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Major Depressive Disorder: Advances in Neuroscience Research and Translational Applications

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

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

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

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Introduction

Neuroimaging advance in depressive disorder.

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

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

Current Situation of Research on Depression

Analysis of published papers.

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

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

Analysis of Patented Technology Application

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

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

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

Analysis of Clinical Trial

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

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

New Medicine Development

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

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

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

Epidemiology of Depression

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

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

Neurobiological Pathogenesis of Depressive Disorder

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

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

Stress-Responsive HPA Axis

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

Glutamate Signaling Pathway

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

Gamma-Aminobutyric Acid (GABA)

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

Neurotrophin Family

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

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

Neuroinflammation

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

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

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

Microbiome-Gut-Brain Axis

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

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

Other Systems and Pathways

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

Advances in Various Kinds of Research on Depressive Disorder

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

Genetic Studies

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

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

Brain Imaging and Neuroimaging Studies

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

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

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

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

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

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

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

Objective Index for Diagnosis of MDD

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

Management of Depression

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

Current Antidepressant Treatment

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

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

Neuromodulation Therapy

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

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

Precision Medicine for Depression

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

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

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

Future Perspectives

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

Change history

17 may 2021.

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

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Acknowledgments

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

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Zezhi Li, Jun Chen & Yiru Fang

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

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

Meihua Ruan

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

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

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

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

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Depression (major depressive disorder).

Displaying 61 studies

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

The purpose of this study is to:

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

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

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

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

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

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

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

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

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

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

Primary Aim

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

Secondary Aims

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

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

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

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

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

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

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

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• What is depression? A Mayo Clinic expert explains.

Learn more about depression from Craig Sawchuk, Ph.D., L.P., clinical psychologist at Mayo Clinic.

Hi, I'm Dr. Craig Sawchuk, a clinical psychologist at Mayo Clinic. And I'm here to talk with you about depression. Whether you're looking for answers for yourself, a friend, or loved one, understanding the basics of depression can help you take the next step.

Depression is a mood disorder that causes feelings of sadness that won't go away. Unfortunately, there's a lot of stigma around depression. Depression isn't a weakness or a character flaw. It's not about being in a bad mood, and people who experience depression can't just snap out of it. Depression is a common, serious, and treatable condition. If you're experiencing depression, you're not alone. It honestly affects people of all ages and races and biological sexes, income levels and educational backgrounds. Approximately one in six people will experience a major depressive episode at some point in their lifetime, while up to 16 million adults each year suffer from clinical depression. There are many types of symptoms that make up depression. Emotionally, you may feel sad or down or irritable or even apathetic. Physically, the body really slows down. You feel tired. Your sleep is often disrupted. It's really hard to get yourself motivated. Your thinking also changes. It can just be hard to concentrate. Your thoughts tend to be much more negative. You can be really hard on yourself, feel hopeless and helpless about things. And even in some cases, have thoughts of not wanting to live. Behaviorally, you just want to pull back and withdraw from others, activities, and day-to-day responsibilities. These symptoms all work together to keep you trapped in a cycle of depression. Symptoms of depression are different for everyone. Some symptoms may be a sign of another disorder or medical condition. That's why it's important to get an accurate diagnosis.

While there's no single cause of depression, most experts believe there's a combination of biological, social, and psychological factors that contribute to depression risk. Biologically, we think about genetics or a family history of depression, health conditions such as diabetes, heart disease or thyroid disorders, and even hormonal changes that happen over the lifespan, such as pregnancy and menopause. Changes in brain chemistry, especially disruptions in neurotransmitters like serotonin, that play an important role in regulating many bodily functions, including mood, sleep, and appetite, are thought to play a particularly important role in depression. Socially stressful and traumatic life events, limited access to resources such as food, housing, and health care, and a lack of social support all contribute to depression risk. Psychologically, we think of how negative thoughts and problematic coping behaviors, such as avoidance and substance use, increase our vulnerability to depression.

The good news is that treatment helps. Effective treatments for depression exist and you do have options to see what works best for you. Lifestyle changes that improve sleep habits, exercise, and address underlying health conditions can be an important first step. Medications such as antidepressants can be helpful in alleviating depressive symptoms. Therapy, especially cognitive behavioral therapy, teaches skills to better manage negative thoughts and improve coping behaviors to help break you out of cycles of depression. Whatever the cause, remember that depression is not your fault and it can be treated.

To help diagnose depression, your health care provider may use a physical exam, lab tests, or a mental health evaluation. These results will help identify various treatment options that best fit your situation.

Help is available. You don't have to deal with depression by yourself. Take the next step and reach out. If you're hesitant to talk to a health care provider, talk to a friend or loved one about how to get help. Living with depression isn't easy and you're not alone in your struggles. Always remember that effective treatments and supports are available to help you start feeling better. Want to learn more about depression? Visit mayoclinic.org. Do take care.

Depression is a mood disorder that causes a persistent feeling of sadness and loss of interest. Also called major depressive disorder or clinical depression, it affects how you feel, think and behave and can lead to a variety of emotional and physical problems. You may have trouble doing normal day-to-day activities, and sometimes you may feel as if life isn't worth living.

More than just a bout of the blues, depression isn't a weakness and you can't simply "snap out" of it. Depression may require long-term treatment. But don't get discouraged. Most people with depression feel better with medication, psychotherapy or both.

