research articles on depression

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• v.9(31); 2021 Nov 6

Major depressive disorder: Validated treatments and future challenges

Rabie karrouri.

Department of Psychiatry, Moulay Ismaïl Military Hospital, Faculty of Medicine and Pharmacy, Sidi Mohamed Ben Abdellah University, Fez 30070, Morocco

Zakaria Hammani

Roukaya benjelloun.

Department of Psychiatry, Faculty of Medicine, Mohammed VI University of Health Sciences, Casablanca 20000, Morocco

Yassine Otheman

Department of Psychiatry, Moulay Ismaïl Military Hospital, Faculty of Medicine and Pharmacy, Sidi Mohamed Ben Abdellah University, Fez 30070, Morocco. [email protected]

Corresponding author: Yassine Otheman, MD, Associate Professor, Chief Doctor, Department of Psychiatry, Moulay Ismaïl Military Hospital, Faculty of Medicine and Pharmacy, Sidi Mohamed Ben Abdellah University, 1893, Km 2.2 road of Sidi Hrazem, Fez 30070, Morocco. [email protected]

Depression is a prevalent psychiatric disorder that often leads to poor quality of life and impaired functioning. Treatment during the acute phase of a major depressive episode aims to help the patient reach a remission state and eventually return to their baseline level of functioning. Pharmacotherapy, especially selective serotonin reuptake inhibitors antidepressants, remains the most frequent option for treating depression during the acute phase, while other promising pharmacological options are still competing for the attention of practitioners. Depression-focused psychotherapy is the second most common option for helping patients overcome the acute phase, maintain remission, and prevent relapses. Electroconvulsive therapy is the most effective somatic therapy for depression in some specific situations; meanwhile, other methods have limits, and their specific indications are still being studied. Combining medications, psychotherapy, and somatic therapies remains the most effective way to manage resistant forms of depression.

Core Tip: Depression is a persistent public health problem for which treatments must be codified and simplified to enhance current practice. Several therapies have been suggested worldwide, with varying levels of validity. This article explores effective and valid therapies for treating depression by addressing current and future research topics for different treatment categories.

INTRODUCTION

Depression is a common psychiatric disorder and a major contributor to the global burden of diseases. According to the World Health Organization, depression is the second-leading cause of disability in the world and is projected to rank first by 2030[ 1 ]. Depression is also associated with high rates of suicidal behavior and mortality[ 2 ].

Treatments administered during the acute phase of a major depressive episode aim to help the patient reach a remission state and eventually return to their baseline level of functioning[ 3 ]. Acute-phase treatment options include pharmacotherapy, depression-focused psychotherapy, combinations of medications and psychotherapy, and somatic therapies such as electroconvulsive therapy (ECT). Nevertheless, managing the acute phase of depression is only the first step in a long therapy process that aims to maintain remission and prevent relapses. In this article, we discuss various treatment options implemented by clinicians, highlighting the role that each option plays in actual psychiatric practice.

PHARMACOTHERAPY

While selective serotonin reuptake inhibitors (SSRIs) remain the gold-standard treatment for depression, new antidepressants are always being developed and tested. The ultimate goal is to discover a molecule that exhibits quick effectiveness with as few side effects as possible.

Daniel Bovet studied the structure of histamine (the causative agent in allergic responses) to find an antagonist, which was finally synthesized in 1937[ 4 ]. Since then, many researchers have studied the link between the structures and activities of different antihistaminic agents, contributing to the discovery of almost all antidepressants[ 5 ].

In the following subsections, we list the main classes of antidepressants in chronological order of apparition, highlighting the most widely used molecules in daily psychiatric practice.

Monoamine oxidase inhibitors

Iproniazid was the first drug defined as an antidepressant; it was later classified as a monoamine oxidase inhibitor (MAOI)[ 6 , 7 ]. Several other MAOIs have been introduced since 1957[ 8 ]. Due to their irreversible inhibition of monoamine oxidase, MOAIs have numerous side effects, such as hepatotoxicity and hypertensive crises, that can lead to lethal intracranial hemorrhages. Consequently, MAOIs have become less commonly used over time[ 9 ].

