new research on depression

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

• View all journals
• Explore content
• About the journal
• Publish with us
• Sign up for alerts
• Published: 18 June 2020

Advances in depression research: second special issue, 2020, with highlights on biological mechanisms, clinical features, co-morbidity, genetics, imaging, and treatment

• Julio Licinio 1 &
• Ma-Li Wong 1  

Molecular Psychiatry volume  25 ,  pages 1356–1360 ( 2020 ) Cite this article

10k Accesses

11 Citations

4 Altmetric

Metrics details

The current speed of progress in depression research is simply remarkable. We have therefore been able to create a second special issue of Molecular Psychiatry , 2020, focused on depression, with highlights on mechanisms, genetics, clinical features, co-morbidity, imaging, and treatment. We are also very proud to present in this issue a seminal paper by Chottekalapanda et al., which represents some of the last work conducted by the late Nobel Laureate Paul Greengard [ 1 ]. This brings to four the number of papers co-authored by Paul Greengard and published in our two 2020 depression special issues [ 1 , 2 , 3 , 4 ].

The research content of this special depression issue starts with Chottekalapanda et al.’s outstanding contribution aimed at determining whether neuroadaptive processes induced by antidepressants are modulated by the regulation of specific gene expression programs [ 1 ]. That team identified a transcriptional program regulated by activator protein-1 (AP-1) complex, formed by c-Fos and c-Jun that is selectively activated prior to the onset of the chronic SSRI response. The AP-1 transcriptional program modulated the expression of key neuronal remodeling genes, including S100a10 (p11), linking neuronal plasticity to the antidepressant response. Moreover, they found that AP-1 function is required for the antidepressant effect in vivo. Furthermore, they demonstrated how neurochemical pathways of BDNF and FGF2, through the MAPK, PI3K, and JNK cascades, regulate AP-1 function to mediate the beneficial effects of the antidepressant response. This newly identified molecular network provides “a new avenue that could be used to accelerate or potentiate antidepressant responses by triggering neuroplasticity.”

A superb paper by Schouten et al. showed that oscillations of glucocorticoid hormones (GC) preserve a population of adult hippocampal neural stem cells in the aging brain [ 5 ]. Moreover, major depressive disorder (MDD) is characterized by alterations in GC-related rhythms [ 6 , 7 ]. GC regulate neural stem/precursor cells (NSPC) proliferation [ 8 , 9 ]. The adrenals secrete GC in ultradian pulses that result in a circadian rhythm. GC oscillations control cell cycle progression and induce specific genome-wide DNA methylation profiles. Schouten et al. studied primary hippocampal NSPC cultures and showed that GC oscillations induced lasting changes in the methylation state of a group of gene promoters associated with cell cycle regulation and the canonical Wnt signaling pathway. Furthermore, in a mouse model of accelerated aging, they showed that disruption of GC oscillations induced lasting changes in dendritic complexity, spine numbers and morphology of newborn granule neurons. Their results indicate that GC oscillations preserve a population of GR-expressing NSPC during aging, preventing their activation possibly by epigenetic programming through methylation of specific gene promoters. These important observations suggest a novel mechanism mediated by GC that controls NSPC proliferation and preserves a dormant NSPC pool, possibly contributing to neuroplasticity reserve in the aging brain.

MDD has a critical interface with addiction and suicide, which is of immense clinical and research importance [ 10 ]. Peciña et al. have reviewed a growing body of research indicating that the endogenous opioid system is directly involved in the regulation of mood and is dysregulated in MDD [ 11 ]. Halikere et al. provide evidence that addiction associated N40D mu-opioid receptor variant modulates synaptic function in human neurons [ 12 ].

Two papers by Amare et al. and Coleman et al. examine different genetic substrates for MDD, identifying novel depression-related loci as well as studying the interface with trauma [ 13 , 14 ].

The dissection of MDD clinical phenotypes, including their interface with other illnesses is a topic of several articles in this special issue. Belvederi Murri et al. examined the symptom network structure of depressive symptoms in late-life in a large European population in the 19 country Survey of Health, Ageing, and Retirement in Europe (SHARE) (mean age 74 years, 59% females, n  = 8557) [ 15 ]. They showed that the highest values of centrality were in the symptoms of death wishes, depressed mood, loss of interest, and pessimism. Another article focused on a specific feature of MDD, namely changes in appetite. Simmons et al. aimed at explaining why some individuals lose their appetite when they become depressed, while others eat more, and brought together data on neuroimaging, salivary cortisol, and blood markers of inflammation and metabolism [ 16 ]. Depressed participants experiencing decreased appetite had higher cortisol levels than other subjects, and their cortisol values correlated inversely with the ventral striatal response to food cues. In contrast, depressed participants experiencing increased appetite exhibited marked immunometabolic dysregulation, with higher insulin, insulin resistance, leptin, c-reactive protein (CRP), interleukin 1 receptor antagonist (IL-1RA), and IL-6, and lower ghrelin than subjects in other groups, and the magnitude of their insulin resistance correlated positively with the insula response to food cues. Their findings support the existence of pathophysiologically distinct depression subtypes for which the direction of appetite change may be an easily measured behavioral marker.

Mulugeta et al. studied the association between major depressive disorder and multiple disease outcomes in the UK Biobank ( n  = 337,536) [ 17 ]. They performed hypothesis-free phenome-wide association analyses between MDD genetic risk score (GRS) and 925 disease outcomes. MDD was associated with several inflammatory and hemorrhagic gastrointestinal diseases, and intestinal E. coli infections. MDD was also associated with disorders of lipid metabolism and ischemic heart disease. Their results indicated a causal link between MDD and a broad range of diseases, suggesting a notable burden of co-morbidity. The authors concluded that “early detection and management of MDD is important, and treatment strategies should be selected to also minimize the risk of related co-morbidities.” Further information on the shared mechanisms between coronary heart disease and depression in the UK Biobank ( n  = 367,703) was explored by Khandaker et al. [ 18 ]. They showed that family history of heart disease was associated with a 20% increase in depression risk; however, a genetic risk score that is strongly associated with CHD risk was not associated with depression. Their data indicate that comorbidity between depression and CHD arises largely from shared environmental factors.

In a systematic review and meta-analysis of cohort studies, Wang et al. examined the interface of depression and anxiety in relation to cancer incidence and mortality [ 19 ]. Their analyses suggest that depression and anxiety may have an etiologic role and prognostic impact on cancer, although there is potential reverse causality.

Several papers in this issue examine imaging in MDD, either to unravel the underlying disease processes or to identify imaging biomarkers of treatment response. Let us first look at the studies focused on elucidating brain circuitry alterations in MDD. Arterial spin labeling (ASL) was used by Cooper et al. to measure cerebral blood flow (CBF; perfusion) in order to discover and replicate alterations in CBF in MDD [ 20 ]. Their analyses revealed reduced relative CBF (rCBF) in the right parahippocampus, thalamus, fusiform, and middle temporal gyri, as well as the left and right insula, for those with MDD. They also revealed increased rCBF in MDD in both the left and the right inferior parietal lobule, including the supramarginal and angular gyri. According to the authors, “these results (1) provide reliable evidence for ASL in detecting differences in perfusion for multiple brain regions thought to be important in MDD, and (2) highlight the potential role of using perfusion as a biosignature of MDD.” Further data on imaging in MDD was provided by a coordinated analysis across 20 international cohorts in the ENIGMA MDD working group. In that paper, van Velzen et al. showed that in a coordinated and harmonized multisite diffusion tensor imaging study there were subtle, but widespread differences in white matter microstructure in adult MDD, which may suggest structural disconnectivity [ 21 ].

Four articles in this special issue examine imaging biomarkers of treatment response. Greenberg et al. studied reward-related ventral striatal activity and differential response to sertraline versus placebo in depressed using functional magnetic resonance imaging while performing a reward task [ 22 ]. They found that ventral striatum (VS) dynamic response to reward expectancy (expected outcome value) and prediction error (difference between expected and actual outcome), likely reflecting serotonergic and dopaminergic deficits, was associated with better response to sertraline than placebo. Their conclusion was that treatment measures of reward-related VS activity may serve as objective neural markers to advance efforts to personalize interventions by guiding individual-level choice of antidepressant treatment. Utilizing whole-brain functional connectivity analysis to identify neural signatures of remission following antidepressant treatment, and to identify connectomic predictors of treatment response, Korgaonkar et al. showed that intrinsic connectomes are a predictive biomarker of remission in major depressive disorder [ 23 ]. Based on their results that team proposed that increased functional connectivity within and between large-scale intrinsic brain networks may characterize acute recovery with antidepressants in depression. Repple et al. created connectome matrices via a combination of T1-weighted magnetic resonance imaging (MRI) and tractography methods based on diffusion-weighted imaging severity of current depression and remission status in 464 MDD patients and 432 healthy controls [ 24 ]. Reduced global fractional anisotropy (FA) was observed specifically in acute depressed patients compared to fully remitted patients and healthy controls. Within the MDD patients, FA in a subnetwork including frontal, temporal, insular, and parietal nodes was negatively associated with symptom intensity, an effect remaining when correcting for lifetime disease severity. Their findings provide new evidence of MDD to be associated with structural, yet dynamic, state-dependent connectome alterations, which covary with current disease severity and remission status after a depressive episode. The effects of electroconvulsive therapy (ECT), the most effective treatment for depression, on the dentate gyrus (DG) were studied by Nuninga et al. through an optimized MRI scan at 7-tesla field strength, allowing sensitive investigation of hippocampal subfields [ 25 , 26 ]. They documented a large and significant increase in DG volume after ECT, while other hippocampal subfields were unaffected. Furthermore, an increase in DG volume was related to a decrease in depression scores, and baseline DG volume predicted clinical response. These findings suggest that the volume change of the DG is related to the antidepressant properties of ECT, possibly reflecting neurogenesis.

Three articles report new directions for antidepressant therapeutics. Papakostas et al. presented the results of a promising phase 2, double-blind, placebo-controlled study of NSI-189 phosphate, a novel neurogenic compound, in MDD patients [ 27 ]. As the endogenous opioid system is thought to play an important role in the regulation of mood, Fava et al. studied the buprenorphine/samidorphan combination as an investigational opioid system modulator for adjunctive treatment of MDD in two phase 3, randomized, double-blind, placebo-controlled studies that utilized the same sequential parallel-comparison design [ 28 ]. One of the studies achieved the primary endpoint, namely change from baseline in Montgomery–Åsberg Depression Rating Scale (MADRS)-10 at week 5 versus placebo) and the other study did not achieve the primary endpoint. However, the pooled analysis of the two studies demonstrated consistently greater reduction in the MADRS-10 scores from baseline versus placebo at multiple timepoints, including end of treatment. These data provide cautious optimism and support further controlled trials for this potential new treatment option for patients with MDD who have an inadequate response to currently available antidepressants. Fava et al. also report the results of a double-blind, placebo-controlled, dose-ranging trial of intravenous (IV) ketamine as adjunctive therapy in treatment-resistant depression, using four doses of ketamine and a control [ 29 , 30 ]. They show that there was evidence for the efficacy of the two higher doses of IV ketamine and no clear or consistent evidence for clinically meaningful efficacy of the two lower doses studied.

Overall, in this issue, immense progress in depression research is provided by outstanding studies that highlight advances in our understanding of MDD biology, clinical features, co-morbidity, genetics, brain imaging (including imaging biomarkers), and treatment. Building on the groundbreaking articles from our previous 2020 special issues on stress and behavior [ 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 ] and on depression [ 2 , 3 , 4 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 , 58 , 59 , 60 , 61 , 62 ], we are proud that the stunning progress presented here found its home in our pages. From inception in 1996, we have aimed at making Molecular Psychiatry promote the integration of molecular medicine and clinical psychiatry [ 63 ]. It is particularly rewarding to see that goal achieved so spectacularly in this second 2020 special issue on MDD, a disorder of gene-environment interactions that represents a pressing public health challenge, with an ever increasing impact on society [ 64 , 65 , 66 ]. We are privileged to have in these two 2020 depression special issues four remarkable papers from Paul Greengard’s teams that provide substantial new data on the mechanisms of antidepressant action [ 1 , 2 , 3 , 4 ]. Such profound advances in basic science are needed to facilitate and guide future translational efforts needed to advance therapeutics [ 67 , 68 ].

Chottekalapanda R, et al. AP-1 controls the p11-dependent antidepressant response. Mol Psychiatry. 2020. https://doi.org/10.1038/s41380-020-0767-8 .

Sagi Y, et al. Emergence of 5-HT5A signaling in parvalbumin neurons mediates delayed antidepressant action. Mol Psychiatry. 2019. https://doi.org/10.1038/s41380-019-0379-3 .

Oh SJ, et al. Hippocampal mossy cell involvement in behavioral and neurogenic responses to chronic antidepressant treatment. Mol Psychiatry. 2019. https://doi.org/10.1038/s41380-019-0384-6 .

Shuto T, et al. Obligatory roles of dopamine D1 receptors in the dentate gyrus in antidepressant actions of a selective serotonin reuptake inhibitor, fluoxetine. Mol Psychiatry. 2018. https://doi.org/10.1038/s41380-018-0316-x .

