a clinical trial, they should know that the primary purpose is to gain new scientific knowledge so that others can be better helped in the future.

Researchers at NIMH and around the country conduct many studies with people with and without depression. We have new and better treatment options today because of what clinical trials have uncovered. Talk to a health care provider about clinical trials, their benefits and risks, and whether one is right for you.

To learn more or find a study, visit:

  • Clinical Trials – Information for Participants : Information about clinical trials, why people might take part in a clinical trial, and what people might experience during a clinical trial
  • Clinicaltrials.gov: Current Studies on Depression   : List of clinical trials funded by the National Institutes of Health (NIH) being conducted across the country
  • Join a Study: Depression—Adults : List of studies currently recruiting adults with depression being conducted on the NIH campus in Bethesda, MD
  • Join a Study: Depression—Children : List of studies currently recruiting children with depression being conducted on the NIH campus in Bethesda, MD
  • Join a Study: Perimenopause-Related Mood Disorders : List of studies on perimenopause-related mood disorders being conducted on the NIH campus in Bethesda, MD
  • Join a Study: Postpartum Depression : List of studies on postpartum depression being conducted on the NIH campus in Bethesda, MD

Where can I learn more about depression?

Free brochures and shareable resources.

  • Chronic Illness and Mental Health: Recognizing and Treating Depression : This fact sheet provides information about the link between depression and chronic disease. It describes what a chronic disease is, symptoms of depression, and treatment options, and presents resources to find help for yourself or someone else.
  • Depression : This brochure provides information about depression, including different types of depression, signs and symptoms, how it is diagnosed, treatment options, and how to find help for yourself or a loved one.
  • Depression in Women: 4 Things to Know : This fact sheet provides information about depression in women, including signs and symptoms, types of depression unique to women, and how to get help.
  • Perinatal Depression : This brochure provides information about perinatal depression, including how it differs from “baby blues,” causes, signs and symptoms, treatment options, and how to find help for yourself or a loved one.
  • Seasonal Affective Disorder : This fact sheet provides information about seasonal affective disorder, including signs and symptoms, how it is diagnosed, causes, and treatment options.
  • Seasonal Affective Disorder (SAD): More Than the Winter Blues : This infographic provides information about how to recognize the symptoms of SAD and what to do to get help.
  • Teen Depression: More Than Just Moodiness : This fact sheet is for teens and young adults and provides information about how to recognize the symptoms of depression and what to do to get help.
  • Digital Shareables on Depression : These digital resources, including graphics and messages, can be used to spread the word about depression and help promote depression awareness and education in your community.

Federal resources

  • Depression   (MedlinePlus - also en español  )
  • Moms’ Mental Health Matters: Depression and Anxiety Around Pregnancy   ( Eunice Kennedy Shriver National Institute of Child Health and Human Development)

Research and statistics

  • Journal Articles   : This webpage provides articles and abstracts on depression from MEDLINE/PubMed (National Library of Medicine).
  • Statistics: Major Depression : This webpage provides the statistics currently available on the prevalence and treatment of depression among people in the United States.
  • Depression Mental Health Minute : Take a mental health minute to watch this video on depression.
  • NIMH Experts Discuss the Menopause Transition and Depression : Learn about the signs and symptoms, treatments, and latest research on depression during menopause.
  • NIMH Expert Discusses Seasonal Affective Disorder : Learn about the signs and symptoms, treatments, and latest research on seasonal affective disorder.
  • Discover NIMH: Personalized and Targeted Brain Stimulation Therapies : Watch this video describing repetitive transcranial magnetic stimulation and electroconvulsive therapy for treatment-resistant depression. Brain stimulation therapies can be effective treatments for people with depression and other mental disorders. NIMH supports studies exploring how to make brain stimulation therapies more personalized while reducing side effects.
  • Discover NIMH: Drug Discovery and Development : One of the most exciting breakthroughs from research funded by NIMH is the development of a fast-acting medication for treatment-resistant depression based on ketamine. This video shares the story of how ketamine infusions meaningfully changed the life of a participant in an NIMH clinical trial.
  • Mental Health Matters Podcast: Depression: The Case for Ketamine : Dr. Carlos Zarate Jr. discusses esketamine—the medication he helped discover—for treatment-resistant depression. The podcast covers the history behind the development of esketamine, how it can help with depression, and what the future holds for this innovative line of clinical research.

Last Reviewed: March 2024

Unless otherwise specified, the information on our website and in our publications is in the public domain and may be reused or copied without permission. However, you may not reuse or copy images. Please cite the National Institute of Mental Health as the source. Read our copyright policy to learn more about our guidelines for reusing NIMH content.

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

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

In this July 10, 2018, file photo, bottles of medications ride on a belt at a mail-in pharmacy warehouse in Florence, N.J.