Trials have demonstrated that MAOIs’ efficacy is comparable to that of tricyclic antidepressants (TCAs)[ 10 , 11 ]. However, considering MAOIs’ drug interactions, dietary restrictions, and potentially dangerous side effects, they are now almost exclusively prescribed for patients who have not responded to several other pharmacotherapies, including TCAs[ 9 ]. Furthermore, MAOIs have demonstrated specific efficacy in treating depression with atypical features, such as reactive moods, reverse neuro-vegetative symptoms, and sensitivity to rejection[ 12 ].

MAOIs are also a potential therapeutic option when ECT is contraindicated[ 13 ]. MAOIs’ effectiveness is still unclear for treating depression in patients who are resistant to multiple sequential trials with SSRIs and serotonin-norepinephrine reuptake inhibitors (SNRIs)[ 14 ]. Nevertheless, psychiatrists’ use of MAOIs has declined over the years[ 15 , 16 ]. The use of MAOIs is generally restricted to patients who do not respond to other treatments.

The first TCA was discovered and released for clinical use in 1957 under the brand name Tofranil[ 5 , 17 ]. Since then, TCAs have remained among the most frequently prescribed drugs worldwide[ 9 ]. TCAs-such as amitriptyline, nortriptyline, protriptyline, imipramine, desipramine, doxepin, and trimipramine-are about as effective as other classes of antidepressants-including SSRIs, SNRIs, and MAOIs-in treating major depression[ 18 , 19 ].

However, some TCAs can be more effective than SSRIs when used to treat hospitalized patients[ 20 ]. This efficacy can be explained by the superiority of TCAs over SSRIs for patients with severe major depressive disorder (MDD) symptoms who require hospitalization[ 21 - 24 ]. However, no differences have been detected in outpatients who are considered less severely ill[ 18 , 20 ]. In most cases, TCAs should generally be reserved for situations when first-line drug treatments have failed[ 25 ].

In December 1987, a series of clinical studies confirmed that an SSRI called fluoxetine was as effective as TCAs for treating depression while causing fewer adverse effects[ 26 ]. After being released onto the market, its use expanded more quickly than that of any other psychotropic in history. In 1994, it was the second-best-selling drug in the world[ 7 ].

Currently available SSRIs include fluoxetine, sertraline, paroxetine, fluvoxamine, citalopram, and escitalopram. They have elicited different tolerance rates and side effects-mostly sexual and digestive (nausea and loss of appetite), as well as irritability, anxiety, insomnia, and headaches[ 27 ]. Nevertheless, SSRIs have a good tolerability profile[ 28 ].

In most systematic reviews and meta-analyses, SSRIs have demonstrated comparable efficacy to TCAs[ 18 , 19 , 29 ], and there is no significant evidence indicating the superiority of any other class or agent over SSRIs[ 29 - 31 ]. Furthermore, studies show no differences in efficacy among individual SSRIs[ 29 , 31 - 34 ]. Therefore, most guidelines currently recommend SSRIs as the first-line treatment for patients with major depression[ 25 ].

Norepinephrine reuptake inhibitors

Other monoamine (norepinephrine, serotonin, and dopamine) neurotransmitter reuptake inhibitors called SNRIs emerged during the 1990s to protect patients against the adverse effects of SSRIs[ 35 ]. Currently available SNRIs are venlafaxine, desvenlafaxine (the principal metabolite of venlafaxine), and duloxetine. The extended-release form of venlafaxine is the most commonly used drug in this class. Clinical guidelines commonly recommend prescribing SNRI to patients who do not respond to SSRIs[ 25 ].

In individual studies, venlafaxine and duloxetine are generally considered effective as SSRIs[ 36 ]. Also, venlafaxine’s efficacy is comparable to that of TCAs[ 37 , 38 ].

According to some meta-analyses, reboxetine (a selective noradrenaline reuptake inhibitor) seems less efficacious than SSRIs[ 39 ]. However, these findings could be due to the relatively poor tolerance of reboxetine[ 40 ].