Schouten M, et al. Circadian glucocorticoid oscillations preserve a population of adult hippocampal neural stem cells in the aging brain. Mol Psychiatry. 2019. https://doi.org/10.1038/s41380-019-0440-2 .

Kling MA, et al. Effects of electroconvulsive therapy on the CRH-ACTH-cortisol system in melancholic depression: preliminary findings. Psychopharmacol Bull. 1994;30:489–94.

CAS   PubMed   Google Scholar  

Sternberg EM, Licinio J. Overview of neuroimmune stress interactions. Implications for susceptibility to inflammatory disease. Ann NY Acad Sci. 1995;771:364–71.

Article   CAS   Google Scholar  

Bornstein SR, et al. Stress-inducible-stem cells: a new view on endocrine, metabolic and mental disease? Mol Psychiatry. 2019;24:2–9. https://doi.org/10.1038/s41380-018-0244-9 .

Article   CAS   PubMed   Google Scholar  

Rubin de Celis MF, et al. The effects of stress on brain and adrenal stem cells. Mol Psychiatry. 2016;21:590–3. https://doi.org/10.1038/mp.2015.230 .

Soares-Cunha C, et al. Nucleus accumbens medium spiny neurons subtypes signal both reward and aversion. Mol Psychiatry. 2019. https://doi.org/10.1038/s41380-019-0484-3 .

Pecina M, et al. Endogenous opioid system dysregulation in depression: implications for new therapeutic approaches. Mol Psychiatry. 2019;24:576–87, https://doi.org/10.1038/s41380-018-0117-2 .

Halikere A, et al. Addiction associated N40D mu-opioid receptor variant modulates synaptic function in human neurons. Mol Psychiatry. 2019. https://doi.org/10.1038/s41380-019-0507-0 .

Amare AT, et al. Bivariate genome-wide association analyses of the broad depression phenotype combined with major depressive disorder, bipolar disorder or schizophrenia reveal eight novel genetic loci for depression. Mol Psychiatry. 2019. https://doi.org/10.1038/s41380-018-0336-6 .

Coleman JRI, et al. Genome-wide gene-environment analyses of major depressive disorder and reported lifetime traumatic experiences in UK Biobank. Mol Psychiatry. 2020 https://doi.org/10.1038/s41380-019-0546-6 .

Belvederi Murri M, Amore M, Respino M, Alexopoulos GS. The symptom network structure of depressive symptoms in late-life: results from a European population study. Mol Psychiatry. 2018. https://doi.org/10.1038/s41380-018-0232-0 .

Article   PubMed   Google Scholar  

Simmons WK, et al. Appetite changes reveal depression subgroups with distinct endocrine, metabolic, and immune states. Mol Psychiatry. 2018. https://doi.org/10.1038/s41380-018-0093-6 .

Article   PubMed   PubMed Central   Google Scholar  

Mulugeta A, Zhou A, King C, Hypponen E. Association between major depressive disorder and multiple disease outcomes: a phenome-wide Mendelian randomisation study in the UK Biobank. Mol Psychiatry. 2019. https://doi.org/10.1038/s41380-019-0486-1 .

Khandaker GM, et al. Shared mechanisms between coronary heart disease and depression: findings from a large UK general population-based cohort. Mol Psychiatry. 2019. https://doi.org/10.1038/s41380-019-0395-3 .

Wang YH, et al. Depression and anxiety in relation to cancer incidence and mortality: a systematic review and meta-analysis of cohort studies. Mol Psychiatry. 2019. https://doi.org/10.1038/s41380-019-0595-x .

Cooper CM, et al. Discovery and replication of cerebral blood flow differences in major depressive disorder. Mol Psychiatry. 2019. https://doi.org/10.1038/s41380-019-0464-7 .

van Velzen LS, et al. White matter disturbances in major depressive disorder: a coordinated analysis across 20 international cohorts in the ENIGMA MDD working group. Mol Psychiatry. 2019. https://doi.org/10.1038/s41380-019-0477-2 .

Greenberg T, et al. Reward related ventral striatal activity and differential response to sertraline versus placebo in depressed individuals. Mol Psychiatry. 2019. https://doi.org/10.1038/s41380-019-0490-5 .

Korgaonkar MS, Goldstein-Piekarski AN, Fornito A & Williams, LM Intrinsic connectomes are a predictive biomarker of remission in major depressive disorder. Mol Psychiatry. 2019. https://doi.org/10.1038/s41380-019-0574-2 .

Repple J, et al. Severity of current depression and remission status are associated with structural connectome alterations in major depressive disorder. Mol Psychiatry. 2019. https://doi.org/10.1038/s41380-019-0603-1 .

Nuninga JO, et al. Volume increase in the dentate gyrus after electroconvulsive therapy in depressed patients as measured with 7T. Mol Psychiatry. 2019. https://doi.org/10.1038/s41380-019-0392-6 .

Koch SBJ, Morey RA & Roelofs K. The role of the dentate gyrus in stress-related disorders. Mol Psychiatry. 2019. https://doi.org/10.1038/s41380-019-0572-4 .

Papakostas GI, et al. A phase 2, double-blind, placebo-controlled study of NSI-189 phosphate, a neurogenic compound, among outpatients with major depressive disorder. Mol Psychiatry. 2019. https://doi.org/10.1038/s41380-018-0334-8 .

Fava M, et al . Opioid system modulation with buprenorphine/samidorphan combination for major depressive disorder: two randomized controlled studies. Mol Psychiatry. 2018. https://doi.org/10.1038/s41380-018-0284-1 .

Fava M, et al. Correction: double-blind, placebo-controlled, dose-ranging trial of intravenous ketamine as adjunctive therapy in treatment-resistant depression (TRD). Mol Psychiatry. 2019. https://doi.org/10.1038/s41380-018-0311-2 .

Fava M, et al. Double-blind, placebo-controlled, dose-ranging trial of intravenous ketamine as adjunctive therapy in treatment-resistant depression (TRD). Mol Psychiatry. 2018. https://doi.org/10.1038/s41380-018-0256-5 (2018).

Licinio J. Advances in research on stress and behavior: special issue, 2020. Mol Psychiatry 2020;25:916–7. https://doi.org/10.1038/s41380-020-0741-5 .

Martinez ME, et al. Thyroid hormone overexposure decreases DNA methylation in germ cells of newborn male mice. Mol Psychiatry. 2020;25:915 https://doi.org/10.1038/s41380-020-0732-6 .

Martinez ME, et al. Thyroid hormone influences brain gene expression programs and behaviors in later generations by altering germ line epigenetic information. Mol Psychiatry. 2020;25:939–50. https://doi.org/10.1038/s41380-018-0281-4 .

Le-Niculescu H, et al. Towards precision medicine for stress disorders: diagnostic biomarkers and targeted drugs. Mol Psychiatry. 2020;25:918–38. https://doi.org/10.1038/s41380-019-0370-z .

Torres-Berrio A, et al. MiR-218: a molecular switch and potential biomarker of susceptibility to stress. Mol Psychiatry. 2020;25:951–64. https://doi.org/10.1038/s41380-019-0421-5

Sillivan SE, et al. Correction: MicroRNA regulation of persistent stress-enhanced memory. Mol Psychiatry. 2020;25:1154 https://doi.org/10.1038/s41380-019-0452-y .

Sillivan SE, et al. MicroRNA regulation of persistent stress-enhanced memory. Mol Psychiatry. 2020;25:965–76. https://doi.org/10.1038/s41380-019-0432-2 .

Shi MM, et al. Hippocampal micro-opioid receptors on GABAergic neurons mediate stress-induced impairment of memory retrieval. Mol Psychiatry. 2020;25:977–92. https://doi.org/10.1038/s41380-019-0435-z .

Mayo LM, et al. Protective effects of elevated anandamide on stress and fear-related behaviors: translational evidence from humans and mice. Mol Psychiatry. 2020;25:993–1005. https://doi.org/10.1038/s41380-018-0215-1 .

Qu N, et al. A POMC-originated circuit regulates stress-induced hypophagia, depression, and anhedonia. Mol Psychiatry. 2020;25:1006–21. https://doi.org/10.1038/s41380-019-0506-1 .

Fox ME, et al. Dendritic remodeling of D1 neurons by RhoA/Rho-kinase mediates depression-like behavior. Mol Psychiatry. 2020;25:1022–34. https://doi.org/10.1038/s41380-018-0211-5 .

Jin J, et al. Ahnak scaffolds p11/Anxa2 complex and L-type voltage-gated calcium channel and modulates depressive behavior. Mol Psychiatry. 2020;25:1035–49. https://doi.org/10.1038/s41380-019-0371-y .

Ben-Yehuda H, et al. Maternal Type-I interferon signaling adversely affects the microglia and the behavior of the offspring accompanied by increased sensitivity to stress. Mol Psychiatry. 2020;25:1050–67. https://doi.org/10.1038/s41380-019-0604-0 .

Pearson-Leary J, et al. The gut microbiome regulates the increases in depressive-type behaviors and in inflammatory processes in the ventral hippocampus of stress vulnerable rats. Mol Psychiatry. 2020;25:1068–79. https://doi.org/10.1038/s41380-019-0380-x .

Walker WH 2nd, et al. Acute exposure to low-level light at night is sufficient to induce neurological changes and depressive-like behavior. Mol Psychiatry. 2020;25:1080–93. https://doi.org/10.1038/s41380-019-0430-4 .

Lei Y, et al. SIRT1 in forebrain excitatory neurons produces sexually dimorphic effects on depression-related behaviors and modulates neuronal excitability and synaptic transmission in the medial prefrontal cortex. Mol Psychiatry. 2020;25:1094–111. https://doi.org/10.1038/s41380-019-0352-1 .

Sargin D, et al. Mapping the physiological and molecular markers of stress and SSRI antidepressant treatment in S100a10 corticostriatal neurons. Mol Psychiatry. 2020;25:1112–29. https://doi.org/10.1038/s41380-019-0473-6 .

Article   Google Scholar  

Iob E, Kirschbaum C, Steptoe A. Persistent depressive symptoms, HPA-axis hyperactivity, and inflammation: the role of cognitive-affective and somatic symptoms. Mol Psychiatry. 2020;25:1130–40. https://doi.org/10.1038/s41380-019-0501-6 .

Cabeza de Baca T, et al. Chronic psychosocial and financial burden accelerates 5-year telomere shortening: findings from the Coronary Artery Risk Development in Young Adults Study. Mol Psychiatry. 2020;25:1141–53. https://doi.org/10.1038/s41380-019-0482-5 .

Licinio J & Wong ML. Advances in depression research: special issue, 2020, with three research articles by Paul Greengard. Mol Psychiatry. 2020;25:1156–58. https://doi.org/10.1038/s41380-020-0781-x .

Teissier A, et al. Early-life stress impairs postnatal oligodendrogenesis and adult emotional behaviour through activity-dependent mechanisms. Mol Psychiatry. 2019. https://doi.org/10.1038/s41380-019-0493-2 .

Zhang Y, et al. CircDYM ameliorates depressive-like behavior by targeting miR-9 to regulate microglial activation via HSP90 ubiquitination. Mol Psychiatry. 2018. https://doi.org/10.1038/s41380-018-0285-0 .

Tan A, et al. Effects of the KCNQ channel opener ezogabine on functional connectivity of the ventral striatum and clinical symptoms in patients with major depressive disorder. Mol Psychiatry. 2018. https://doi.org/10.1038/s41380-018-0283-2 .

Kin K, et al. Cell encapsulation enhances antidepressant effect of the mesenchymal stem cells and counteracts depressive-like behavior of treatment-resistant depressed rats. Mol Psychiatry. 2018. https://doi.org/10.1038/s41380-018-0208-0 .

Orrico-Sanchez A, et al. Antidepressant efficacy of a selective organic cation transporter blocker in a mouse model of depression. Mol Psychiatry. 2019. https://doi.org/10.1038/s41380-019-0548-4 .

Han Y, et al. Systemic immunization with altered myelin basic protein peptide produces sustained antidepressant-like effects. Mol Psychiatry. 2019. https://doi.org/10.1038/s41380-019-0470-9 .

Wittenberg GM, et al. Effects of immunomodulatory drugs on depressive symptoms: a mega-analysis of randomized, placebo-controlled clinical trials in inflammatory disorders. Mol Psychiatry. 2019. https://doi.org/10.1038/s41380-019-0471-8 .

Beydoun MA, et al. Systemic inflammation is associated with depressive symptoms differentially by sex and race: a longitudinal study of urban adults. Mol Psychiatry. 2019. https://doi.org/10.1038/s41380-019-0408-2 .

Felger JC, et al. What does plasma CRP tell us about peripheral and central inflammation in depression? Mol Psychiatry. 2018. https://doi.org/10.1038/s41380-018-0096-3 .

Clark SL, et al. A methylation study of long-term depression risk. Mol Psychiatry. 2019. https://doi.org/10.1038/s41380-019-0516-z .

Aberg KA, et al. Methylome-wide association findings for major depressive disorder overlap in blood and brain and replicate in independent brain samples. Mol Psychiatry. 2018. https://doi.org/10.1038/s41380-018-0247-6 .