Depression care at Mayo Clinic

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Although depression may occur only once during your life, people typically have multiple episodes. During these episodes, symptoms occur most of the day, nearly every day and may include:

• Feelings of sadness, tearfulness, emptiness or hopelessness
• Angry outbursts, irritability or frustration, even over small matters
• Loss of interest or pleasure in most or all normal activities, such as sex, hobbies or sports
• Sleep disturbances, including insomnia or sleeping too much
• Tiredness and lack of energy, so even small tasks take extra effort
• Reduced appetite and weight loss or increased cravings for food and weight gain
• Anxiety, agitation or restlessness
• Slowed thinking, speaking or body movements
• Feelings of worthlessness or guilt, fixating on past failures or self-blame
• Trouble thinking, concentrating, making decisions and remembering things
• Frequent or recurrent thoughts of death, suicidal thoughts, suicide attempts or suicide
• Unexplained physical problems, such as back pain or headaches

For many people with depression, symptoms usually are severe enough to cause noticeable problems in day-to-day activities, such as work, school, social activities or relationships with others. Some people may feel generally miserable or unhappy without really knowing why.

Depression symptoms in children and teens

Common signs and symptoms of depression in children and teenagers are similar to those of adults, but there can be some differences.

• In younger children, symptoms of depression may include sadness, irritability, clinginess, worry, aches and pains, refusing to go to school, or being underweight.
• In teens, symptoms may include sadness, irritability, feeling negative and worthless, anger, poor performance or poor attendance at school, feeling misunderstood and extremely sensitive, using recreational drugs or alcohol, eating or sleeping too much, self-harm, loss of interest in normal activities, and avoidance of social interaction.

Depression symptoms in older adults

Depression is not a normal part of growing older, and it should never be taken lightly. Unfortunately, depression often goes undiagnosed and untreated in older adults, and they may feel reluctant to seek help. Symptoms of depression may be different or less obvious in older adults, such as:

• Memory difficulties or personality changes
• Physical aches or pain
• Fatigue, loss of appetite, sleep problems or loss of interest in sex — not caused by a medical condition or medication
• Often wanting to stay at home, rather than going out to socialize or doing new things
• Suicidal thinking or feelings, especially in older men

When to see a doctor

If you feel depressed, make an appointment to see your doctor or mental health professional as soon as you can. If you're reluctant to seek treatment, talk to a friend or loved one, any health care professional, a faith leader, or someone else you trust.

When to get emergency help

If you think you may hurt yourself or attempt suicide, call 911 in the U.S. or your local emergency number immediately.

Also consider these options if you're having suicidal thoughts:

• Call your doctor or mental health professional.
• Contact a suicide hotline.
• In the U.S., call or text 988 to reach the 988 Suicide & Crisis Lifeline, available 24 hours a day, seven days a week. Or use the Lifeline Chat . Services are free and confidential.
• U.S. veterans or service members who are in crisis can call 988 and then press “1” for the Veterans Crisis Line . Or text 838255. Or chat online .
• The Suicide & Crisis Lifeline in the U.S. has a Spanish language phone line at 1-888-628-9454 (toll-free).
• Reach out to a close friend or loved one.
• Contact a minister, spiritual leader or someone else in your faith community.

If you have a loved one who is in danger of suicide or has made a suicide attempt, make sure someone stays with that person. Call 911 or your local emergency number immediately. Or, if you think you can do so safely, take the person to the nearest hospital emergency room.

More Information

Depression (major depressive disorder) care at Mayo Clinic

• Male depression: Understanding the issues
• Nervous breakdown: What does it mean?
• Pain and depression: Is there a link?

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It's not known exactly what causes depression. As with many mental disorders, a variety of factors may be involved, such as:

• Biological differences. People with depression appear to have physical changes in their brains. The significance of these changes is still uncertain, but may eventually help pinpoint causes.
• Brain chemistry. Neurotransmitters are naturally occurring brain chemicals that likely play a role in depression. Recent research indicates that changes in the function and effect of these neurotransmitters and how they interact with neurocircuits involved in maintaining mood stability may play a significant role in depression and its treatment.
• Hormones. Changes in the body's balance of hormones may be involved in causing or triggering depression. Hormone changes can result with pregnancy and during the weeks or months after delivery (postpartum) and from thyroid problems, menopause or a number of other conditions.
• Inherited traits. Depression is more common in people whose blood relatives also have this condition. Researchers are trying to find genes that may be involved in causing depression.
• Marijuana and depression
• Vitamin B-12 and depression

Risk factors

Depression often begins in the teens, 20s or 30s, but it can happen at any age. More women than men are diagnosed with depression, but this may be due in part because women are more likely to seek treatment.

Factors that seem to increase the risk of developing or triggering depression include:

• Certain personality traits, such as low self-esteem and being too dependent, self-critical or pessimistic
• Traumatic or stressful events, such as physical or sexual abuse, the death or loss of a loved one, a difficult relationship, or financial problems
• Blood relatives with a history of depression, bipolar disorder, alcoholism or suicide
• Being lesbian, gay, bisexual or transgender, or having variations in the development of genital organs that aren't clearly male or female (intersex) in an unsupportive situation
• History of other mental health disorders, such as anxiety disorder, eating disorders or post-traumatic stress disorder
• Abuse of alcohol or recreational drugs
• Serious or chronic illness, including cancer, stroke, chronic pain or heart disease
• Certain medications, such as some high blood pressure medications or sleeping pills (talk to your doctor before stopping any medication)

Complications

Depression is a serious disorder that can take a terrible toll on you and your family. Depression often gets worse if it isn't treated, resulting in emotional, behavioral and health problems that affect every area of your life.