Other antidepressants

Trazodone is the oldest medication of the so-called “other antidepressants” group that is still in wide use[ 41 , 42 ]. It has been shown to be an effective antidepressant in placebo-controlled research. However, in contemporary practice, it is much more likely to be used in low doses as a sedative-hypnotic than as an antidepressant[ 41 , 42 ].

Nefazodone’s structure is analogous to that of trazodone, though it has different pharmacological properties[ 43 ]. Its efficacy and overall tolerability are comparable to those of SSRIs, as indicated by comparative trials[ 43 ]. However, its use is associated with rare (but fatal) cases of clinical idiosyncratic hepatotoxicity[ 44 ].

Bupropion’s mechanism of action remains unclear, though it is classified as a norepinephrine and dopamine reuptake inhibitor[ 45 ]. It appears to have a more activating profile than SSRIs that are modestly superior to bupropion in patients with MDD[ 46 ]. However, for individuals with low to moderate levels of anxiety, the efficacy of bupropion in treating MDD is comparable to that of SSRIs[ 46 ]. Moreover, bupropion has a better tolerability profile than SSRIs, with minimal weight gain (or even leading to weight loss)[ 46 ]. In addition, bupropion is more likely than some SSRIs to improve symptoms of fatigue and sleepiness[ 47 ].

Mirtazapine and mianserin are tetracyclic compounds believed to increase the availability of serotonin or norepinephrine (or both), at least initially. Mirtazapine’s ability to antagonize serotoninergic subtypes receptors, <5-HT2A> and <5-HT2C>, could also increase norepinephrine and dopamine release in cortical regions[ 25 ]. Mirtazapine is about as effective as SSRIs[ 48 ].

Recently, drugs have been developed that block serotonin reuptake while affecting a variety of 5-HT receptor subtypes. The advantages of these agents ( e.g. , vilazodone and vortioxetine) over SSRIs are not fully clear. However, they appear to produce less sexual dysfunction and, in the specific case of vortioxetine, have particular benefits in depression-related cognitive impairment[ 49 ]. Indeed, vortioxetine is a very recent antidepressant with a multimodal mechanism that is thought to have a high affinity for serotonin transporters and 5-HT3, 5HT1A, 5HT7 receptors. Such a specific profile seems to indicate a level of efficacy to other antidepressants with a specific action on cognitive impairments[ 50 , 51 ].

In conclusion, no significant differences have been found between different classes of antidepressants in terms of their efficacy[ 52 ], though some drugs show some weak-to-moderate evidence indicating they are more effective than some other drugs[ 53 ]. Concerning the acceptability of these drugs, citalopram, escitalopram, fluoxetine, sertraline, and vortioxetine have been deemed more tolerable than other antidepressants, whereas amitriptyline, clomipramine, duloxetine, fluvoxamine, trazodone, and venlafaxine had the highest dropout rates[ 53 ] because of their more frequent and severe side effects. Nausea and vomiting were the most common reasons for treatment discontinuation; sexual dysfunction, sedation, priapism, and cardiotoxicity were also reported[ 31 , 41 ].

Ketamine and related molecules

In intravenous sub-anesthetic doses, ketamine has very quick effects on resistant unipolar (and, possibly, bipolar) depression and acute suicidal ideation[ 54 , 55 ]. The antidepressant effect of ketamine can persist for several days but eventually wanes. A few reports are have cited oral and intranasal formulations of ketamine for treatment-resistant depression[ 56 , 57 ], but there is still no data about the potential link between the onset of action and the route of administration.

Common adverse effects of ketamine include dizziness, neurotoxicity, cognitive dysfunction, blurred vision, psychosis, dissociation, urological dysfunction, restlessness, headache, nausea, vomiting, and cardiovascular symptoms[ 58 ]. Such adverse effects tend to be brief in acute, low-dose treatments[ 36 ], whereas prolonged exposure may predispose patients to neurotoxicity and drug dependence[ 56 ]. Lastly, since ketamine is associated with a higher risk of drug abuse and addiction, it cannot be recommended in daily clinical practice[ 59 , 60 ].

Ketamine is not a miracle drug, and many important factors still need to be defined, such as the most effective dose and the optimal administration route[ 61 , 62 ]. The current lack of guidelines about the therapeutic monitoring of ketamine treatment for depression further complicates the expanding use of this treatment[ 56 ]. Even though ketamine might never reach the market, it has stimulated research in the neurobiology of depression, including studies on potential fast and long-lasting antidepressants.