Wei YB, et al. A functional variant in the serotonin receptor 7 gene (HTR7), rs7905446, is associated with good response to SSRIs in bipolar and unipolar depression. Mol Psychiatry. 2019. https://doi.org/10.1038/s41380-019-0397-1 .

Licinio J. Molecular Psychiatry: the integration of molecular medicine and clinical psychiatry. Mol Psychiatry. 1996;1:1–3.

Steenblock C, et al. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and the neuroendocrine stress axis. Mol Psychiatry. 2020. https://doi.org/10.1038/s41380-020-0758-9 .

Wong ML, Dong C, Andreev V, Arcos-Burgos M, Licinio J. Prediction of susceptibility to major depression by a model of interactions of multiple functional genetic variants and environmental factors. Mol Psychiatry. 2012;17:624–33. https://doi.org/10.1038/mp.2012.13 .

Article   CAS   PubMed   PubMed Central   Google Scholar  

Lee SH, Paz-Filho G, Mastronardi C, Licinio J, Wong ML. Is increased antidepressant exposure a contributory factor to the obesity pandemic? Transl Psychiatry. 2016;6:e759 https://doi.org/10.1038/tp.2016.25 .

Bornstein SR, Licinio J. Improving the efficacy of translational medicine by optimally integrating health care, academia and industry. Nat Med. 2011;17:1567–9. https://doi.org/10.1038/nm.2583 .

Licinio J, Wong ML. Launching the ‘war on mental illness’. Mol Psychiatry. 2014;19:1–5. https://doi.org/10.1038/mp.2013.180 .

Download references

Author information

Authors and affiliations.

State University of New York, Upstate Medical University, Syracuse, NY, 13210, USA

Julio Licinio & Ma-Li Wong

You can also search for this author in PubMed   Google Scholar

Corresponding author

Correspondence to Julio Licinio .

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Cite this article.

Licinio, J., Wong, ML. Advances in depression research: second special issue, 2020, with highlights on biological mechanisms, clinical features, co-morbidity, genetics, imaging, and treatment. Mol Psychiatry 25 , 1356–1360 (2020). https://doi.org/10.1038/s41380-020-0798-1

Download citation

Published : 18 June 2020

Issue Date : July 2020

DOI : https://doi.org/10.1038/s41380-020-0798-1

Share this article

Anyone you share the following link with will be able to read this content:

Sorry, a shareable link is not currently available for this article.

Provided by the Springer Nature SharedIt content-sharing initiative

This article is cited by

Upregulation of carbonic anhydrase 1 beneficial for depressive disorder.

Acta Neuropathologica Communications (2023)

Introducing a depression-like syndrome for translational neuropsychiatry: a plea for taxonomical validity and improved comparability between humans and mice

• Iven-Alex von Mücke-Heim
• Lidia Urbina-Treviño
• Jan M. Deussing

Molecular Psychiatry (2023)

Reply to: “The serotonin theory of depression: a systematic umbrella review of the evidence” published by Moncrieff J, Cooper RE, Stockmann T, Amendola S, Hengartner MP, Horowitz MA in Molecular Psychiatry (2022 Jul 20. doi: 10.1038/s41380-022-01661-0)

• Lucie Bartova
• Rupert Lanzenberger
• Siegfried Kasper

Is the serotonin hypothesis/theory of depression still relevant? Methodological reflections motivated by a recently published umbrella review

• Hans-Jürgen Möller
• Peter Falkai

European Archives of Psychiatry and Clinical Neuroscience (2023)

The heterogeneity of late-life depression and its pathobiology: a brain network dysfunction disorder

• Kurt A. Jellinger

Journal of Neural Transmission (2023)

Quick links

• Explore articles by subject
• Guide to authors
• Editorial policies

An official website of the United States government

The .gov means it’s official. Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

The site is secure. The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

• Publications
• Account settings

Preview improvements coming to the PMC website in October 2024. Learn More or Try it out now .

• Advanced Search
• Journal List
• Neurosci Bull
• v.37(6); 2021 Jun

Major Depressive Disorder: Advances in Neuroscience Research and Translational Applications

1 Clinical Research Center and Division of Mood Disorders of Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, 200030 China

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

Meihua Ruan

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

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

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

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

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

Current Situation of Research on Depression

Analysis of published papers.

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

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

Analysis of Patented Technology Application

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

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

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

Analysis of Clinical Trial

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

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

New Medicine Development

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

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

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

Epidemiology of Depression

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

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

Neurobiological Pathogenesis of Depressive Disorder

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

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

Stress-Responsive HPA Axis

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

Glutamate Signaling Pathway

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

Gamma-Aminobutyric Acid (GABA)

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

Neurotrophin Family

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

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

Neuroinflammation

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

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

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

Microbiome-Gut-Brain Axis

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

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

Other Systems and Pathways

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

Advances in Various Kinds of Research on Depressive Disorder

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

Genetic Studies

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

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

Brain Imaging and Neuroimaging Studies

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

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

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

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

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

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

The most important and promising studies were conducted by the ENIGMA (Enhancing NeuroImaging Genetics through Meta Analysis) Consortium, which investigated the human brain across 43 countries. The ENIGMA-MDD Working Group was launched in 2012 to detect the structural and functional changes associated with MDD reliably and replicate them in various samples around the world [ 128 ]. So far, the ENIGMA-MDD Working Group has collected data from 4,372 MDD patients and 9,788 healthy controls across 14 countries, including 45 cohorts [ 128 ]. Their findings to date are shown in Table ​ Table1 1 [ 128 – 137 ].

Findings of the ENIGMA (Enhancing NeuroImaging Genetics through Meta Analysis) Consortium.

Objective Index for Diagnosis of MDD

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

Management of Depression

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

Current Antidepressant Treatment

Antidepressants approved by the US Food and Drug Administration (FDA) are shown in Table ​ Table2. 2 . Due to the relatively limited understanding of the etiology and pathophysiology of depression, almost all the previous antidepressants were discovered by accident a few decades ago. Although most antidepressants are usually safe and effective, there are still some limitations, including delayed efficacy (usually 2 weeks) and side-effects that affect the treatment compliance [ 147 ]. In addition, <50% of all patients with depression show complete remission through optimized treatment, including trials of multiple drugs with and without simultaneous psychotherapy. In the past few decades, most antidepressant discoveries focused on finding faster, safer, and more selective serotonin or norepinephrine receptor targets. In addition, there is an urgent need to develop new approaches to obtain more effective, safer, and faster antidepressants. In 2019, the FDA approved two new antidepressants: Esketamine for refractory depression and Bresanolone for postpartum depression. Esmolamine, a derivative of the anesthetic drug ketamine, was approved by the FDA for the treatment of refractory depression, based on a large number of preliminary clinical studies [ 148 ]. For example, several randomized controlled trials and meta-analysis studies showed the efficacy and safety of Esketamine in depression or treatment-resistant depression [ 26 , 149 , 150 ]. Although both are groundbreaking new interventions for these debilitating diseases and both are approved for use only under medical supervision, there are still concerns about potential misuse and problems in the evaluation of mental disorders [ 151 ].

Antidepressants approved across the world.

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

Neuromodulation Therapy

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

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

Precision Medicine for Depression

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

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

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

Future Perspectives

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

Acknowledgments

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

Conflicts of interest

The authors declare no conflicts of interest.

Transforming the understanding and treatment of mental illnesses.

Información en español

Celebrating 75 Years! Learn More >>

• Science News
• Meetings and Events
• Social Media
• Press Resources
• Email Updates
• Innovation Speaker Series

Science News About Depression

August 21, 2024 • Research Highlight

NIMH-supported research suggests AI tools built on smartphone data may struggle to predict clinical outcomes like depression in large and diverse groups of people.

June 5, 2024 • Research Highlight

In a new neuroimaging study funded by the National Institute of Mental Health, researchers used repetitive transcranial magnetic stimulation to target regions deep in the brain to help reduce depression symptoms.

May 23, 2024 • Press Release

An NIMH-funded research consortium has produced the largest and most advanced multidimensional maps of gene regulation networks in the brains of people with and without mental disorders.

May 14, 2024 • Feature Story • 75th Anniversary

Decades of NIMH-supported basic research led to a pioneering treatment for postpartum depression and continues to power exciting advances in women's mental health care.

February 27, 2024 • Press Release

Results from a large clinical trial funded by the National Institutes of Health show that an intervention for anxiety provided to pregnant women living in Pakistan significantly reduced the likelihood of the women developing moderate-to-severe anxiety, depression, or both six weeks after birth.

December 18, 2023 • Research Highlight

This clinical trial found that MST is equally effective at reducing depression symptoms as ECT, but with fewer side effects.

October 27, 2023 • Feature Story • 75th Anniversary

NIMH supported science and NIMH researchers helped pave the way for the development of ketamine—a groundbreaking treatment that has improved the lives of those who are impacted by treatment-resistant depression.

June 16, 2023 • Research Highlight

In this NIMH-funded study, researchers examined how trauma gets passed from one generation to the next.

May 15, 2023 • Research Highlight

New NIMH-funded research tracked population-level rates of postpartum depression among new mothers before, during, and after pregnancy.

January 9, 2023 • Research Highlight

An NIMH-supported study suggests that a brief self-association training program can extend the effects of a single ketamine infusion by shifting people’s negative self-beliefs.

September 29, 2022 • Research Highlight

In a recent study supported by the National Institute of Mental Health, researchers examined the impact of a family-based intervention on suicide risk in youth and found risk-reduction benefits up to 10 years later.

May 9, 2022 • Research Highlight

NIMH-supported researchers have found an online mindfulness-based cognitive behavioral therapy—called Mindful Mood Balance—is effective at reducing residual depressive symptoms and at reducing suicidal ideation in those who experience these symptoms.

March 25, 2022 • Research Highlight

TMS can only directly stimulate the outermost layer of the brain, but NIMH researchers have found that mapping a person’s brain architecture may make it possible to guide TMS to deep brain targets.

February 28, 2022 • Research Highlight

A recent NIMH-supported study investigated whether deep brain stimulation could be personalized for individuals with treatment-resistant depression.

May 26, 2021 • Research Highlight

NIMH-supported researchers investigated suicide risk among women in the year before and year after giving birth.

April 15, 2021 • Research Highlight

NIMH is working to meet the urgent need for rapid-acting suicide prevention interventions by supporting research investigating the feasibility and safety of treatment protocols that have the potential to quickly reduce severe suicide risk in youth and adults.

February 9, 2021 • Press Release

A new study conducted by researchers at NIMH suggests that differences in the expression of gene transcripts – readouts copied from DNA that help maintain and build our cells – may hold the key to understanding how mental disorders with shared genetic risk factors result in different patterns of onset, symptoms, course of illness, and treatment responses.

October 29, 2020 • Research Highlight

In a project funded by the NIMH Small Business Technology Transfer program, researchers are investigating whether mobile technology can be used to create a passive monitoring system that can predict teens’ depressive symptoms and improve the quality of their care.

October 22, 2020 • Institute Update

Carlos Zarate Jr., M.D., chief of the Experimental Therapeutics and Pathophysiology Branch within the NIMH Intramural Research Program, has been elected to the National Academy of Medicine.

April 20, 2020 • Press Release

Researchers investigating how temperament shapes adult life-course outcomes have found that behavioral inhibition in infancy predicts a reserved, introverted personality at age 26 and for some, a risk of internalizing psychopathology such as anxiety and depression.

March 30, 2020 • Press Release

An innovative NIMH-funded trial shows that a receptor involved in the brain’s reward system may be a viable target for treating anhedonia (or lack of pleasure), a key symptom of several mood and anxiety disorders.

February 25, 2020 • Research Highlight

For many adults who have a mental disorder, symptoms were present—but often not recognized or addressed—in childhood and adolescence. Early treatment can help prevent more severe, lasting impairment or disability as a child grows up.

The use of right unilateral ultrabrief pulse (RUL-UB) electroconvulsive therapy (ECT) in combination with the antidepressant venlafaxine to treat depression in elderly patients is well tolerated and results in minimal neurocognitive side effects, according to a new NIH-funded study published in the American Journal of Geriatric Psychiatry.

February 10, 2020 • Press Release

NIH-funded research uses machine learning algorithm to predict individual response to a commonly-prescribed antidepressant.

November 18, 2019 • Press Release

A single, low-dose ketamine infusion was relatively free of side effects for patients with treatment-resistant depression.

October 2, 2019 • Press Release

Researchers have uncovered sex-based differences in the development of the hippocampus and amygdala—brain areas that have been implicated in the biology of several mental disorders that impact males and females differently.

September 3, 2019 • Institute Update

Mental health research center directors emerged from a recent meeting with a renewed commitment to help each other achieve their common mission – to transform care of children, adolescents and adults with severe psychiatric disorders.

April 29, 2019 • Press Release

A study conducted by researchers at several universities, hospitals, and the National Institute of Mental Health (NIMH) found that the Netflix show “13 Reasons Why” was associated with a 28.9% increase in suicide rates among U.S. youth ages 10-17 in the month (April 2017) following the shows release, after accounting for ongoing trends in suicide rates.