Examples of complications associated with depression include:

• Excess weight or obesity, which can lead to heart disease and diabetes
• Pain or physical illness
• Alcohol or drug misuse
• Anxiety, panic disorder or social phobia
• Family conflicts, relationship difficulties, and work or school problems
• Social isolation
• Suicidal feelings, suicide attempts or suicide
• Self-mutilation, such as cutting
• Premature death from medical conditions
• Depression and anxiety: Can I have both?

There's no sure way to prevent depression. However, these strategies may help.

• Take steps to control stress, to increase your resilience and boost your self-esteem.
• Reach out to family and friends, especially in times of crisis, to help you weather rough spells.
• Get treatment at the earliest sign of a problem to help prevent depression from worsening.
• Consider getting long-term maintenance treatment to help prevent a relapse of symptoms.
• Brown AY. Allscripts EPSi. Mayo Clinic, Rochester, Minn. Nov. 17, 2016.
• Research report: Psychiatry and psychology, 2016-2017. Mayo Clinic. http://www.mayo.edu/research/departments-divisions/department-psychiatry-psychology/overview?_ga=1.199925222.939187614.1464371889. Accessed Jan. 23, 2017.
• Depressive disorders. In: Diagnostic and Statistical Manual of Mental Disorders DSM-5. 5th ed. Arlington, Va.: American Psychiatric Association; 2013. http://www.psychiatryonline.org. Accessed Jan. 23, 2017.
• Depression. National Institute of Mental Health. https://www.nimh.nih.gov/health/topics/depression/index.shtml. Accessed Jan. 23, 2017.
• Depression. National Alliance on Mental Illness. http://www.nami.org/Learn-More/Mental-Health-Conditions/Depression/Overview. Accessed Jan. 23, 2017.
• Depression: What you need to know. National Institute of Mental Health. https://www.nimh.nih.gov/health/publications/depression-what-you-need-to-know/index.shtml. Accessed Jan. 23, 2017.
• What is depression? American Psychiatric Association. https://www.psychiatry.org/patients-families/depression/what-is-depression. Accessed Jan. 23, 2017.
• Depression. NIH Senior Health. https://nihseniorhealth.gov/depression/aboutdepression/01.html. Accessed Jan. 23, 2017.
• Children’s mental health: Anxiety and depression. Centers for Disease Control and Prevention. https://www.cdc.gov/childrensmentalhealth/depression.html#depression. Accessed. Jan. 23, 2017.
• Depression and complementary health approaches: What the science says. National Center for Complementary and Integrative Health. https://nccih.nih.gov/health/providers/digest/depression-science. Accessed Jan. 23, 2017.
• Depression. Natural Medicines. https://naturalmedicines.therapeuticresearch.com/databases/medical-conditions/d/depression.aspx. Accessed Jan. 23, 2017.
• Natural medicines in the clinical management of depression. Natural Medicines. http://naturaldatabase.therapeuticresearch.com/ce/CECourse.aspx?cs=naturalstandard&s=ND&pm=5&pc=15-111. Accessed Jan. 23, 2017.
• The road to resilience. American Psychological Association. http://www.apa.org/helpcenter/road-resilience.aspx. Accessed Jan. 23, 2017.
• Simon G, et al. Unipolar depression in adults: Choosing initial treatment. http://www.uptodate.com/home. Accessed Jan. 23, 2017.
• Stewart D, et al. Risks of antidepressants during pregnancy: Selective serotonin reuptake inhibitors (SSRIs). http://www.uptodate.com/home. Accessed Jan. 23, 2017.
• Kimmel MC, et al. Safety of infant exposure to antidepressants and benzodiazepines through breastfeeding. http://www.uptodate.com/home. Accessed Jan. 23, 2017.
• Bipolar and related disorders. In: Diagnostic and Statistical Manual of Mental Disorders DSM-5. 5th ed. Arlington, Va.: American Psychiatric Association; 2013. http://www.psychiatryonline.org. Accessed Jan. 23, 2017.
• Hirsch M, et al. Monoamine oxidase inhibitors (MAOIs) for treating depressed adults. http://www.uptodate.com/home. Accessed Jan. 24, 2017.
• Hall-Flavin DK (expert opinion). Mayo Clinic, Rochester, Minn. Jan. 31, 2017.
• Krieger CA (expert opinion). Mayo Clinic, Rochester, Minn. Feb. 2, 2017.
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• Volume 14, Issue 4
• Repurposing of dextromethorphan as an adjunct therapy in patients with major depressive disorder: a randomised, group sequential adaptive design, controlled clinical trial protocol
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• Shampa Maji 1 ,
• Debadatta Mohapatra 2 ,
• Monalisa Jena 1 ,
• Anand Srinivasan 1 ,
• http://orcid.org/0000-0003-4063-9178 Rituparna Maiti 1
• 1 Pharmacology , All India Institute of Medical Sciences , Bhubaneswar , Odisha , India
• 2 Psychiatry , All India Institute of Medical Sciences , Bhubaneswar , Odisha , India
• Correspondence to Dr Rituparna Maiti; pharm_rituparna{at}aiimsbhubaneswar.edu.in

Background Therapeutic latency, lack of efficacy and adverse drug reactions are the major concerns in current antidepressant therapies. To overcome these treatment hurdles, add-on therapy to conventional antidepressant medications may lead to better therapeutic outcomes. The present randomised controlled trial has been planned to evaluate the efficacy and safety of add-on dextromethorphan to selective serotonin reuptake inhibitors (SSRIs) in major depressive disorder (MDD).