Ketamine has an active metabolite (hydroxynorketamine) that can produce rapid and sustained glutamatergic stimulation. It also seems to be free of many of the safety problems associated with ketamine and, thus, should be studied.

Research on the S-enantiomer of ketamine (S-ketamine, or esketamine, especially intranasal) could also be valuable, as it has a 3 to 4 times greater affinity than ketamine for the N-methyl-D-aspartate (NMDA) receptor[ 40 ]. It was approved by the United States Food and Drug Administration in March 2019 for treatment-resistant depression. However, current knowledge about the effects of prolonged esketamine therapy is still preliminary. In addition, regarding the potential risk of abuse, esketamine use must be carefully monitored[ 63 - 65 ].

Other glutamate receptor modulators have been evaluated in small studies as monotherapy agents or as adjuncts to other antidepressants. Examples include noncompetitive NMDA receptor antagonists (memantine, dextromethorphan/quinidi-ne, dextromethorphan/bupropion, and lanicemine), NR2B subunit-specific NMDA receptor antagonists (traxoprodil), NMDA receptor glycine site partial agonists (D-cycloserine, rapastinel), and metabotropic glutamate receptor antagonists (basimglurant, declogurant)[ 66 - 68 ] (Table ​ (Table1). 1 ).

Main classes of antidepressants with their date of approval, contributions, and disadvantages

NMDA: N-methyl-D-aspartate; SSRI: DSelective serotonin reuptake inhibitors; MDD: Major depressive disorder; MAOI: Monoamine oxidase inhibitor.

Perspectives

A purely neurotransmitter-based explanation for antidepressant drug action-especially serotonin-inhibiting drugs-is challenged by the significant percentage of patients who never achieve full remission[ 6 ] and the delayed clinical onset, which varies from two to four weeks. Moreover, studies show an acute increase in monoamines in the synaptic cleft immediately following treatment[ 69 ], even when the depletion of tryptophan (serotonin’s precursor) does not induce depressive-like behavior in healthy humans[ 70 , 71 ].

This finding shows that research on the pharmacological options for treating depression must go beyond monoaminergic neurotransmission systems. Research on the development of new antidepressants should explore several mechanisms of action on several types of receptors: Antagonism, inhibition of the reuptake of neurotransmitters, and modulators of glutamate receptors, as well as interactions with α-amino-3-acid receptors, hydroxy-5-methyl-4-isoxazolepropionic, brain-derived neurotrophic factor, tyrosine kinase B receptor (the mechanistic target of rapamycin), and glycogen synthase kinase-3[ 72 ].

Identifying the cellular targets of rapid-acting agents like ketamine could help practitioners develop more effective antidepressant molecules by revealing other receptors involved in gamma-aminobutyric acid regulation and glutamate transmission[ 73 ].

PSYCHOTHERAPY

Psychotherapeutic interventions are widely used to treat and prevent most psychiatric disorders. Such interventions are common in cases of depression, psychosocial difficulties, interpersonal problems, and intra-psychic conflicts. The specific psychotherapy approach chosen for any given case depends on the patient’s preference, as well as on the clinician’s background and availability[ 74 ] . Psychotherapy for patients with depression strengthens the therapeutic alliance and enables the patient to monitor their mood, improve their functioning, understand their symptoms better, and master the practical tools they need to cope with stressful events[ 75 ]. The following subsections briefly describe psychotherapeutic interventions that have been designed specifically for patients with depression.

Overview of psychotherapy in depression

Depression-focused psychotherapy is typically considered the initial treatment method for mild to moderate MDD. Based on significant clinical evidence, two specific psychotherapeutic methods are recommended: Cognitive-behavioral therapy (CBT) and interpersonal therapy (IPT). Supportive therapy (ST) and psychoeducational intervention (PEI) have also been recommended, those the evidence supporting these methods s not as strong. In more cases of severe depression, ST and PEI are used only to augment pharmacological treatments.