The National Institutes of Health invites students ages 16 to 18 years old to participate in the “Speaking Up About Mental Health!” essay contest to explore ways to address the stigma and social barriers that adolescents from racial and ethnic minority populations may face when seeking mental health treatment.

April 11, 2019 • Press Release

Researchers have identified ketamine-induced brain-related changes that are responsible for maintaining the remission of behaviors related to depression in mice — findings that may help researchers develop interventions that promote lasting remission of depression in humans.

March 19, 2019 • Media Advisory

FDA approval of the postpartum depression treatment brexanolone represents the final phase of a bench-to-bedside journey for this drug — a journey that began in the NIMH Intramural Research Program. NIMH experts are available to provide information on postpartum depression and the importance of, and the science underlying, this new drug.

March 13, 2019 • Press Release

Researchers have identified changes in brain connectivity and brain activity during rest and reward anticipation in children with anhedonia, a condition where people lose interest and pleasure in activities they used to enjoy.

March 11, 2019 • Press Release

A research team found nearly one-third of youth ages 10 to 12 years screened positive for suicide risk in emergency department settings, including those seeking help for physical concerns only.

December 13, 2018 • Science Update

A new study looking at interactions among sleep, energy, activity level, and mood suggests that instability in activity and sleep systems could lead to mood changes. The findings suggest new targets for depression treatment.

June 20, 2018 • Press Release

Researchers funded by the National Institutes of Health have shown that a therapy-based treatment for disruptive behavioral disorders can be adapted and used as an effective treatment option for early childhood depression.

April 16, 2018 • Institute Update

On May 3, 2018, join NIMH for a Twitter chat on teen depression with experts Dr. Argyris Stringaris and Dr. Ken Towbin.

March 1, 2018 • Science Update

Depression, schizophrenia and autism spectrum disorder share some of the same patterns of suspect gene expression – molecular signatures.

February 13, 2018 • Science Update

On February 20, 2018, join NIMH for a Twitter chat on Seasonal Affective Disorder with expert Dr. Matthew Rudorfer.

November 2, 2017 • Press Release

Using a molecular method likely to become widely adopted by the field, researchers have discovered brain circuitry essential for alertness – and for brain states more generally.

August 28, 2017 • Science Update

Brain gene expression associated with depression differed markedly between men and women. Such divergent “transcriptional signatures” may signal divergent underlying illness processes requiring sex-specific treatments.

July 20, 2017 • Institute Update

This November 2016 RDoC webinar highlights the role of fear and anxiety in disorders such as phobias and depression.

May 31, 2017 • Science Update

NIMH grantee Karl Deisseroth, M.D., Ph.D., of Stanford University, has been awarded one of science’s most generous prizes. A German foundation presented the inventor of technologies that are transforming neuroscience with its 4 million euros Fresenius Prize.

A streamlined behavioral therapy delivered in a pediatrics practice offered much greater benefit to youth with anxiety and depression than a more standard referral to mental health care with follow-up in a clinical trial comparing the two approaches.

April 19, 2017 • Science Update

Brain scans reveal that fluctuations in estrogen can trigger atypical functioning in a key brain memory circuit in women with a common version of a gene. Since working memory function is often disturbed in mental disorders, such gene-hormone interactions are suspect mechanisms that may confer risk.

August 1, 2016 • Press Release

Scientists have discovered 15 genome sites – the first ever – linked to depression in people of European ancestry. But – in a twist – the researchers didn’t have to sequence anyone’s genes! Instead, they analyzed data already shared by people who had purchased their own genetic profiles via an online service and elected to participate in its research option.

July 18, 2016 • Science Update

An individualized program of follow-up treatment with electroconvulsive therapy (ECT) combined with an antidepressant was effective in preventing relapse in patients 60 years and older who had had a successful initial course of treatment for severe depression.

June 16, 2016 • Live Chat

A live Twitter chat discussing African American men’s mental health.

May 4, 2016 • Press Release

A chemical byproduct, or metabolite, created as the body breaks down likely holds the secret to its rapid antidepressant action .

March 17, 2016 • Science Update

On March 17, 2016, NIMH hosts a Facebook Q&A on electroconvulsive therapy with expert Dr. Sarah Lisanby.

February 19, 2016 • Science Update

Is mobile mental health research the next frontier for smartphones? Based on Dr. Patricia Areán’s pioneering BRIGHTEN study, research via smartphone app is already a reality.

August 12, 2015 • Science Update

View the archived webinars with NIMH experts and grantees, which focus on training, research, and methodology

July 16, 2015 • Science Update

A new video about postpartum depression marks the launch of a mental health education collaboration by two NIH Institutes and one of the nation’s largest African-American women’s organizations.

July 14, 2015 • Live Chat

NIMH and NCI host a Twitter chat on how patients and caregivers, across all ages, can deal with the psychological impact of cancer.

January 29, 2015 • Science Update

Risk genes for different mental disorders work through same pathways

November 5, 2014 • Live Chat

NIMH Twitter Chat on Men and Depression

October 17, 2014 • Press Release

A drug being studied as a fast-acting mood-lifter restored pleasure-seeking behavior independent of – and ahead of – its other antidepressant effects.

October 2, 2014 • Science Update

NIMH Twitter Chat on Depression and the Development of Novel Medications

July 29, 2014 • Science Update

NIMH Twitter Chat on Premenstrual Dysphoric Disorder

June 10, 2014 • Science Update

May 5, 2014 • Science Update

NIMH Twitter Chat on Postpartum Depression

April 17, 2014 • Press Release

Scientists have traced vulnerability to depression-like behaviors to out-of-balance neuronal electrical activity and made mice resilient by reversing it.

March 11, 2014 • Science Update

Girls in public housing benefited emotionally from a move to a better neighborhood while boys fared worse than if they’d stayed in the poor neighborhood. Rates of depression and conduct disorder markedly increased in boys and decreased in girls. Boys also experienced significantly increased rates of post-traumatic stress disorder (PTSD), complicating housing policy decision-making.

• Depression in Children
• Depression in Teens
• Depression in College
• Depression in Women
• Depression in Men
• Depression in Older People
• How Is Depression Diagnosed?
• Related Conditions
• What Are the Different Types of Depression?
• Mild Depression
• Major Depressive Disorder
• Overview of Treatment
• Psychotherapy
• Complementary & Alternative Therapy
• Overview of Antidepressants
• Selective Serotonin Reuptake Inhibitors (SSRIs)
• Tricyclic and Tetracyclic Antidepressants (TCAs)
• Side Effects
• Treatment-Resistant Depression (TRD)
• Family & Relationships
• Diet & Exercise
• Complications
• Support & Resources
• Appointment Prep
• View Full Guide

Depression: The Latest Research

If you’re one of more than 17 million adults or 3.2 million teens in the United States with major depression, you may know that treatment often falls short. The latest research on this common mental health disorder, also called clinical depression , aims to help you feel better faster, and with fewer side effects.

Right now, doctors don’t have a precise way to tell which medication is best for you. That’s part of the reason that many people with depression have to try more than one drug before they feel better.

Most antidepressants , the type of drug doctors often use to treat depression, take weeks to months to work. That means a lot of time can pass before you know if the treatment helps your symptoms. And, about 30% of people don’t feel better even after trying several medications. Doctors call this treatment-resistant depression.

Because this trial-and-error process takes time -- and sometimes doesn’t work -- depression can continue to affect your ability to live your life.

Recent numbers from the National Institute of Mental Health show that depression causes major distress and life disruption for more 63% of adults and more than 70% of teens with the disorder. Depression can also lead you to think more about or to attempt suicide.

Here’s a look at what researchers are studying now and how their work may help you if you have depression.

Fast-Acting Antidepressants

Fast-acting antidepressants can work in hours to help you feel better if you have depression or suicidal thoughts . The FDA in 2019 approved the first, a nasal spray called esketamine for treatment-resistant depression. A year later the FDA approved it for depression that includes suicidal thinking.

Esketamine, which you might take with a traditional antidepressant, is made from an older medication called ketamine. Doctors first used ketamine years ago as an anesthetic, a drug used to put people to sleep.

Ketamine can also rapidly improve depression but can cause serious side effects. These include out-of-body experiences and hallucinations . Some people abuse ketamine.

Esketamine can cause similar side effects and abuse problems. However, a 2021 review of studies published in Frontiers in Neuroscience reported that its effects are usually mild to moderate and don’t last long.

Scientists think esketamine improves depression by raising levels of glutamate, a chemical that helps brain cells communicate. Researchers are studying a number of newer agents that work on glutamate or on GABA, another of your brain’s chemical messengers. Scientists hope they may have fewer side effects than current options.

The FDA has given breakthrough therapy status to several experimental fast-acting antidepressants. The agency gives this status to speed development of drugs that may be able to outperform available treatments for serious conditions like depression.

More Exact Antidepressant Selection

Right now, doctors rely mostly on guesswork to choose your antidepressant. The latest research may give them tools that can help them pick the best treatment for individuals. Tests and tools that may cut down on trial and error in antidepressant treatment include:

Blood tests. Recent studies show blood tests that measure levels of certain proteins can predict whether particular antidepressants are likely to relieve your symptoms.

Gene tests. Tests for certain genes and how they affect your body’s response to specific drugs may help guide your doctor to the best treatment for you. In one recent study, people who took a 10-gene test to help direct treatment choice got better more often than those whose treatment was chosen without the test.

Brain imaging. Researchers are testing SPECT (single positron emission computed tomography ) and PET (positron emission tomography) to see if these imaging tools can help doctors choose the right drug for you. They show activity in different areas of your brain.

A recent review of studies found that using PET to look at how the brain uses glucose, or sugar, could help predict whether an antidepressant would improve a person’s depression.

Artificial intelligence (AI) that reads brain scans. Some scientists hope to treat depression with AI programs that can find patterns in EEG ( electroencephalogram ) scans. These scans measure your brain’s electrical activity. A 2020 Nature Biotechnology study found that an AI program could use a person’s EEG data to predict whether the most common type of antidepressant would work for them.

Causes of Depression

New knowledge about the causes of depression could open the door to new treatments. These biological processes may play a role:

Inflammation.   Inflammation is your body’s natural defense against infections and injury. But when it happens when it shouldn’t or gets out of control it can lead to or worsen many different diseases. Depression is one of them, according to the latest research.

In the largest-ever study of depression and inflammation, published in 2021 in the American Journal of Psychiatry , scientists confirmed the link between the two. They found people with depression had more inflammation than those without the mental health disorder. This was true even after scientists accounted for other factors involved in depression.

This means that medications that lower inflammation may be helpful add-ons to antidepressant treatment. Lifestyle changes that can reduce inflammation, such as exercise and a healthy diet, may also help improve symptoms of depression .

The gut-brain connection . You’ve got trillions of bacteria and microorganisms, or microbes, in your gut. Some are helpful and some can be harmful. When the balance isn’t right, it can add to health problems, including depression and inflammation.

Some of the latest research has found that probiotics, which can give you a better balance of gut microbes, may also ease symptoms of depression. Probiotics are living bacteria found in fermented foods like yogurt or in supplements . They have few side effects.

Scientists need to learn more about how probiotics work in people with depression. Some studies find they work best when you use them along with antidepressant drugs. Research also suggests different strains, or types, of probiotics may help with different symptoms of depression.

In the meantime, it’s probably safe to try a probiotic for a month to see if it improves your mood. Just don’t stop any of your prescribed medications without the OK from your doctor.

Top doctors in ,

Find more top doctors on, related links.

• Depression News
• Depression Reference
• Depression Slideshows
• Depression Quizzes
• Depression Blogs
• Depression Videos
• Depression Medications
• Find a Psychiatrist
• Anxiety & Panic Disorders
• Binge Eating Disorder
• Bipolar Disorder
• Crisis Assistance
• Mental Health
• Pain Management
• Pill Identifier
• Postpartum Depression
• Stress Management
• Substance Abuse & Addiction
• More Related Topics

FDA Approves Rapid-Acting Oral Antidepressant

Information & authors, metrics & citations, view options.

Auvelity Offers Rapid Depression Relief, Trials Suggest

Who will benefit most from auvelity, information, published in.

• major depression
• treatment-resistant depression
• antidepressant
• rapid acting antidepressant
• dextromethorphan
• cough suppressant
• Food and Drug Administration
• clinical trial
• NMDA receptor
• CYP26 enzyme
• rational drug design
• side effects
• Dan Iosifescu
• James Murrough
• Alan Schatzberg
• American Journal of Psychiatry

Export Citations

If you have the appropriate software installed, you can download article citation data to the citation manager of your choice. Simply select your manager software from the list below and click Download. For more information or tips please see 'Downloading to a citation manager' in the Help menu .

To download the citation to this article, select your reference manager software.

There are no citations for this item

View options

Login options.

Already a subscriber? Access your subscription through your login credentials or your institution for full access to this article.

Not a subscriber?

Subscribe Now / Learn More

PsychiatryOnline subscription options offer access to the DSM-5-TR ® library, books, journals, CME, and patient resources. This all-in-one virtual library provides psychiatrists and mental health professionals with key resources for diagnosis, treatment, research, and professional development.

Need more help? PsychiatryOnline Customer Service may be reached by emailing [email protected] or by calling 800-368-5777 (in the U.S.) or 703-907-7322 (outside the U.S.).