Methods and analysis A randomised, double-blind, add-on, placebo-controlled, group sequential design clinical trial will be conducted on patients with MDD who will be randomly assigned to the control and the test group in a 1:1 ratio. Patients in the test group will get dextromethorphan 30 mg once daily, whereas patients in the control group will receive a placebo once daily as an add-on to ongoing SSRI treatment for 8 weeks. All patients will be evaluated for the primary outcome (change in the Montgomery-Åsberg Depression Rating Scale score) and secondary outcomes (treatment response rate, remission rate, Clinical Global Impression, serum brain-derived neurotrophic factor, serum dextromethorphan and treatment-emergent adverse events) over the period of 8 weeks. Intention-to-treat analysis will be done for all parameters using suitable statistical tools.

Ethics and dissemination This study was approved by the Institutional Ethics Committee of All India Institute of Medical Sciences, Bhubaneswar, India, and the study conformed to the provisions of the Declaration of Helsinki and ICMR’s ethical guidelines for biomedical research on human subjects (2017). Written informed consent will be obtained from the participants before recruitment. The results of this study will be published in peer-reviewed publications.

Trial registration number NCT05181527 .

• Depression & mood disorders
• CLINICAL PHARMACOLOGY
• Adult psychiatry
• Randomized Controlled Trial

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

https://doi.org/10.1136/bmjopen-2023-080500

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STRENGTHS AND LIMITATIONS OF THIS STUDY

This is the first randomised, double-blind clinical trial on dextromethorphan in major depressive disorder.

Group sequential adaptive design will allow two interim analyses and will save resources.

Being a single-centre study, generalisability may be limited.

The study is not going to compare the time to response between the study groups.

Evaluation of multiple doses of dextromethorphan and a longer follow-up period with multiple time points would have strengthened the study data.

Major depressive disorder (MDD) is a common psychiatric disorder with a substantial socioeconomic burden with a global prevalence rate of 16%. 1 The underlying pathophysiology of depression is still not understood completely. 2 Among the different proposed hypotheses, the most accepted is the monoamine hypothesis, which is the basis of conventional antidepressant medications like tricyclic antidepressants, monoamine oxidase inhibitors, selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors. Although many medications are available, a significant proportion of patients become either partial responders (less than 25% improvement on a depression rating scale), non-responders (improvement between 25% and 50% on a rating scale) or treatment-resistant depression (TRD) patients (when at least two trials with antidepressants from different pharmacological classes in adequate dose, duration and compliance fail to produce a significant clinical improvement). 3–5 Another major concern is the therapeutic lag period with all these monoaminergic antidepressants. Additionally, most of the available antidepressant medications have many adverse effects, which increase with increments in dose. The discovery of the rapid and sustained antidepressant effect of a subanaesthetic dose of ketamine, especially in the treatment of non-responders and treatment-resistant cases, 1 6 has led to extensive clinical and preclinical research in the recent past. The US Food and Drug Administration (FDA) has also approved esketamine nasal spray for the treatment of TRD in adults. 7 As repeated doses of ketamine are related to abusive potential and many other adverse effects, 8 the search for a similar antidepressant agent is going on that acts via a similar mechanism with a better safety profile.

Dextromethorphan, a US FDA-approved over-the-counter antitussive medication, has a similar property of non-competitively blocking N-methyl-D-aspartate (NMDA) receptors of glutamate, like ketamine. 9 Additionally, dextromethorphan has serotonin reuptake transporter (SERT) inhibitory and norepinephrine transporter (NET) inhibitory properties, 10 so it can also increase the availability of serotonin in synapses, hence may achieve a synergistic effect with SSRIs. 11 12 In 2010, US-FDA approved dextromethorphan plus quinidine (Nuedexta) for use in pseudobulbar affect, 9 10 13 and currently, it is under investigation as a potential antidepressant agent in MDD ( NCT01882829 , NCT02153502 ). 10 13 A phase IIa clinical trial by Murrough et al has reported acceptable tolerability and efficacy of dextromethorphan/quinidine combination in TRD. 14 In 2022, the US FDA approved dextromethorphan hydrobromide and bupropion hydrochloride fixed-dose combination (Auvelity) for the treatment of MDD in adult patients. 15 Akbar et al , in their systematic review, evaluated the efficacy and safety of the dextromethorphan-bupropion combination for depression and highlighted the importance of evaluating the potential impact of combining dextromethorphan with other CYP2D6 inhibitors, such as antidepressants known to interact with CYP2D6, specifically in patients diagnosed with MDD. 16 Previous preclinical and clinical studies 14 17–25 on dextromethorphan in depression have been presented in online supplemental table S1 .

Supplemental material

In the present background, we hypothesise that the major concerns of antidepressant therapy, like therapeutic latency, lack of efficacy and adverse drug reactions, may be overcome by adding dextromethorphan to SSRI in MDD. As SSRIs inhibit CYP2D6, the addition of quinidine with dextromethorphan may not be reasonable and, hence, not considered in the present study. Our literature search found that, to date, there is no randomised controlled trial on dextromethorphan as an add-on therapy to first-line antidepressants like SSRIs. So, the present randomised controlled trial has been planned with an objective to evaluate the efficacy and safety of add-on dextromethorphan to SSRIs in MDD.