After remission, CBT, PEI, and mindfulness-based cognitive therapy (MBCT) are proposed to maintain and prevent depression. However, when psychotherapy has been effective during the initial phases of a depressive episode, it should be continued to maintain remission and prevent relapses while reducing the frequency of sessions[ 25 , 75 , 76 ].

Specific and intensive psychotherapeutic support is recommended for patients with chronic depression because of high rates of comorbidity with personality disorders, early trauma, and attachment deficits. The European Psychiatric Association recommends using the Cognitive Behavioral Analysis System of Psychotherapy (CBASP) for treating chronic depression and utilizing specific approaches suited to each patient’s preferences[ 77 ]. All these therapeutic options are summarized in Figure ​ Figure1 1 .

Overview of psychotherapy in different clinical situations of depression. MDD: Major depressive disorder; CBT: Cognitive-behavioral therapy; IPT: Interpersonal therapy; ST: Supportive therapy; PEI: Psycho-educational intervention; MBCT: Mindfulness based cognitive therapy; SIPS: Specific and intensive psychotherapeutic support; CBASP: Cognitive Behavioral Analysis System of Psychotherapy.

Structured psychotherapies

Cognitive and behavioral therapies: Based on robust evidence, CBT is one of the most well-documented and validated psychotherapeutic methods available. Interventional strategies are based on modifying dysfunctional behaviors and cognitions[ 77 ]. CBT targets depressed patients’ irrational beliefs and distorted cognitions that perpetuate depressive symptoms by challenging and reversing them[ 3 ]. Thus, CBT is a well-known effective treatment method for MDD[ 78 ] and has been recommended in most guidelines as a first-line treatment[ 79 - 81 ].

However, the effectiveness of CBT depends on patient’s capacity to observe and change their own beliefs and behaviors. Some simple techniques were developed to overcome this issue, especially in primary care management. Behavioral activation is one such technique, consisting of integrating pleasant activities into daily life to increase the number and intensity of the positive interactions that the patient has with their environment[ 82 , 83 ].

Acceptance and commitment therapy is another form of CBT. This type of therapy, which is based on functional contextualism, can help patients accept and adjusting to persistent problems. It appears to be effective in reducing depressive symptoms and preventing relapses[ 77 , 84 ].

Another form of CBT is computerized CBT (CCBT), implemented via a computer with a CD-ROM, DVD, or online CCBT, allowing patients to benefit from this therapy under conditions of reduced mobility, remoteness, confinement, or quarantine[ 79 ] .

CCBT and guided bibliotherapy based on CBT could be considered for self-motivated patients with mild to moderate major depression or as a complementary treatment to pharmacotherapy[ 25 ]. CBT is also recommended for patients with resistant depression in combination with antidepressants[ 85 ].

Schema therapy is another CBT-derived therapy that can be used in patients who have failed classical CBT, like patients with personality disorder comorbidity. Schema therapy is about as effective as CBT for treating depression[ 86 ]. In adolescent patients with depression, CBT is also a recommended option with plenty of evidence from multiple trials. Meanwhile, it remains the first-line treatment in children despite mixed findings across trials[ 87 ] . CBT is also a promising option for elderly depressed patients, though substantial evidence is still lacking because of the limited data on the subject[ 88 ] .

IPT: The goal of IPT is to identify the triggers of depressive symptoms or episodes. These triggers may include losses, social isolation, or difficulties in social interactions. The role of the intervention is to facilitate mourning (in the case of bereavement), help the patient recognize their own affect, and resolve social interaction dysfunction by building their social skills and social supports[ 89 ]. IPT, like CBT, is a first-line treatment for mild to moderate major depressive episodes in adults; it is also a well-established intervention for adolescents with depression[ 25 ] .

Problem-solving therapy: The problem-solving therapy (PST) approach combines cognitive and interpersonal elements, focusing on negative assessments of situations and problem-solving strategies. PST has been used in different clinical situations, like preventing depression among the elderly and treating patients with mild depressive symptoms, especially in primary care. Despite its small effect sizes, PST is comparable to other psychotherapeutic methods used to treat depression[ 88 , 90 ].