Share article link

Copying failed.

PREVIOUS ARTICLE

Next article, request username.

Can't sign in? Forgot your username? Enter your email address below and we will send you your username

If the address matches an existing account you will receive an email with instructions to retrieve your username

Create a new account

Change password, password changed successfully.

Your password has been changed

Reset password

Can't sign in? Forgot your password?

Enter your email address below and we will send you the reset instructions

If the address matches an existing account you will receive an email with instructions to reset your password.

Your Phone has been verified

As described within the American Psychiatric Association (APA)'s Privacy Policy and Terms of Use , this website utilizes cookies, including for the purpose of offering an optimal online experience and services tailored to your preferences. Please read the entire Privacy Policy and Terms of Use. By closing this message, browsing this website, continuing the navigation, or otherwise continuing to use the APA's websites, you confirm that you understand and accept the terms of the Privacy Policy and Terms of Use, including the utilization of cookies.

• See us on facebook
• See us on twitter
• See us on youtube
• See us on linkedin
• See us on instagram

Stanford Medicine-led research identifies a subtype of depression

Using surveys, cognitive tests and brain imaging, researchers have identified a type of depression that affects about a quarter of patients. The goal is to diagnose and treat the condition more precisely.

June 22, 2023 - By Emily Moskal

Knowing what type of depression a patient has can help clinicians provide the best treatment. Yurchanka Siarhei/Shutterstock.com

Scientists at Stanford Medicine conducted a study describing a new category of depression — labeled the cognitive biotype — which accounts for 27% of depressed patients and is not effectively treated by commonly prescribed antidepressants.

Cognitive tasks showed that these patients have difficulty with the ability to plan ahead, display self-control, sustain focus despite distractions and suppress inappropriate behavior; imaging showed decreased activity in two brain regions responsible for those tasks.

Because depression has traditionally been defined as a mood disorder, doctors commonly prescribe antidepressants that target serotonin (known as selective serotonin reuptake inhibitors or SSRIs), but these are less effective for patients with cognitive dysfunction. Researchers said that targeting these cognitive dysfunctions with less commonly used antidepressants or other treatments may alleviate symptoms and help restore social and occupational abilities.

The study , published June 15 in JAMA Network Open , is part of a broader effort by neuroscientists to find treatments that target depression biotypes, according to the study’s senior author, Leanne Williams , PhD, the Vincent V.C. Woo Professor and professor of psychiatry and behavioral sciences.

“One of the big challenges is to find a new way to address what is currently a trial-and-error process so that more people can get better sooner,” Williams said. “Bringing in these objective cognitive measures like imaging will make sure we’re not using the same treatment on every patient.”

Finding the biotype

In the study, 1,008 adults with previously unmedicated major depressive disorder were randomly given one of three widely prescribed typical antidepressants: escitalopram (brand name Lexapro) or sertraline (Zoloft), which act on serotonin, or venlafaxine-XR (Effexor), which acts on both serotonin and norepinephrine. Seven hundred and twelve of the participants completed the eight-week regimen.

Leanne Williams

Before and after treatment with the antidepressants, the participants’ depressive symptoms were measured using two surveys one, clinician-administered, and the other, a self-assessment, which include questions related to changes in sleep and eating. Measures on social and occupation functioning, as well as quality of life, were tracked as well.

The participants also completed a series of cognitive tests, before and after treatment, measuring verbal memory, working memory, decision speed and sustained attention, among other tasks.

Before treatment, scientists scanned 96 of the participants using functional magnetic resonance imaging as they engaged in a task called the “GoNoGo” that requires participants to press a button as quickly as possible when they see “Go” in green and to not press when they see “NoGo” in red. The fMRI tracked neuronal activity by measuring changes in blood oxygen levels, which showed levels of activity in different brain regions corresponding to Go or NoGo responses. Researchers then compared the participants’ images with those of individuals without depression.

The researchers found that 27% of the participants had more prominent symptoms of cognitive slowing and insomnia, impaired cognitive function on behavioral tests, as well as reduced activity in certain frontal brain regions — a profile they labeled the cognitive biotype.  

“This study is crucial because psychiatrists have few measurement tools for depression to help make treatment decisions,” said Laura Hack , MD, PhD, the lead author of the study and an assistant professor of psychiatry and behavioral sciences. “It’s mostly making observations and self-report measures. Imaging while performing cognitive tasks is rather novel in depression treatment studies.”

Pre-treatment fMRI showed those with the cognitive biotype had significantly reduced activity in the dorsolateral prefrontal cortex and dorsal anterior cingulate regions during the GoNoGo task compared with the activity levels in participants who did not have the cognitive biotype. Together, the two regions form the cognitive control circuit, which is responsible for limiting unwanted or irrelevant thoughts and responses and improving goal selection, among other tasks.

After treatment, the researchers found that for the three antidepressants administered, the overall remission rates — the absence of overall depression symptoms — were 38.8% for participants with the newly discovered biotype and 47.7% for those without it. This difference was most prominent for sertraline, for which the remission rates were 35.9% and 50% for those with the biotype and those without, respectively.

“Depression presents in different ways in different people, but finding commonalities — like similar profiles of brain function — helps medical professionals effectively treat participants by individualizing care,” Williams said.

Depression isn’t one size fits all

Williams and Hack propose that behavior measurement and imaging could help diagnose depression biotypes and lead to better treatment. A patient could complete a survey on their own computer or in the doctor’s office, and if they are found to display a certain biotype, they might be referred to imaging for confirmation before undergoing treatment.

Researchers at the Stanford Center for Precision Mental Health and Wellness , which Williams directs, in partnership with the Stanford Translational Precision Mental Health Clinic, which Hack directs, are studying another medication — guanfacine — that specifically targets the dorsolateral prefrontal cortex region with support from Stanford University Innovative Medicines Accelerator . They believe this treatment could be more effective for patients with the cognitive subtype.

Williams and Hack hope to conduct studies with participants who have the cognitive biotype, comparing different types of medication with treatments such as transcranial magnetic stimulation and cognitive behavioral therapy. In transcranial magnetic stimulation, commonly referred to as TMS, magnetic fields stimulate nerve cells; in cognitive behavioral therapy, patients are taught to use problem-solving strategies to counter negative thoughts that contribute to both emotional dysregulation and loss of social and occupational abilities.

“I regularly witness the suffering, the loss of hope and the increase in suicidality that occurs when people are going through our trial-and-error process,” Hack said. “And it’s because we start with medications that have the same mechanism of action for everyone with depression, even though depression is quite heterogeneous. I think this study could help change that.”

Researchers from the Sierra-Pacific Mental Illness Research, Education and Clinical Center; the Veterans Affairs Palo Alto Health Care System; Brain Dynamic Centre, Westmead Institute for Medical Research; and the University of Sydney, Westmead, contributed to the work.

The study was funded through Brain Resource Company Operations Pty Ltd. and Stanford University’s Clinical and Translation Science Award Program overseen by the National Center for Advancing Translational Sciences at the National Institutes of Health (grant UL1TR003142-01).

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 .

The majestic cell

How the smallest units of life determine our health

• Latest news
• UCL in the media
• Services for media
• Student news
• Tell us your story

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

20 July 2022

Writing in The Conversation, Professor Joanna Moncrieff and Dr Mark Horowitz (both UCL Psychiatry) report on their new research showing no clear evidence that serotonin levels or serotonin activity are responsible for depression.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

This article originally appeared in  The Conversation on 20 July 2022.

• Article in  The Conversation
• Article in  The Conversation  (Spanish)
• Professor Joanna Moncrieff's academic profile
• Dr Mark Horowitz's academic profile
• UCL Division of Psychiatry
• UCL Faculty of Brain Sciences

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

• Find a Therapist
• Find a Treatment Center
• Find a Psychiatrist
• Find a Support Group
• Find Online Therapy
• United States
• Brooklyn, NY
• Chicago, IL
• Houston, TX
• Los Angeles, CA
• New York, NY
• Portland, OR
• San Diego, CA
• San Francisco, CA
• Seattle, WA
• Washington, DC
• Asperger's
• Bipolar Disorder
• Chronic Pain
• Eating Disorders
• Passive Aggression
• Personality
• Goal Setting
• Positive Psychology
• Stopping Smoking
• Low Sexual Desire
• Relationships
• Child Development
• Self Tests NEW
• Therapy Center
• Diagnosis Dictionary
• Types of Therapy

Sticking up for yourself is no easy task. But there are concrete skills you can use to hone your assertiveness and advocate for yourself.

• Emotional Intelligence
• Gaslighting
• Affective Forecasting
• Neuroscience

• Latest Latest
• The West The West
• Sports Sports
• Opinion Opinion
• Magazine Magazine

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

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

By Lois M. Collins

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

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

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

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

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

Experts are divided and the study has drawn some pushback.

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

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

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

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

Targeting serotonin

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

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

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

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

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

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

Study nuts and bolts

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

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

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

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

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

Public perception

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

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

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

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

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

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

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

Some experts disagree

The research has attracted some pushback.

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

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

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

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

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

Advertisement

• Register for Free
• My account Orders Downloads Address Payment methods Account details
• About About Psychiatrist.com About JCP About PCC About CME Institute

Error: Search field were incomplete.

Study Reveals Differences Between Psilocybin, Escitalopram in Depression Treatment

by Denis Storey August 30, 2024 at 7:46 AM UTC

Clinical relevance: New research explores how psilocybin therapy and escitalopram alter brain dynamics in different ways to treat major depressive disorder (MDD).

• A double-blind, phase II trial with nearly four dozen MDD patients used fMRI scans to assess brain hierarchy changes after psilocybin or escitalopram treatment.
• Psilocybin flattens brain hierarchy, promoting decentralized organization, while escitalopram reinforces top-down control mechanisms, stabilizing brain function.
• The study highlights distinct mechanisms of antidepressants, suggesting personalized treatments and reinforcing the role of brain hierarchy in neuropsychiatric disorders.

New research offers fresh insights into how different major depressive disorder (MDD) treatments can transform brain dynamics. More specifically, this paper – appearing in Nature Mental Health – compares how psilocybin therapy and escitalopram alter the brain’s functional hierarchical organization to treat depression. The results of the double-blind, phase II randomized controlled trial suggest that recalibrating the brain’s hierarchical structure could help with neuropsychiatric disorders beyond MDD.

Methodology

The research project included nearly four dozen patients diagnosed with MDD, who the researchers randomly assigned to one of two treatment groups.

• The first, comprising 22 patients, received two doses of 25 mg oral psilocybin, spaced three weeks apart. Researchers also administered a daily placebo for six weeks.
• The second group, made up of another 20 patients, received two doses of 1 mg psilocybin, also three weeks apart, alongside a daily dose of escitalopram (10-20 mg) over the same period.

The researchers designed the study to assess the influence these treatments might have on brain dynamics. To do that, the team relied on resting-state functional magnetic resonance imaging (fMRI) scans taken at the start of the trial and again three weeks after the final psilocybin dose.

Investigating Brain Hierarchy

Researchers zeroed in on how these treatments influenced the mind’s functional hierarchy — a concept that refers to the organization of regions from top to bottom in terms of the level of control over general brain activity. Scientists argue that this hierarchical structure remains a critical component of healthy brain operations. Consequently, any disruptions to this hierarchy can lead to neuropsychiatric problems – such as depression.

To quantify changes in brain hierarchy, the study’s authors relied on a technique dubbed generative effective connectivity (GEC), which models whole-brain dynamics. By assessing the direction and strength of cerebral connections, the researchers isolated where each region of the brain fit with the overall hierarchy. The team then used what it called “measures of directedness and trophic levels — a concept lifted from ecological studies that indicate a node’s position in a network — to track changes in the brain’s dynamics.

Psilocybin vs. Escitalopram vs. Depression

The researchers found that psilocybin and escitalopram led to dramatically different reconfigurations of the brain’s hierarchy. Psilocybin treatment typically causes a flattening of the brain’s hierarchical structure, marked by reduced directedness and less pronounced differences in trophic levels across brain regions. The authors interpreted this as a shift toward a more decentralized brain organization, which aligns with earlier theories that psychedelics can disrupt rigid, top-down control mechanisms in the brain. This, of course, allows for more malleable, bottom-up processing.

Conversely, the authors noted that escitalopram treatment led to an uptick in the brain’s hierarchical directedness. This, they insisted,  implies that the treatment reinforced the top-down control mechanisms within the brain, potentially stabilizing the brain’s functional organization in a way that supports more controlled and consistent brain activity.

The researchers also leveraged machine learning to break down the patterns of hierarchical reconfiguration before and after the treatment.

Notably, the team observed that the machine learning models could predict treatment outcomes with 86 percent accuracy. This reinforced the authors’ argument that artificial intelligence can help caregivers mold treatment to someone’s brain dynamics.

Implications for Depression Treatment

The results only add to the mounting body of work that shows that various antidepressant treatments work through distinct mechanisms at the level of brain dynamics. Psilocybin’s effect on leveling brain hierarchy might offer a novel approach to treating patients resistant to more traditional pharmaceutical treatments, such as SSRIs, which appear to buttress the existing hierarchical framework.