Objectives of the study

Primary objective.

To evaluate the change in symptoms of Depression using the Montgomery-Asberg Depression Rating Scale (MADRS) score from baseline after 8 weeks treatment with add-on dextromethorphan in patients with MDD.

Secondary objectives

To evaluate the treatment response rate (defined as a reduction of ≥50% of the MADRS score from baseline) at 8 weeks.

To evaluate the remission rate (defined as a score of <7 MADRS post-treatment) after 8 weeks.

To evaluate clinical status assessed by Clinical Global Impression (CGI) (severity and improvement) from baseline after 8 weeks.

To evaluate the neurotrophic effect of add-on dextromethorphan in terms of change in serum level of brain-derived neurotrophic factor (BDNF) from baseline after 8 weeks.

To evaluate the serum level of dextromethorphan after 8 weeks.

To evaluate the adverse drug effect profile of oral dextromethorphan.

Study design

The proposed study is a randomised, double-blind, add-on placebo-controlled, parallel-arm, group sequential design clinical trial. The study protocol has been prepared following the guidelines of Standard Protocol Item Recommendations for Interventional Trials and registered with ClinicalTrials.gov. The present study is a single-centred study and will be conducted in the departments of Pharmacology and Psychiatry of our institute. The approval from the Institutional Ethics Committee, All India Institute of Medical Sciences, Bhubaneswar, India, was obtained on 14 December 2021.

The present trial will follow a group sequential design with two interim analyses. The first interim analysis will be done after completion of follow-up of 34 participants (17 in each group), and the second interim analysis will be done after completion of 60 participants (30 in each group) ( figure 1 ). If the z value breaches the O'Brien-Fleming boundary of futility or efficacy during any interim analysis, the trial will be stopped ( figure 2 ).

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Study flow chart. SSRI, selective serotonin reuptake inhibitor.

O'Brien Fleming boundary targets along with sample size provided the allocation ratio is maintained as 1:1 throughout the study. (Z-score 2.868, 2.060 and 1.708 corresponds to a p value of 0. 0.0021, 0.0197 and 0.0438, respectively).

Study population and eligibility

Patients attending the outpatient psychiatry department of our institute with MDD will be screened, and enrolment will be done as per predefined inclusion and exclusion criteria. After direct communication with the principal investigator, detailed information regarding interventions, assessment methods, benefits and potential adverse reactions will be explained, and a patient information sheet will be provided to the participants. Written informed consent will be obtained from all participants before they participate in the study (participant informed consent form has been provided under online supplemental material ).

Diagnostic criteria

The diagnosis of depression will be solely clinical and Diagnostic, and the Statistical Manual of Mental Disorders-5 (DSM5) criteria 26 for diagnosing MDD will be followed:

‘A. Five (or more) of the following symptoms have been present during the same 2-week period and represent a change from previous functioning; at least one of the symptoms is either depressed mood or loss of interest or pleasure.

Depressed mood most of the day, nearly every day, as indicated by either subjective report (eg, feels sad, empty, hopeless) or observation made by others (eg, appears tearful).

Markedly diminished interest or pleasure in all, or almost all, activities most of the day, nearly every day (as indicated by either subjective account or observation.

Significant weight loss when not dieting or weight gain (eg, a change of more than 5% of body weight in a month) or decrease or increase in appetite nearly every day.

Insomnia or hypersomnia nearly every day.

Psychomotor agitation or retardation nearly every day (observable by others, not merely subjective feelings of restlessness or being slowed down).

Fatigue or loss of energy nearly every day.

Feelings of worthlessness or excessive or inappropriate guilt (which may be delusional) nearly every day (not merely self-reproach or guilt about being sick).

Diminished ability to think or concentrate, or indecisiveness, nearly every day (either by subjective account or as observed by others).

Recurrent thoughts of death (not just fear of dying), recurrent suicidal ideation without a specific plan, or a suicide attempt or a specific plan for committing suicide.

B. The symptoms cause clinically significant distress or impairment in social, occupational or other important areas of functioning.

C. The episode is not attributable to the physiological effects of a substance or another medical condition.’

Inclusion criteria

Patients diagnosed with MDD (DSM5) of either gender within the age group of 18–65 years.

Patients with MADRS scores ≥7 and ≤34 (patients having mild to moderate MDD).

Patients who are on a stable dose of sertraline 50 mg or any other SSRI therapy in an equivalent dose (fluoxetine 20 mg/day, paroxetine 20 mg/day, escitalopram 10 mg/day, fluvoxamine 75 mg/day). 27

Patients who have given written informed consent.

Exclusion criteria

Patients who have been treated with electroconvulsive therapy recently.

History of epilepsy, or other major neurological or medical disorders, head trauma.

Patients with a history of bipolar depression.

Patients with schizophrenia or other psychotic disorders.

Patients with cognitive impairment.

Initiating or stopping formal psychotherapy within 6 weeks before enrolment.

Patients with comorbidities like any malignancies, hepatic, renal, cardiovascular, neurological or endocrinal, or respiratory dysfunction.

Substance abuse history of psychoactive agents.

Pregnant and lactating mothers.