Marital and family therapy: Marital and family therapy (MFT) is effective in treating some aspects of depression. Family therapy has also been used to treat severe forms of depression associated with medications and hospitalization[ 91 ]. Marital and family problems can make people more vulnerable to depression, and MFT addresses these issues[ 92 ]. Marital therapy includes both members of the couple, as depression is considered in an interpersonal context in such cases. Some of the goals of this therapy are to facilitate communication and resolve different types of marital conflict. Family therapy uses similar principles as other forms of therapy while involving all family members and considering depression within the context of pathological family dynamics[ 93 ].

ST: Although ST is not as well-structured or well-evaluated as CBT or IPT, it is still commonly used to support depressed patients. In addition to sympathetic listening and expressing concern for the patient’s problems, ST requires emotionally attuned listening, empathic paraphrasing, explaining the nature of the patient’s suffering, and reassuring and encouraging them. These practices allow the patient to ventilate and accept their feelings, increase their self-esteem, and enhance their adaptive coping skills[ 94 ].

Psychodynamic therapy: Psychodynamic therapy encompasses a range of brief to long-term psychological interventions derived from psychoanalytic theories. This type of therapy focuses on intrapsychic conflicts related to shame, repressed impulses, problems in early childhood with one’s emotional caretakers that lead to low self-esteem and poor emotional self-regulation[ 93 , 95 ]. Psychodynamic therapy’s efficacy in the acute phase of MDD is well-established compared to other forms of psychotherapy.

Group therapy: The application of group therapy (GT) to MDD remains limited. Some data support the efficacy of specific types of GT inspired by CBT and IPT[ 96 - 98 ]. Group CBT for patients with subthreshold depression is an effective post-depressive-symptomatology treatment but not during the follow-up period[ 99 ]. Supportive GT and group CBT reduce depressive symptoms[ 96 ], especially in patients with common comorbid conditions[ 100 ]. However, studies are still lacking in this domain.

MBCT: MBCT is a relatively recent technique that combines elements of CBT with mindfulness-based stress reduction[ 101 ]. Studies have shown that eight weeks of MBCT treatment during remission reduces relapse. Thus, it is a potential alternative to reduce, or even stop, antidepressant treatment without increasing the risk of depressive recurrence, especially for patients at a high risk of relapse ( i.e. , patients with more than two previous episodes and patients who have experienced childhood abuse or trauma)[ 102 ].

Other psycho-interventions

Psycho-education: This type of intervention educates depressed patients and (with their permission) family members involved in the patient’s life about depression symptoms and management. This education should be provided in a language that the patient understands. Issues such as misperceptions about medication, treatment duration, the risk of relapse, and prodromes of depression should be addressed. Moreover, patients should be encouraged to maintain healthy lifestyles and enhance their social skills to prevent depression and boost their overall mental health. Many studies have highlighted the role of psycho-education in improving the clinical course, treatment adherence, and psychosocial functioning in patients with depression[ 103 ].

Physical exercise: Most guidelines for treating depression, including the National Institute for Health and Care Excellence, the American Psychiatric Association, and the Royal Australian and New Zealand College of Psychiatrists, recommend that depressed patients perform regular physical activity to alleviate symptoms and prevent relapses[ 104 ] . Exercise also promotes improvements in one’s quality of life in general[ 105 ] . However, exercise is considered an adjunct to other anti-depressive treatments[ 25 ] .

Although psychotherapy is effective for treating depression and improving patients’ quality of life, its direct actions against depressive symptoms are not fully understood[ 106 ]. Identifying factors ( e.g. , interpersonal variables) linked to treatment responses can help therapists choose the right therapeutic strategy for each patient and guide research to modify existing therapies and develop new ones[ 107 ].

Since depression is a primary care problematic, simplifying psychotherapy procedures will increase the use of psychological interventions for depression, especially in general practice. Brief forms (six to eight sessions) of CBT and PST have already shown their effectiveness for treating depression[ 108 ]. Nevertheless, simpler solutions must be made available to practitioners to help them manage and prevent depression.