The research also supports the theory that neuropsychiatric disorders – such as depression – could be tied directly to interference with the brain’s hierarchy. By addressing that, these treatments could help restore healthy brain functions – just a little bit differently.

While the researchers found the results encouraging, they added that future research would be necessary to replicate these findings in larger populations.

Either way, this study illustrates a new way of understanding how different treatments can reconfigure brain dynamics in depression, offering hope for more targeted and effective therapies.

Original Research

Perinatal Timing of Obsessive-Compulsive Disorder Onset

Findings show that OCD is most likely to begin in the early postpartum, with a rapid transition from symptoms to disorder. People with pre-existing OCD are vulnerable to symptom exacerbation postpartum, and in those without pre-existing OCD, onset can occur up to 8 months postpar...

Nichole Fairbrother and others

Case Report

Adalimumab-Associated Depressive Symptoms in a Patient With Vasculitis, Autoinflammation, Immunodeficiency, and Hematologic Defects Syndrome

A 16-year-old boy with vasculitis, autoinflammation, immunodeficiency, and hematologic defects syndrome, who was taking adalimumab, presented with features of depression.

Prabin Pradeep and others

Search Articles

Related articles, table of contents.

Danish research discovers significant depression-risk interaction between personality and brain chemistry

By Henrik Larsen

This discovery advances our understanding of the causes of major depressive disorder and indicates the need to target novel therapies. “These could include a combination of psychedelic compounds and psychotherapy,” says head of the Danish research project, Professor Vibe Frøkjær.

A Danish research team is the first to demonstrate that healthy individuals with a specific brain chemistry and psychological profile have a long-term risk for developing major depressive disorder.

This discovery has just been published in Nature Mental Health , one of the world’s most important scientific journals. The study was conducted by researchers from Rigshospitalet, University of Copenhagen and Mental Health Services in the Capital Region of Denmark.

The Nature article reveals that otherwise healthy individuals, oblivious to the existence of this threat to their mental health, are at high risk for depression stemming from an interaction between two factors:

Psychologically, a personality profile characterised by high neuroticism, including pronounced anxiety, self-consciousness and a low threshold for enduring stress.

Brain chemistry, involving receptors which mediate the brain’s internal communication by means of serotonin (serotoni n2A receptor type in particular), a signalling substance.

“When these personality and brain chemistry factors are present at the same time in an individual, their long-term risk for major depression increases. This is what we have been able to demonstrate,” explains Frøkjær, Professor in Neuropsychiatry at the Neurobiology Research Unit (NRU) at Rigshospitalet and Mental Health Services, Capital Region of Denmark. Frøkjær headed up the team that published the Nature article, and received research funding from the Lundbeck Foundation and Innovation Fund Denmark.

This discovery advances our understanding of major depressive disorder, which is very promising,” says Professor Frøkjær, adding: 

“Anyone can develop depression, and in some cases, it appears to come on with no warning. But the better we understand the complex interactions of psychological and brain chemistry factors underlying depression, the better we’ll be able to treat and prevent this mental disorder. Our discovery also points to the necessity in some cases of being open to 

using new modes of treatment for depression. These could include a combination of psychotherapy and psychedelic compounds such as psilocybin. This is another important finding we made,” explains Frøkjær.

The Nature article is based on brain research data from 131 Danes, who in the period 2000-2008 were recruited as healthy participants for studies at Rigshospitalet. The initial study was approved by the Regional Research Ethics Committee and the Danish Data Protection Agency. Participants, aged 18-81 at enrollment, were recruited through advertised calls and gave informed consent to take part in the studies which involved PET and MRI brain scans as well as personality testing. The brain scans were used to assess the distribution of the participants’ serotonin 2A receptor brain binding, while personality tests evaluated neuroticism levels.

Following approval from the Danish Health Data Authority’s Research Services, researchers conducted a registry-based follow-up study. This allowed them to link the original PET and personality research data to relevant health registries, which provided longitudinal health information. To protect participant privacy, the data were de-identified and anonymized by the data controllers at Statistics Denmark, ensuring that individuals could not be identified while still allowing researchers to track whether participants were later hospitalised with depression, had been diagnosed with a major depressive disorder, or had been prescribed antidepressants. By examining all these factors in all 131 study participants for a period of up to 19 years, the scientists were finally able to present scientific evidence for the existence of the distinct risk profile.

The original study was conducted at the Lundbeck Foundation Center for Integrated Molecular Brain Imaging (Cimbi), Neurobiology Research Unit (NRU), Rigshospitalet. Cimbi was established in 2006 via a Lundbeck Foundation grant.

WHO ARE AT RISK?

The distinct depression-risk link between personality traits and brain chemistry discovered by the Danish research team raises the question: How many people have this profile?

Anyone can develop depression, and in some cases, it appears to come on with no warning. But the better we understand the complex interactions of psychological and brain chemistry factors underlying depression, the better we’ll be able to treat and prevent this mental disorder. 

“The study does not set out to estimate this number in the Danish population, but it offers important insights into a specific profile that is associated with heightened risk for depression- a finding we hope will take us one step closer to understanding the disorder’s complex pathophysiology.” says Anjali Sankar, from the Neurobiology Research Unit (NRU) at Rigshospitalet. Sankar who holds a PhD in psychology and neuroscience, is the first author of the Nature article, and spearheaded the analyses that resulted in discovery of the special risk profile.

Depression research has long-since established that the 2A serotonin receptors featured in the recent Nature article are involved in depression. It is also known that various psychedelic compounds such as psilocybin, which is present in a number of ‘magic’ mushrooms, such as the liberty cap ( Psilocybe semilanceata ) can beneficially stimulate these receptors as part of antidepressant therapy sessions. For this reason, research is ongoing worldwide, including in Denmark, on combinations of psychotherapy and medicinal treatment with psychedelic compounds such as psilocybin. This is carried out in controlled studies supervised by medical doctors and clinical psychologists. Another psychedelic compound under investigation in trials of antidepressant therapy is LSD.

“ We studied a total of 131 healthy individuals who underwent brain scans and psychometric testing, with a subsequent 19 years of follow up in Danish health registries. In addition to the specific risk profile that is associated with developing a future depressive episode, we found that the risk for depression measured over the entire period was 24 percent in women as opposed to seven percent in men. This reflects the reality we’re already familiar with from depression studies: that women are far more likely than men to be diagnosed with major depressive disorder,” says Sankar. 

But now that the risk profile among healthy individuals for being diagnosed with severe depression has been established, it should be possible to put that knowledge to use in devising a form of screening test, as a kind of early warning of future depression.

Although that is an interesting idea, it is not exactly possible to do in practice, as Professor Frøkjær explains:

“As I see it, the best thing is to try to live naturally, making the most of life without harm to our mental health. And the aim should be to concentrate on stress management, and coming to terms with the inevitability and necessity of occasional adversity in life.”

The Neurobiology Research Unit at Rigshospitalet received a research grant of DKK 40 million from the Lundbeck Foundation in 2019 for the project, which also includes researchers from the University of Copenhagen and the Mental Health Services, Capital Region of Denmark. The main aim is to identify factors that can predict how patients with epilepsy or depression will respond to medical treatment, thereby improving the effectiveness of the treatment. Read more about the project: https://braindrugs.nru.dk/

Neocortical serotonin 2A receptor binding, neuroticism and risk of developing depression in healthy individuals | Nature Mental Health

Related news

Here’s how you know

• U.S. Department of Health and Human Services
• National Institutes of Health

Whole Person Health: What It Is and Why It's Important

.header_greentext{color:greenimportant;font-size:24pximportant;font-weight:500important;}.header_bluetext{color:blueimportant;font-size:18pximportant;font-weight:500important;}.header_redtext{color:redimportant;font-size:28pximportant;font-weight:500important;}.header_darkred{color:#803d2fimportant;font-size:28pximportant;font-weight:500important;}.header_purpletext{color:purpleimportant;font-size:31pximportant;font-weight:500important;}.header_yellowtext{color:yellowimportant;font-size:20pximportant;font-weight:500important;}.header_blacktext{color:blackimportant;font-size:22pximportant;font-weight:500important;}.header_whitetext{color:whiteimportant;font-size:22pximportant;font-weight:500important;}.header_darkred{color:#803d2fimportant;}.green_header{color:greenimportant;font-size:24pximportant;font-weight:500important;}.blue_header{color:blueimportant;font-size:18pximportant;font-weight:500important;}.red_header{color:redimportant;font-size:28pximportant;font-weight:500important;}.purple_header{color:purpleimportant;font-size:31pximportant;font-weight:500important;}.yellow_header{color:yellowimportant;font-size:20pximportant;font-weight:500important;}.black_header{color:blackimportant;font-size:22pximportant;font-weight:500important;}.white_header{color:whiteimportant;font-size:22pximportant;font-weight:500important;} what is whole person health.

Whole person health involves looking at the whole person—not just separate organs or body systems—and considering multiple factors that promote either health or disease. It means helping and empowering individuals, families, communities, and populations to improve their health in multiple interconnected biological, behavioral, social, and environmental areas. Instead of just treating a specific disease, whole person health focuses on restoring health, promoting resilience, and preventing diseases across a lifespan.

.header_greentext{color:green!important;font-size:24px!important;font-weight:500!important;}.header_bluetext{color:blue!important;font-size:18px!important;font-weight:500!important;}.header_redtext{color:red!important;font-size:28px!important;font-weight:500!important;}.header_darkred{color:#803d2f!important;font-size:28px!important;font-weight:500!important;}.header_purpletext{color:purple!important;font-size:31px!important;font-weight:500!important;}.header_yellowtext{color:yellow!important;font-size:20px!important;font-weight:500!important;}.header_blacktext{color:black!important;font-size:22px!important;font-weight:500!important;}.header_whitetext{color:white!important;font-size:22px!important;font-weight:500!important;}.header_darkred{color:#803d2f!important;}.Green_Header{color:green!important;font-size:24px!important;font-weight:500!important;}.Blue_Header{color:blue!important;font-size:18px!important;font-weight:500!important;}.Red_Header{color:red!important;font-size:28px!important;font-weight:500!important;}.Purple_Header{color:purple!important;font-size:31px!important;font-weight:500!important;}.Yellow_Header{color:yellow!important;font-size:20px!important;font-weight:500!important;}.Black_Header{color:black!important;font-size:22px!important;font-weight:500!important;}.White_Header{color:white!important;font-size:22px!important;font-weight:500!important;} Why is whole person health important?

Health and disease are not separate, disconnected states but instead occur on a path that can move in two different directions, either toward health or toward disease.

On this path, many factors, including one’s biological makeup; some unhealthy behaviors, such as poor diet, sedentary lifestyle, chronic stress, and poor sleep; as well as social aspects of life—the conditions in which people are born, grow, live, work, and age—can lead to chronic diseases of more than one organ system. On the other hand, self-care, lifestyle, and behavioral interventions may help with the return to health.

Chronic diseases, such as diabetes, cardiovascular disease, obesity, and degenerative joint disease, can also occur with chronic pain, depression, and opioid misuse—all conditions exacerbated by chronic stress. Some chronic diseases increase the immediate and long-term risks with COVID-19 infection. Understanding the condition in which a person has lived, addressing behaviors at an early stage, and managing stress can not only prevent multiple diseases but also help restore health and stop the progression to disease across a person’s lifespan.

.header_greentext{color:green!important;font-size:24px!important;font-weight:500!important;}.header_bluetext{color:blue!important;font-size:18px!important;font-weight:500!important;}.header_redtext{color:red!important;font-size:28px!important;font-weight:500!important;}.header_darkred{color:#803d2f!important;font-size:28px!important;font-weight:500!important;}.header_purpletext{color:purple!important;font-size:31px!important;font-weight:500!important;}.header_yellowtext{color:yellow!important;font-size:20px!important;font-weight:500!important;}.header_blacktext{color:black!important;font-size:22px!important;font-weight:500!important;}.header_whitetext{color:white!important;font-size:22px!important;font-weight:500!important;}.header_darkred{color:#803d2f!important;}.Green_Header{color:green!important;font-size:24px!important;font-weight:500!important;}.Blue_Header{color:blue!important;font-size:18px!important;font-weight:500!important;}.Red_Header{color:red!important;font-size:28px!important;font-weight:500!important;}.Purple_Header{color:purple!important;font-size:31px!important;font-weight:500!important;}.Yellow_Header{color:yellow!important;font-size:20px!important;font-weight:500!important;}.Black_Header{color:black!important;font-size:22px!important;font-weight:500!important;}.White_Header{color:white!important;font-size:22px!important;font-weight:500!important;} Is whole person health being used now in health care?

Some health care systems and programs are now focusing more on whole person health.