Sample size calculation

The sample size has been calculated based on the expected change in the primary outcome measure (MADRS score), and for the calculation, data have been taken from a previous randomised, controlled trial done by Kamijima et al where the mean (SD) difference in MADRS score was 7.2 (SD 7) between the groups. 28 Our calculation found that a sample size of 42/group (N=84) can achieve a power of 90% to detect an intergroup difference of 5 in the MADRS score, considering an SD of 7, alpha as 0.05 and allocation ratio 1:1.

We have planned a group sequential design with three analyses (two interim and the final analysis) during the course of the study. To control the increase in the chance of occurrence of type I error during the interim analyses, the O'Brien-Fleming boundary (with z scores and p value) has been defined as provided in figure 2 . The study will be terminated if the Z value of the effect size crosses the boundary on either side during an interim analysis. Sample size calculation was done using the software R (rpact). 29

Randomisation, allocation concealment and blinding

All the recruited patients will be randomised into two treatment groups by block randomisation using computer-generated codes. The fixed block size of 6 has been decided to be used for random code generation. The allocation ratio will be 1:1 throughout the study. For blinding purposes, the random allocation code of the participants will be generated by the investigator, who will not be involved in patient recruitment. The sequentially numbered and identical-looking medication dispensers will be used for allocation concealment. The randomisation sequence will be blinded to both participants and the investigators. For interim analysis, the randomisation code will be opened, and the analysis will be done by an investigator who will be blinded to the group allocation.

Interventions

Patients in the test group will get a dextromethorphan 30 mg capsule once daily orally as an add-on to ongoing SSRI treatment, whereas patients in the control group will get an identical-looking capsule containing a placebo (starch) once daily in addition to SSRI. Both placebo and test medication have to be consumed for 8 weeks.

Study procedure and data collection

Patients aged 18–65 years, of either gender, attending the psychiatry outpatient department of our institute, and having a diagnosis of MDD will be screened. Enrolment will be done after considering the predefined inclusion and exclusion criteria and obtaining written informed consent. A detailed history and basic clinical details will be recorded. At baseline, MADRS and CGI-S scores will be recorded. A 5 mL venous blood will be collected to estimate serum BDNF level at baseline. By using computer-generated algorithms, recruited patients will be randomised into test and control groups. Patients in the test group will get dextromethorphan 30 mg once daily orally as an add-on to ongoing SSRI treatment, whereas patients in the control group will get an identical-looking capsule containing a placebo (starch) once daily in addition to SSRI. Both placebo and test medication have to be consumed for 8 weeks. All patients are going to be followed up after 8 weeks, and post-treatment re-evaluation of all the above parameters, that is, MADRS scores, CGI scores, and serum BDNF levels, will be done. The detailed visit schedule is presented in online supplemental table S2 . There can be unscheduled visits due to deterioration of depressive symptoms or adverse drug reactions. Treatment-emergent adverse events will be reported and managed according to severity. Causality assessment will be done for adverse drug reactions by using the WHO-Uppsala Monitoring Centre (WHO-UMC) system.

Outcome measures

Primary outcome measure.

MADRS scores at baseline and 8 weeks follow-up. MADRS is a 10-item diagnostic questionnaire to measure the severity of depressive episodes in patients with mood disorders. Each item yields a score of 0–6; the overall score thus ranges from 0 to 60. The higher MADRS score indicates more severe depression. 30

Secondary outcome measures

The response rate of the patients, that is, percentage of patients showing 50% decrease in MADRS scores from baseline, at 8-week follow-up.

The remission rate, that is, percentage of patients achieving MADRS scores <7 at 8-week follow-up.

CGI scores: CGI-S (severity) at both baseline and follow-up and CGI-I (improvement) at 8 weeks. The CGI provides an overall clinician-determined summary measure that considers all available information, including a knowledge of the patient’s history, psychosocial circumstances, symptoms, behaviour and the impact of the symptoms on the patient’s ability to function. The CGI has two components: the CGI-Severity, which rates illness severity, and the CGI-Improvement, which rates change from the initiation (baseline) of treatment on a 7-point scale. 31

Serum BDNF level at baseline and at 8-week follow-up. Serum BDNF levels will be measured using a commercially available human ELISA kit.

Serum dextromethorphan level after completion of 8-week therapy using high-performance liquid chromatography (HPLC). For quantitative analysis of dextromethorphan, the HPLC method with fluorometric detection will be done as described by Lin et al. 32

Safety evaluation: During the follow-up visit, the occurrence of treatment-emergent adverse events will be assessed by non-directive questioning of the patient. Patients can directly access the investigators to report any adverse effects they have experienced. Whether previously known or not, all adverse events will be recorded with their description, intensity, duration, action taken, outcome and causal relationship to SSRIs and dextromethorphan. Treatment-emergent adverse events will be reported and managed according to severity. Causality assessment will be done for adverse drug reactions by using the WHO-UMC system.

Evaluation of medication adherence

The patient will be asked to return the remaining medication at the end of the 8-week period. The medication adherence (SSRI and dextromethorphan) will be calculated by pill count method. The patient will be considered compliant if there is >80% adherence to the pills used. Additionally, the serum dextromethorphan level will give an idea of compliance.

Discontinuation

In case of the following emergencies, participants will be allowed to discontinue and withdraw from the current study: (a) any allergic reactions or adverse events that should be withdrawn according to the physician’s judgement and (b) poor compliance (<80% medication adherence).