SOMATIC TREATMENTS

In many situations, depression can also be managed via somatic treatments. ECT is the most well-known treatment for resistant depression, and solid evidence supports its effectiveness and safety. In recent decades, various innovative techniques have been proposed, such as repetitive transcranial magnetic stimulation (rTMS), transcranial direct current stimulation (tDCS), vagus nerve stimulation (VNS), deep brain stimulation (DBS), and magnetic seizure therapy, with varying efficiency levels[ 109 ].

ECT is arguably the most effective treatment modality in psychiatry, and its superiority over pharmacotherapy for major unipolar depression is widely supported[ 110 ]. ECT reduces the number of hospital readmissions and lightens the burden of depression, leading to a better quality of life[ 111 , 112 ].

Moreover, ECT is considered safe[ 113 ]. Advances in anesthesia and ECT techniques have decreased complications related to ECT while also improving cognitive outcomes and patient satisfaction.

However, the stigma surrounding ECT limits its use. Most misconceptions date back to early ECT techniques (when it was performed without muscle relaxants or anesthesia). Nevertheless, some people still consider ECT as the last option for treating depression, even though most studies indicate that ECT is more beneficial in patients with fewer pharmacological treatments[ 114 - 116 ].

ECT is typically recommended for patients with severe and psychotic depression, a high risk of suicide, or Parkinson’s disease, as well as pregnant patients[ 117 - 119 ]. The maintenance ECT also appears to prevent relapses[ 120 ]. The current practice of ECT continues to improve as protocols become more advanced, mainly owing to bioinformatics, and as more research is carried out in this domain[ 121 - 125 ].

This method, which is a type of biological stimulation that affects brain metabolism and neuronal electrical activity, has been widely used in research on depression[ 126 ]. Recent literature shows a significant difference between rTMS and fictitious stimulation regarding its improvements in depressive symptoms[ 127 ]. Preliminary research has revealed synergistic ( e.g. , rTMS/quetiapine) and antagonizing ( e.g. , rTMS/cannabinoid receptor (CB1) antagonist) interactions between neuro-modulation and pharmacotherapy[ 128 ]. Treatments combining rTMS and antidepressants are significantly more effective than placebo conditions, with mild side effects and good acceptability[ 129 ]. Although these results are encouraging, they remain inconsistent due to differences in rTMS treatment frequencies, parameters, and stimulation sites[ 129 ]. Therefore, clinical trials with large sample sizes are needed to specify which factors promote favorable therapeutic responses. Also, additional preclinical research should investigate the synergistic effects of other pharmacological molecules and guide integrated approaches (rTMS plus pharmacotherapy).

This technique delivers weak currents to the brain via electrodes placed on the scalp[ 130 ]. It is easy to use, safe, and tolerable[ 131 ]. The tDCS technique significantly outperforms the simulator in terms of the rate of response and remission[ 132 ]. However, its effect remains lower than that of antidepressants[ 133 ] and rTMS[ 134 ]. It can be used as a complementary intervention or as monotherapy to reduce depressive symptoms in unipolar or bipolar depression patients[ 135 ]. The antidepressant effects of tDCS may involve long-term neuroplastic changes that continue to occur even after the acute phase of treatment, which explains its delayed efficacy[ 135 ].

Recently, neurophysiological studies have shown that the clinical effects of tDCS do not have a direct linear relationship with the dose of stimulation[ 136 ]. tDCS, as a relatively simple and portable technology, is well-suited for remote supervised treatment and assessment at home, thus facilitating long treatment durations[ 136 ].

Since the optimal clinical effects of tDCS are delayed, future clinical trials should use longer evaluation periods and aim to identify responsive patients using algorithms[ 137 ].

VNS is a therapeutic method that has been used for the last sixteen years to treat resistant unilateral or bipolar depression. However, despite several clinical studies attesting to its favorable benefit-risk ratio and its approval by the Food Drug Administration in 2005, it is not used very often[ 138 ].

VNS involves the implantation of a pacemaker under the collarbone that is connected to an electrode surrounding the left vagus nerve. The left vagus nerve is preferred because it exposes the patient to fewer potential adverse cardiac effects. Indeed, most cardiac afferent fibers originate from the right vagus nerve[ 139 ]. Since the turn of the century, numerous studies have demonstrated the efficacy of VNS in resistant depression[ 140 - 142 ].