By Lois M. Collins

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

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

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

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

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

Experts are divided and the study has drawn some pushback.

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

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

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

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

Targeting serotonin

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

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

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

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

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

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

Study nuts and bolts

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

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

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

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

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

Public perception

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

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

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

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

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

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

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

Some experts disagree

The research has attracted some pushback.

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

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

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

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

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

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Weight gain is kicked to the curb in antipsychotic drug breakthrough

28 May 2024

Sad overweight man sitting on the end of his bed

Now, world first research from the University of South Australia shows that antipsychotics can be reformulated with a strategically engineered coating that not only mitigates unwanted weight gain but also boosts serotonin levels by more than 250%.

Funded by the Hospital Research Foundation (THRF) Group , researchers specifically tested Lurasidone , a drug used in the treatment of schizophrenia and bipolar depression, finding that the new coatings target the gut microbiome to improve drug absorption by 8-fold, while concurrently overcoming common side effects such as weight gain.

The coatings are created from tiny core-shell particles made from the dietary fibre, inulin, and bioactive medium chain triglycerides. The inulin shell boosts the gut microbiome by providing an energy source for gut bacteria, while the medium chain triglycerides facilitate drug absorption into the bloodstream.

It’s a breakthrough discovery that has the potential to change the lives of millions of people worldwide.

Lead researcher UniSA’s Dr Paul Joyce says microbiota-targeting microcapsules have the potential to improve treatment outcomes of mental health medications.

“Most patients suffering from schizophrenia or bipolar disorder are prescribed a range of antipsychotic medications, which trigger significant adverse effects by disrupting the gut microbiome – the microbial ecosystem that naturally colonises the gut,” Dr Joyce says.

“The most notable side effect is weight gain, with many patients often seeing increases of between 10-15% of their body weight after just three months of treatment.

“Because the gut microbiome plays a major role in regulating overall health, especially mood and cognition, the detrimental impact of these medications on the microbiome often makes them counterproductive.

Schematic showing how drug coating works

THe strategically engineered coating mitigates unwanted weight gain and boosts serotonin levels by more than 250%.

“Instead of improving mood and cognition, the medication leads to a cascading cycle of poor mental and metabolic health as patients now struggle with excess weight and mental health issues.

“To make matters worse, most antipsychotics need to be consumed with food to maximise their effect. Yet for a very vulnerable patient population, ensuring this happens is challenging, with most patients gaining suboptimal drug levels.

“Clearly, new strategies are needed to eliminate side effects and the need for these medications to be taken with food – and that’s exactly what we’ve achieved with the drug Lurasidone.

“This research shows that when antipsychotic drugs are formulated with our new smart core-shell microparticles, drug absorption increases, mitigating the need for the medication to be consumed with food, while also boosting the diversity and abundance of the gut microbiome to overcome common side effects, such as weight gain.

“Importantly, because we are not developing new drugs, rather reformulating them, the new therapies can be fast-tracked for clinical use, so we could expect them within the next few years rather than the 10-15 years needed for new drug molecules to be approved by regulatory bodies.”

Next steps are to test the efficacy of these re-formulated therapies within human patients, with longer term goals being to extend these technologies across all mental health therapies, including anti-depressants, to mitigate any adverse effects.

Notes to editors:

The research papers connected to this research are:

  • R. Meola, A. Elz, A. Wignall, K. Paxton, A. Hunter, A. Ariaee, S. Kamath, S. E. Reuter, C. A. Prestidge, P. Joyce,  Inulin-Lipid Core–Shell Microcapsules Target the Gut Microbiota and Mimic the Pharmaceutical Food Effect for Improved Oral Antipsychotic Delivery .  Adv. Funct. Mater. 2024, 2403914. 

Srinivas Kamath, Alexander Hunter, Kate Collins, Anthony Wignall and Paul Joyce, The atypical antipsychotic lurasidone positively modulates the gut microbiota in rats: A comparative study to olanzapine . bioRxiv, 2024.

………………………………………………………………………………………………………………………

Media contact: Annabel Mansfield M: +61 479 182 489 E: [email protected]

Researcher : Dr Paul Joyce E: [email protected]

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depression new research

ScienceDaily

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

  • Mental Health
  • Disorders and Syndromes
  • Intelligence
  • Neurotransmitter
  • Methamphetamine
  • Bipolar disorder
  • Psychometrics
  • Clinical depression
  • Confirmation bias

Story Source:

Materials provided by University College London . Note: Content may be edited for style and length.

Journal Reference :

  • Joanna Moncrieff, Ruth E. Cooper, Tom Stockmann, Simone Amendola, Michael P. Hengartner, Mark A. Horowitz. The serotonin theory of depression: a systematic umbrella review of the evidence . Molecular Psychiatry , 2022; DOI: 10.1038/s41380-022-01661-0

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