Data management

All demographic and clinical data will be captured in a case report form (CRF), and the data entry will be done with the sequence code of each recruited patient. One investigator will monitor the clinical data once a week. Signed consent forms will be attached to the individual CRF and will be accessible only to authorised investigators. A specific investigator will access and analyse the final datasheet.

Statistical analysis

Categorical variables such as gender, remission rate and response rate will be represented as percentage/proportion and continuous data like age, MADRS score, CGI score, serum BDNF as mean±SD or median and IQR if the data is non-parametric. For performing statistical analyses, R software will be used. 33 For the calculation of statistical significance, a p<0.05 will be considered. Analyses will be conducted with the intention-to-treat principle. Missing values will be analysed using multiple imputations, and the pooled data will be used for analysis. Fisher’s exact test will compare categorical variables between the groups. For comparing means/medians, the unpaired t-test/ Mann-Whitney U test (between the groups) and the two-sided paired t-test/Wilcoxon signed-rank test (within the group) will be used. The correlation between serum BDNF and disease severity treatment response will be checked using Pearson’s correlation coefficient calculation. Logistic regression will be performed to assess the factors affecting the response rates in MDD patients.

Ethics and dissemination

This study was approved by the Institutional Ethics Committee of All India Institute of Medical Sciences, Bhubaneswar, India, and the study conformed to the provisions of the Declaration of Helsinki and ICMR’s ethical guidelines for biomedical research on human subjects (2017). After explaining the benefits and harm of the study, written informed consent will be taken from all participants. The confidentiality of the study subjects will be maintained throughout the study duration by restricting access to specific investigators. They can exit from the study at their discretion. Being an academic clinical trial with limited funding, there will be no provision of post-trial access to the trial medication. In case of any treatment-emergent adverse events, the participant will be treated free of cost in the institute. The results of this research will be presented at academic conferences and published in peer-reviewed journals. The International Committee of Medical Journal Editors guidelines on authorship criteria will be followed, and the manuscript will be drafted and edited by the authors, not by any professional writers. The protocol is available on ClinicalTrials.gov, and the participant-level data set will be available from the corresponding author on reasonable request.

Study status

The recruitment started on 10 February 2022, and the follow-up of the 60th patients was completed on 30 September 2023. The second interim analysis was done for the primary outcome measure in October 2023. The result of the second interim analysis showed a statistically significant difference between the study groups in terms of reduction of MADRS score from baseline to the 8-week follow-up, and the O'Brien Fleming boundary was breached. Hence, the trial was terminated, and all secondary outcome measures were assessed.

Patient and public involvement

Patients and/or the public were not involved in the design, conduct, reporting or dissemination plans of this research.

Therapeutic latency, lack of efficacy and adverse drug reactions are the major limitations of current antidepressant therapies. To overcome these treatment hurdles, add-on therapy to conventional antidepressant medications may lead to better therapeutic outcomes. As dextromethorphan has the property of non-competitively blocking NMDA receptors (like ketamine) with additional SERT and NET inhibitory action, we hypothesise that adding dextromethorphan to the SSRI regimen can improve clinical outcomes in MDD. So, the present randomised controlled trial has been planned to evaluate the efficacy and safety of add-on dextromethorphan to SSRIs in MDD.

In the present randomised controlled trial, the potential of add-on therapy of dextromethorphan will be evaluated in comparison to add-on placebo therapy. The efficacy parameters are the change in MADRS scoring, responder rate, remission rate and change in serum BDNF from baseline. MADRS is an established and validated scoring system to assess the severity of depression and is used widely by psychiatrists for research and clinical practice. The definition of response and remission rate has been validated by Riedel et al , and the present study will follow the same. 34 On the other hand, the neurotrophic hypothesis of depression is based on BDNF, a neurotrophin that plays a significant role in the survival and development of neurons. 35 36 The connection between the BDNF signalling pathway and MDD is well established; hence, serum BDNF has been used as a biomarker in this study. 37 38 The estimation of serum dextromethorphan will help to assess compliance and ensure the therapeutic level required for the drug effect. Though SSRIs and dextromethorphan are well-tolerated medications, all treatment-emergent adverse events will be monitored.

The proposed clinical trial is the first registered trial on dextromethorphan as an add-on therapy to first-line antidepressants like SSRIs in MDD. The major strength of the study lies in its robust methodology and statistical analysis. The proposed study has certain limitations. First, as the study is a single-centre study, the generalisability of the data may be limited. Second, the outcome parameter, like time to response, could have been included to compare therapeutic latency between the groups. Third, instead of a single dose level of 30 mg, multiple doses could have been evaluated. Investigators opted for a safe dose for the present exploratory study. However, depending on the study results, a higher dose of 45 mg and 60 mg may be evaluated in future. Fourthly, a longer follow-up period with multiple time points would have strengthened the study data. However, the previous clinical trials on dextromethorphan in MDD by Iosifescu et al and Tabuteau et al were for a duration of 6 weeks. 39 40 So, we expect to generate clinically meaningful data with a follow-up period of 8 weeks. If the study results prove favourable, prescribing add-on dextromethorphan to first-line antidepressants, the dose requirement of antidepressant medications may decrease, there may be less chance of adverse drug reactions, and it may lead to better compliance and better clinical outcomes. Hence, the present study is expected to generate evidence on the use of adjuvant dextromethorphan with first-line antidepressant medications in MDD and contribute to practising guidelines.

Ethics statements

Patient consent for publication.

Consent obtained directly from patient(s).

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Supplementary materials

Supplementary data.