.header_greentext{color:green!important;font-size:24px!important;font-weight:500!important;}.header_bluetext{color:blue!important;font-size:18px!important;font-weight:500!important;}.header_redtext{color:red!important;font-size:28px!important;font-weight:500!important;}.header_darkred{color:#803d2f!important;font-size:28px!important;font-weight:500!important;}.header_purpletext{color:purple!important;font-size:31px!important;font-weight:500!important;}.header_yellowtext{color:yellow!important;font-size:20px!important;font-weight:500!important;}.header_blacktext{color:black!important;font-size:22px!important;font-weight:500!important;}.header_whitetext{color:white!important;font-size:22px!important;font-weight:500!important;}.header_darkred{color:#803d2f!important;}.Green_Header{color:green!important;font-size:24px!important;font-weight:500!important;}.Blue_Header{color:blue!important;font-size:18px!important;font-weight:500!important;}.Red_Header{color:red!important;font-size:28px!important;font-weight:500!important;}.Purple_Header{color:purple!important;font-size:31px!important;font-weight:500!important;}.Yellow_Header{color:yellow!important;font-size:20px!important;font-weight:500!important;}.Black_Header{color:black!important;font-size:22px!important;font-weight:500!important;}.White_Header{color:white!important;font-size:22px!important;font-weight:500!important;} U.S. Department of Veterans Affairs (VA) Whole Health Approach

The VA’s Whole Health System of Care and Whole Health approach aims to improve the health and well-being of veterans and to address lifestyle and environmental root causes of chronic disease. The approach shifts from a disease-centered focus to a more personalized approach that engages and empowers veterans early in and throughout their lives to prioritize healthy lifestyle changes in areas like nutrition, activity, sleep, relationships, and surroundings. Conventional testing and treatment are combined with complementary and integrative health approaches that may include acupuncture, biofeedback, massage therapy, yoga, and meditation.

.header_greentext{color:green!important;font-size:24px!important;font-weight:500!important;}.header_bluetext{color:blue!important;font-size:18px!important;font-weight:500!important;}.header_redtext{color:red!important;font-size:28px!important;font-weight:500!important;}.header_darkred{color:#803d2f!important;font-size:28px!important;font-weight:500!important;}.header_purpletext{color:purple!important;font-size:31px!important;font-weight:500!important;}.header_yellowtext{color:yellow!important;font-size:20px!important;font-weight:500!important;}.header_blacktext{color:black!important;font-size:22px!important;font-weight:500!important;}.header_whitetext{color:white!important;font-size:22px!important;font-weight:500!important;}.header_darkred{color:#803d2f!important;}.Green_Header{color:green!important;font-size:24px!important;font-weight:500!important;}.Blue_Header{color:blue!important;font-size:18px!important;font-weight:500!important;}.Red_Header{color:red!important;font-size:28px!important;font-weight:500!important;}.Purple_Header{color:purple!important;font-size:31px!important;font-weight:500!important;}.Yellow_Header{color:yellow!important;font-size:20px!important;font-weight:500!important;}.Black_Header{color:black!important;font-size:22px!important;font-weight:500!important;}.White_Header{color:white!important;font-size:22px!important;font-weight:500!important;} U.S. Department of Defense Total Force Fitness Program

The Total Force Fitness program arose within the U.S. Department of Defense Military Health System in response to the need for a more holistic approach—a focus on the whole person instead of separate parts or only symptoms—to the demands of multiple deployments and the strains on the U.S. Armed Forces and their family members. The focus extends the idea of total fitness to include the health, well-being, and resilience of the whole person, family, community, and U.S. military.

.header_greentext{color:green!important;font-size:24px!important;font-weight:500!important;}.header_bluetext{color:blue!important;font-size:18px!important;font-weight:500!important;}.header_redtext{color:red!important;font-size:28px!important;font-weight:500!important;}.header_darkred{color:#803d2f!important;font-size:28px!important;font-weight:500!important;}.header_purpletext{color:purple!important;font-size:31px!important;font-weight:500!important;}.header_yellowtext{color:yellow!important;font-size:20px!important;font-weight:500!important;}.header_blacktext{color:black!important;font-size:22px!important;font-weight:500!important;}.header_whitetext{color:white!important;font-size:22px!important;font-weight:500!important;}.header_darkred{color:#803d2f!important;}.Green_Header{color:green!important;font-size:24px!important;font-weight:500!important;}.Blue_Header{color:blue!important;font-size:18px!important;font-weight:500!important;}.Red_Header{color:red!important;font-size:28px!important;font-weight:500!important;}.Purple_Header{color:purple!important;font-size:31px!important;font-weight:500!important;}.Yellow_Header{color:yellow!important;font-size:20px!important;font-weight:500!important;}.Black_Header{color:black!important;font-size:22px!important;font-weight:500!important;}.White_Header{color:white!important;font-size:22px!important;font-weight:500!important;} Whole Health Institute

Established in 2020, the Whole Health Institute’s Whole Health model helps people identify what matters most to them and build a plan for their journey to whole health. The model provides tools to help people take good care of their body, mind, and spirit, and involves working with a health care team as well as tapping into the support of family, friends, and communities.

.header_greentext{color:green!important;font-size:24px!important;font-weight:500!important;}.header_bluetext{color:blue!important;font-size:18px!important;font-weight:500!important;}.header_redtext{color:red!important;font-size:28px!important;font-weight:500!important;}.header_darkred{color:#803d2f!important;font-size:28px!important;font-weight:500!important;}.header_purpletext{color:purple!important;font-size:31px!important;font-weight:500!important;}.header_yellowtext{color:yellow!important;font-size:20px!important;font-weight:500!important;}.header_blacktext{color:black!important;font-size:22px!important;font-weight:500!important;}.header_whitetext{color:white!important;font-size:22px!important;font-weight:500!important;}.header_darkred{color:#803d2f!important;}.Green_Header{color:green!important;font-size:24px!important;font-weight:500!important;}.Blue_Header{color:blue!important;font-size:18px!important;font-weight:500!important;}.Red_Header{color:red!important;font-size:28px!important;font-weight:500!important;}.Purple_Header{color:purple!important;font-size:31px!important;font-weight:500!important;}.Yellow_Header{color:yellow!important;font-size:20px!important;font-weight:500!important;}.Black_Header{color:black!important;font-size:22px!important;font-weight:500!important;}.White_Header{color:white!important;font-size:22px!important;font-weight:500!important;} North Carolina Department of Health and Human Services

The North Carolina Department of Health and Human Services has incorporated a whole person health approach into its health care system by focusing on integrating physical, behavioral, and social health. The state has taken steps to encourage collaborative behavioral health care and help resolve widespread inequities in social conditions, such as housing and nutritious food access.

.header_greentext{color:green!important;font-size:24px!important;font-weight:500!important;}.header_bluetext{color:blue!important;font-size:18px!important;font-weight:500!important;}.header_redtext{color:red!important;font-size:28px!important;font-weight:500!important;}.header_darkred{color:#803d2f!important;font-size:28px!important;font-weight:500!important;}.header_purpletext{color:purple!important;font-size:31px!important;font-weight:500!important;}.header_yellowtext{color:yellow!important;font-size:20px!important;font-weight:500!important;}.header_blacktext{color:black!important;font-size:22px!important;font-weight:500!important;}.header_whitetext{color:white!important;font-size:22px!important;font-weight:500!important;}.header_darkred{color:#803d2f!important;}.Green_Header{color:green!important;font-size:24px!important;font-weight:500!important;}.Blue_Header{color:blue!important;font-size:18px!important;font-weight:500!important;}.Red_Header{color:red!important;font-size:28px!important;font-weight:500!important;}.Purple_Header{color:purple!important;font-size:31px!important;font-weight:500!important;}.Yellow_Header{color:yellow!important;font-size:20px!important;font-weight:500!important;}.Black_Header{color:black!important;font-size:22px!important;font-weight:500!important;}.White_Header{color:white!important;font-size:22px!important;font-weight:500!important;} Ornish Program for Reversing Heart Disease

The Ornish Program for Reversing Heart Disease is an intensive cardiac rehabilitation program that has been shown to reverse the progression of coronary heart disease through lifestyle changes, without drugs or surgery. The program is covered by Medicare and some health insurance companies. The program’s lifestyle changes include exercise, smoking cessation, stress management, social support, and a whole-foods, plant-based diet low in total fat. The program is offered by a team of health care professionals who provide the support that individuals need to make and maintain lasting changes in lifestyle.

.header_greentext{color:green!important;font-size:24px!important;font-weight:500!important;}.header_bluetext{color:blue!important;font-size:18px!important;font-weight:500!important;}.header_redtext{color:red!important;font-size:28px!important;font-weight:500!important;}.header_darkred{color:#803d2f!important;font-size:28px!important;font-weight:500!important;}.header_purpletext{color:purple!important;font-size:31px!important;font-weight:500!important;}.header_yellowtext{color:yellow!important;font-size:20px!important;font-weight:500!important;}.header_blacktext{color:black!important;font-size:22px!important;font-weight:500!important;}.header_whitetext{color:white!important;font-size:22px!important;font-weight:500!important;}.header_darkred{color:#803d2f!important;}.Green_Header{color:green!important;font-size:24px!important;font-weight:500!important;}.Blue_Header{color:blue!important;font-size:18px!important;font-weight:500!important;}.Red_Header{color:red!important;font-size:28px!important;font-weight:500!important;}.Purple_Header{color:purple!important;font-size:31px!important;font-weight:500!important;}.Yellow_Header{color:yellow!important;font-size:20px!important;font-weight:500!important;}.Black_Header{color:black!important;font-size:22px!important;font-weight:500!important;}.White_Header{color:white!important;font-size:22px!important;font-weight:500!important;} What does research show about whole person health?

A growing body of research suggests the benefits of healthy behaviors, environments, and policies to maintain health and prevent, treat, and reverse chronic diseases. This research includes several large, long-term epidemiological studies—such as the Framingham Heart Study, Nurses’ Health Study, and Adventist Health Studies—that have evaluated the connections between lifestyle, diet, genetics, health, and disease.

There is a lack, however, of randomized controlled trials and other types of research on multicomponent interventions and whole person health. Challenges come with conducting this type of research and with finding appropriate ways to assess the evidence. But opportunities are emerging to explore new paths toward reliable and rigorous research on whole person health.

.header_greentext{color:green!important;font-size:24px!important;font-weight:500!important;}.header_bluetext{color:blue!important;font-size:18px!important;font-weight:500!important;}.header_redtext{color:red!important;font-size:28px!important;font-weight:500!important;}.header_darkred{color:#803d2f!important;font-size:28px!important;font-weight:500!important;}.header_purpletext{color:purple!important;font-size:31px!important;font-weight:500!important;}.header_yellowtext{color:yellow!important;font-size:20px!important;font-weight:500!important;}.header_blacktext{color:black!important;font-size:22px!important;font-weight:500!important;}.header_whitetext{color:white!important;font-size:22px!important;font-weight:500!important;}.header_darkred{color:#803d2f!important;}.Green_Header{color:green!important;font-size:24px!important;font-weight:500!important;}.Blue_Header{color:blue!important;font-size:18px!important;font-weight:500!important;}.Red_Header{color:red!important;font-size:28px!important;font-weight:500!important;}.Purple_Header{color:purple!important;font-size:31px!important;font-weight:500!important;}.Yellow_Header{color:yellow!important;font-size:20px!important;font-weight:500!important;}.Black_Header{color:black!important;font-size:22px!important;font-weight:500!important;}.White_Header{color:white!important;font-size:22px!important;font-weight:500!important;} Will the National Center for Complementary and Integrative Health (NCCIH) fund research on whole person health?

Yes, NCCIH plans to fund research on whole person health . (Details can be found in the NCCIH Strategic Plan FY 2021–2025: Mapping a Pathway to Research on Whole Person Health . )

By deepening the scientific understanding of the connections that exist across the different areas of human health, researchers can better understand how conditions interrelate, identify multicomponent interventions that address these problems, and determine the best ways to support individuals through the full continuum of their health experience, including the return to health.

.header_greentext{color:green!important;font-size:24px!important;font-weight:500!important;}.header_bluetext{color:blue!important;font-size:18px!important;font-weight:500!important;}.header_redtext{color:red!important;font-size:28px!important;font-weight:500!important;}.header_darkred{color:#803d2f!important;font-size:28px!important;font-weight:500!important;}.header_purpletext{color:purple!important;font-size:31px!important;font-weight:500!important;}.header_yellowtext{color:yellow!important;font-size:20px!important;font-weight:500!important;}.header_blacktext{color:black!important;font-size:22px!important;font-weight:500!important;}.header_whitetext{color:white!important;font-size:22px!important;font-weight:500!important;}.header_darkred{color:#803d2f!important;}.Green_Header{color:green!important;font-size:24px!important;font-weight:500!important;}.Blue_Header{color:blue!important;font-size:18px!important;font-weight:500!important;}.Red_Header{color:red!important;font-size:28px!important;font-weight:500!important;}.Purple_Header{color:purple!important;font-size:31px!important;font-weight:500!important;}.Yellow_Header{color:yellow!important;font-size:20px!important;font-weight:500!important;}.Black_Header{color:black!important;font-size:22px!important;font-weight:500!important;}.White_Header{color:white!important;font-size:22px!important;font-weight:500!important;} For More Information

Nccih clearinghouse.

The NCCIH Clearinghouse provides information on NCCIH and complementary and integrative health approaches, including publications and searches of Federal databases of scientific and medical literature. The Clearinghouse does not provide medical advice, treatment recommendations, or referrals to practitioners.