This web only file has been produced by the BMJ Publishing Group from an electronic file supplied by the author(s) and has not been edited for content.

• Data supplement 1
• Data supplement 2

Contributors Research conception and design: RM and DM. Literature review: SM and MJ. Statistical plan: AS and DM. Drafting of the manuscript: SM and RM. Critical revision of the manuscript: AM and MJ. All authors approved the final manuscript as submitted and agreed to be accountable for all aspects of the work.

Funding The first author has received funding from the Indian Council of Medical Research (ICMR), New Delhi, India, vide grant number No.3/2/Decembe-2021/PGThesis-HRD(12).

Competing interests None declared.

Patient and public involvement Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.

Provenance and peer review Not commissioned; externally peer reviewed.

Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.

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April 9, 2024, heart disease, depression linked by inflammation: study.

Coronary artery disease and major depression may be genetically linked via inflammatory pathways to an increased risk for cardiomyopathy, a degenerative heart muscle disease, researchers at Vanderbilt University Medical Center and Massachusetts General Hospital have found.

Their report, published April 5 in the journal Nature Mental Health , suggests that drugs prescribed for coronary artery disease and depression, when used in combination, potentially may reduce inflammation and prevent the development of cardiomyopathy.

“This work suggests that chronic low-level inflammation may be a significant contributor to both depression and cardiovascular disease,” said the paper’s corresponding author, Lea Davis , PhD, associate professor of Medicine in the Division of Genetic Medicine and Vanderbilt Genetics Institute.

The connection between depression and other serious health conditions is well known. As many as 44% of patients with coronary artery disease (CAD), the most common form of cardiovascular disease, also have a diagnosis of major depression. Yet the biological relationship between the two conditions remains poorly understood.

A possible connection is inflammation. Changes in the levels of inflammatory markers have been observed in both conditions, suggesting that there may be a common biological pathway linking neuroinflammation in depression with atherosclerotic inflammation in CAD.

In the current study, the researchers used a technique called transcriptome-wide association scans to map single nucleotide polymorphisms (genetic variations) involved in regulating the expression of genes associated with both CAD and depression.

The technique identified 185 genes that were significantly associated with both depression and CAD, and which were “enriched” for biological roles in inflammation and cardiomyopathy. This suggests that predisposition to both depression and CAD, which the researchers called (major) depressive CAD, or (m)dCAD, may further predispose individuals to cardiomyopathy.

However, when the researchers scanned large electronic health record databases at VUMC, Mass General, and the National Institutes of Health’s All of Us Research Program, they found the actual incidence of cardiomyopathy in patients with the enriched genes for (m)dCAD was lower than in patients with CAD alone.

One possible explanation is that medications prescribed for CAD and depression, such as statins and antidepressants, may prevent development of cardiomyopathy by reducing inflammation, the researchers concluded.

“More research is needed to investigate optimal treatment mechanisms,” Davis added, “but at a minimum this work suggests that patient heart and brain health should be considered together when developing management plans to treat depression or cardiovascular disease.”

Kritika Singh, PhD, the paper’s first author, is a former graduate student in the Davis lab who is now a postdoctoral Innovation Fellow at Novartis in Cambridge, Massachusetts.

Other VUMC co-authors are Tyne Miller-Fleming, PhD, Peter Straub, MS, Nancy Cox, PhD, founding director of the Vanderbilt Genetics Institute, and institute members Quinn Wells, MD, PharmD, MSCI, associate professor of Medicine in the Division of the Cardiovascular Medicine, and Emily Hodges, PhD, assistant professor of Biochemistry.

The research was supported by National Institutes of Health grants R56MH120736, R01H118233, 1F31MH124306, and 1R01HL140074, and an American Heart Association Fellowship.

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Physical Fitness Linked to Better Mental Health in Young People

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

By Matt Richtel

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

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

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

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

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

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

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

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

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

The Big Picture

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

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

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

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

Understanding A.D.H.D.

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The Mental Health Toll of Covid-19 Appears to Be Fading

Impact of covid-19 pandemic on mental health.

Aside from killing 1.2 million Americans, putting millions in the hospital and wreaking havoc on the country’s economy, the Covid-19 pandemic also took a heavy toll on mental health . Data compiled by the U.S. Census Bureau and the National Center for Health Statistics clearly showed a spike in the prevalence of symptoms associated with anxiety and/or depressive disorder following the onset of the pandemic. These psychologial effects of Covid-19 even outlived the pandemic itself, as in March/April 2024, symptoms of anxiety or depression were still roughly twice as common as they were in April 2019. However, the latest results published by the National Center for Health Statistics indicate a positive trend, as the mental toll of the pandemic finally appears to be fading. In April 2024, 21 percent of respondents reported symptoms of anxiety or depression, down from 34 percent in October 2023 and from a peak of 43 percent in November 2020.

The latest findings are derived from the Household Pulse Survey, which has been launched to produce data on the social and economic impacts of Covid-19 on American households. Since April 2020, tens of thousands of Americans have been asked to complete the web survey in order to "gauge the impact of the pandemic on employment status, consumer spending, food security, housing, education disruptions, and dimensions of physical and mental wellness." Among other things, respondents were asked to report how often they have felt down, depressed, hopeless or anxious in the last week, how often they have been unable to stop worrying or shown little interest or pleasure in doing things – all symptoms that have been shown to be associated with diagnoses of generalized anxiety disorder or major depressive disorder.

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