Toll-free in the U.S.: 1-888-644-6226

Telecommunications relay service (TRS): 7-1-1

Website: https://www.nccih.nih.gov

Email: [email protected] (link sends email)

Know the Science

NCCIH and the National Institutes of Health (NIH) provide tools to help you understand the basics and terminology of scientific research so you can make well-informed decisions about your health. Know the Science features a variety of materials, including interactive modules, quizzes, and videos, as well as links to informative content from Federal resources designed to help consumers make sense of health information.

Explaining How Research Works (NIH)

Know the Science: How To Make Sense of a Scientific Journal Article

Understanding Clinical Studies (NIH)

A service of the National Library of Medicine, PubMed® contains publication information and (in most cases) brief summaries of articles from scientific and medical journals. For guidance from NCCIH on using PubMed, see How To Find Information About Complementary Health Approaches on PubMed .

Website: https://pubmed.ncbi.nlm.nih.gov/

.header_greentext{color:green!important;font-size:24px!important;font-weight:500!important;}.header_bluetext{color:blue!important;font-size:18px!important;font-weight:500!important;}.header_redtext{color:red!important;font-size:28px!important;font-weight:500!important;}.header_darkred{color:#803d2f!important;font-size:28px!important;font-weight:500!important;}.header_purpletext{color:purple!important;font-size:31px!important;font-weight:500!important;}.header_yellowtext{color:yellow!important;font-size:20px!important;font-weight:500!important;}.header_blacktext{color:black!important;font-size:22px!important;font-weight:500!important;}.header_whitetext{color:white!important;font-size:22px!important;font-weight:500!important;}.header_darkred{color:#803d2f!important;}.Green_Header{color:green!important;font-size:24px!important;font-weight:500!important;}.Blue_Header{color:blue!important;font-size:18px!important;font-weight:500!important;}.Red_Header{color:red!important;font-size:28px!important;font-weight:500!important;}.Purple_Header{color:purple!important;font-size:31px!important;font-weight:500!important;}.Yellow_Header{color:yellow!important;font-size:20px!important;font-weight:500!important;}.Black_Header{color:black!important;font-size:22px!important;font-weight:500!important;}.White_Header{color:white!important;font-size:22px!important;font-weight:500!important;} Key References

• Aggarwal M, Ornish D, Josephson R, et al. Closing gaps in lifestyle adherence for secondary prevention of coronary heart disease. American Journal of Cardiology. 2021;145:1-11.
• Centers for Medicare & Medicaid Services. Decision Memo for Intensive Cardiac Rehabilitation (ICR) Program—Dr. Ornish’s Program for Reversing Heart Disease (CAG-00419N). Accessed at https://www.cms.gov/ on April 26, 2021.
• Deuster PA, O’Connor FG. Human performance optimization: culture change and paradigm shift. Journal of Strength and Conditioning Research. 2015;29(suppl 11):S52-S56.
• Gaudet T, Kligler B. Whole health in the whole system of the Veterans Administration: how will we know we have reached this future state? Journal of Alternative and Complementary Medicine. 2019;25(S1):S7-S11.
• Malecki HL, Gollie JM, Scholten J. Physical activity, exercise, whole health, and integrative health coaching. Physical Medicine and Rehabilitation Clinics of North America. 2020;31(4):649-663.
• National Center for Complementary and Integrative Health. NCCIH Strategic Plan FY 2021–2025: Mapping a Pathway to Research on Whole Person Health. National Center for Complementary and Integrative Health website. Accessed at https://www.nccih.nih.gov/about/nccih-strategic-plan-2021-2025 on May 14, 2021.
• North Carolina Department of Health and Human Services website. Healthy Opportunities and Medicaid Transformation. Accessed at https://www.ncdhhs.gov/about/department-initiatives/healthy-opportunities/healthy-opportunities-pilots/healthy on April 26, 2021.
• Military Health System website. Total Force Fitness. Accessed at https://health.mil/Military-Health-Topics/Total-Force-Fitness on April 26, 2021.
• Tilson EC, Muse A, Colville K, et al. Investing in whole person health: working toward an integration of physical, behavioral, and social health. North Carolina Medical Journal. 2020;81(3):177-180.
• U.S. Department of Veterans Affairs website. Whole Health. Accessed at https://www.va.gov/wholehealth/ on April 26, 2021.
• U.S. Department of Veterans Affairs website. Whole Health Library. Accessed at  https://www.va.gov/wholehealthlibrary/ on April 26, 2021.
• Vodovotz Y, Barnard N, Hu FB, et al. Prioritized research for the prevention, treatment, and reversal of chronic disease: recommendations from the Lifestyle Medicine Research Summit. Frontiers in Medicine (Lausanne). 2020;7:585744.
• Whitehead AM, Kligler B. Innovations in care: complementary and integrative health in the Veterans Health Administration Whole Health System. Medical Care. 2020;58(9S)(suppl 2):S78-S79.

.header_greentext{color:green!important;font-size:24px!important;font-weight:500!important;}.header_bluetext{color:blue!important;font-size:18px!important;font-weight:500!important;}.header_redtext{color:red!important;font-size:28px!important;font-weight:500!important;}.header_darkred{color:#803d2f!important;font-size:28px!important;font-weight:500!important;}.header_purpletext{color:purple!important;font-size:31px!important;font-weight:500!important;}.header_yellowtext{color:yellow!important;font-size:20px!important;font-weight:500!important;}.header_blacktext{color:black!important;font-size:22px!important;font-weight:500!important;}.header_whitetext{color:white!important;font-size:22px!important;font-weight:500!important;}.header_darkred{color:#803d2f!important;}.Green_Header{color:green!important;font-size:24px!important;font-weight:500!important;}.Blue_Header{color:blue!important;font-size:18px!important;font-weight:500!important;}.Red_Header{color:red!important;font-size:28px!important;font-weight:500!important;}.Purple_Header{color:purple!important;font-size:31px!important;font-weight:500!important;}.Yellow_Header{color:yellow!important;font-size:20px!important;font-weight:500!important;}.Black_Header{color:black!important;font-size:22px!important;font-weight:500!important;}.White_Header{color:white!important;font-size:22px!important;font-weight:500!important;} Other References

• Alborzkouh P, Nabati M, Zainali M, et al. A review of the effectiveness of stress management skills training on academic vitality and psychological well-being of college students. Journal of Medicine and Life. 2015;8(4):39-44.
• Bisht K, Sharma K, Tremblay M-È. Chronic stress as a risk factor for Alzheimer's disease: roles of microglia-mediated synaptic remodeling, inflammation, and oxidative stress. Neurobiology of Stress. 2018;9:9-21.
• Buettner D, Skemp S. Blue Zones: lessons from the world’s longest lived. American Journal of Lifestyle Medicine. 2016;10(5):318-321.
• Chen T-L, Chang S-C, Hsieh H-F, et al. Effects of mindfulness-based stress reduction on sleep quality and mental health for insomnia patients: a meta-analysis. Journal of Psychosomatic Research. 2020;135:110144.
• Conversano C, Orrù G, Pozza A, et al. Is mindfulness-based stress reduction effective for people with hypertension? A systematic review and meta-analysis of 30 years of evidence. International Journal of Environmental Research and Public Health. 2021;18(6):2882.
• Katz DL, Karlsen MC, Chung M, et al. Hierarchies of evidence applied to lifestyle medicine (HEALM): introduction of a strength-of-evidence approach based on a methodological systematic review. BMC Medical Research Methodology. 2019;19(1):178.
• Kruk J, Aboul-Enein BH, Bernstein J, et al. Psychological stress and cellular aging in cancer: a meta-analysis. Oxidative Medicine and Cellular Longevity. 2019;2019:1270397.
• Levesque C. Therapeutic lifestyle changes for diabetes mellitus. Nursing Clinics of North America. 2017;52(4):679-692.
• Ni Y, Ma L, Li J. Effects of mindfulness-based stress reduction and mindfulness-based cognitive therapy in people with diabetes: a systematic review and meta-analysis. Journal of Nursing Scholarship. 2020;52(4):379-388.
• Ornish Lifestyle Medicine website. The Ornish Reversal Program: Intensive Cardiac Rehabilitation. Accessed at https://www.ornish.com/intensive-cardiac-rehab/ on April 26, 2021.
• Schneiderman N, Ironson G, Siegel SD. Stress and health: psychological, behavioral, and biological determinants. Annual Review of Clinical Psychology. 2005;1:607-628.
• Seal KH, Becker WC, Murphy JL, et al. Whole Health Options and Pain Education (wHOPE): a pragmatic trial comparing whole health team vs primary care group education to promote nonpharmacological strategies to improve pain, functioning, and quality of life in veterans—rationale, methods, and implementation. Pain Medicine. 2020;21(suppl 2):S91-S99.
• Tamashiro KL, Sakai RR, Shively CA, et al. Chronic stress, metabolism, and metabolic syndrome. Stress. 2011;14(5):468-474.
• Whayne TF Jr, Saha SP. Genetic risk, adherence to a healthy lifestyle, and ischemic heart disease. Current Cardiology Reports. 2019;21(1):1.
• Whole Health Institute website. Accessed at https://www.wholehealth.org/ on May 19, 2021.

Acknowledgments

NCCIH thanks Mary Beth Kester, M.S., and Helene M. Langevin, M.D., NCCIH, for their review of this publication.

This publication is not copyrighted and is in the public domain. Duplication is encouraged.

NCCIH has provided this material for your information. It is not intended to substitute for the medical expertise and advice of your health care provider(s). We encourage you to discuss any decisions about treatment or care with your health care provider. The mention of any product, service, or therapy is not an endorsement by NCCIH.

Related Topics

NCCIH Strategic Plan FY 2021–⁠2025 Mapping a Pathway to Research on Whole Person Health

Methodological Approaches for Whole Person Research Workshop

Transforming Veterans’ Health: Implementing a Whole Health System of Care

Complementary, Alternative, or Integrative Health: What’s In a Name?

In-Person Contact Linked With Lower Levels of Loneliness in Older Adults

Despite our hopes for technological ways to bridge connections between older adults and social partners, phone and digital contact cannot alleviate loneliness in the same way.

Photo-Illustration: Martha Morales

In-person contact helps lead to lower levels of loneliness in older people, but other ways of staying in touch, such as phoning, emailing or texting, are not as effective in lowering loneliness, a team of researchers at The University of Texas at Austin and the University of Michigan have found.

The findings, out today in the The Journals of Gerontology: Series B Psychological Science , have implications for the health and well-being of many older people. 

“We were interested to see how older adults react when they are lonely and the effects that different types of social contact had on that loneliness,” said Shiyang Zhang, the paper’s first author and a UT postdoctoral fellow in human development and family sciences. “We found that when older adults feel lonely, they are more likely to pick up the phone and call someone. But in-person visits were the only type of contact that actually decreased levels of reported loneliness.”

Scientists have long known that regular social contact is important for mental and physical health and contributes to longevity in older age, while loneliness has been linked with heart disease, cognitive decline and even premature death. Although many older adults face chronic health conditions and mobility issues that may make in-person contact more difficult, the new study suggests that in-person contact is an important component of any widespread effort to address loneliness in older adults. 

The study was conducted in the Austin, Texas, area in 2016 and 2017, before the COVID-19 pandemic expanded the use of digital communications for many people and increased levels of isolation for many older people. But even after the pandemic, a sizable proportion of older adults do not own smartphones or use the internet. The study followed more than 300 people over the age of 65 and asked them every three waking hours about levels of loneliness and social contact, including whether that social contact was in person, by phone or digitally, which the researchers defined as texting or connecting via social media. 

The study also examined whether the social contact was between people with close or weak social ties. Researchers found that when older adults felt lonely, they were likely to reach out to their close friends and family. It turns out that in-person contact — even with someone with whom they had only weak ties, such as an acquaintance — was predictive of lower levels of loneliness better than, say, a phone call with a family member or friend with whom ties were stronger. 

“Although phone contact is available at most times and provides older adults with opportunities for social connections when they feel lonely, it appears that phone contact may not be as effective in reducing loneliness as in-person contact,” Zhang said. “Phone and digital contact do not provide older adults with the same emotional closeness and comfort as in-person contact. It’s just not a substitute.”

Karen Fingerman, who holds the Sonia Wolf Wilson Regents Administrative Professorship in Human Ecology in UT’s Department of Human Development and Family Sciences, UT graduate student Zexi Zhou and University of Michigan’s Kira S. Birditt were also authors of the paper. Funding for the research was provided by the National Institute on Aging, the Center on Aging and Population Sciences at UT, and the Eunice Kennedy Shriver National Institute of Child Health and Human Development. The research was supported by Texas Aging and Longevity Consortium at UT Austin. 

• Share on Facebook
• Share on LinkedIn
• Show and hide the URL copier tool.
• Share via email
• Human Development and Family Sciences
• Human Ecology

Insider Insights: Meet Public Health Major Kena Desai

August 27, 2024 • by Sowmya Sridhar

Transitioning Gender Identities Is Not Linked With Depression

May 22, 2024 • by Esther Robards-Forbes

Whole Communities — Whole Health

Faculty Collaborations Awarded 'Fast Track to Impact' Support

May 21, 2024 • by Staff Writer