However, only one randomized, double-blind, controlled trial comparing VNS with usual medical treatment has been conducted over a short period of 10 wk[ 141 ]. Moreover, the results of this study did not indicate that the combination of VNS with typical medical treatments was better than the typical medical treatment on its own.

However, VNS has demonstrated progressively increasing improvements in depressive symptoms, with significant positive outcomes observed after six to 12 mo; these benefits can last for up to two years[ 143 ].

More long-term studies are needed to fully determine the predictors of the correct response.

According to the literature, DBS of the subgenual cingulate white matter (Brodmann area = BA 25) elicited a clinical response in 60% of resistant depression patients after six months and clinical remission in 35% of patients, with benefits maintained for over 12 mo[ 144 ]. The stimulation of other targets, in particular the nucleus accumbens, to treat resistant depression has gained interest recently. Behavioral effects indicate the quick and favorable impact of stimulation on anhedonia, with significant effects on mood appearing as early as week one after treatment begins[ 145 ].

Magnetic seizure therapy

Magnetic seizure therapy involves inducing a therapeutic seizure by applying magnetic stimulation to the brain while the patient is under anesthesia. This technique is still being investigated as a viable alternative to ECT to treat many psychiatric disorders. Evidence supporting its effectiveness on depressive symptoms continues to grow, and it appears to induce fewer neurocognitive effects than ECT[ 146 , 147 ].

Luxtherapy (phototherapy)

The first description of reduced depression symptoms due to intense light exposure was presented in 1984[ 148 ]. Optimal improvements were obtained with bright light exposure of 2500 Lux for two hours per day, with morning exposure shown to be superior to evening exposure[ 149 ].

A review and meta-analysis[ 150 ] showed that more intense (but shorter) exposures (10000 Lux for half an hour per day or 6000 Lux for 1.5 h per day) have the same efficacy. Importantly, this treatment method is effective both for those with seasonal and non-seasonal depression. Benefits of phototherapy related to sleep deprivation and drug treatments have also been reported[ 151 ].

Neuro-modulation treatments offer a range of treatment options for patients with depression. ECT remains the most documented and effective method in this category[ 151 ]. rTMS is an interesting technique as well, as it offers a well-tolerated profile[ 85 ], while tDCS offers encouraging but varying results that depend on the study’s design and the techniques used[ 130 ].

More investigations are needed to specify which indications are the best for each method according to the clinical and biological profiles of patients. The uses of such methods are expanding, probably, with their efficiency increasing when they are tailored to the patient. Furthermore, somatic interventions for depression need to be regularly assessed and integrated into psychiatrists’ therapeutic arsenals.

Treating depression is still a significant challenge. Finding the best option for each patient is the best way to obtaining short- and long-term effectiveness. The three principal methods available to caregivers are antidepressants, specifically structured psychotherapies, and somatic approaches. Research on depression pharmacotherapy continues to examine new molecules implicated in gamma-aminobutyric acid regulation and glutamate transmission. Also, efforts to personalize and simplify psychotherapeutic interventions are ongoing. Protocols using somatic interventions need to be studied in more depth, and their indications must be specified. ECT is the only somatic treatment with confirmed indications for certain forms of depression. Combinations of medications, psychotherapy, and somatic therapies remain the most effective ways to manage resistant forms of depression.

Conflict-of-interest statement: All authors declare that they have no conflict of interest related to this article.

Manuscript source: Invited manuscript

Peer-review started: March 31, 2021

First decision: June 5, 2021

Article in press: October 11, 2021

Specialty type: Medicine, research and experimental

Country/Territory of origin: Morocco

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P-Reviewer: Narumiya K S-Editor: Fan JR L-Editor: A P-Editor: Fan JR

Contributor Information

Rabie Karrouri, Department of Psychiatry, Moulay Ismaïl Military Hospital, Faculty of Medicine and Pharmacy, Sidi Mohamed Ben Abdellah University, Fez 30070, Morocco.

Zakaria Hammani, Department of Psychiatry, Moulay Ismaïl Military Hospital, Faculty of Medicine and Pharmacy, Sidi Mohamed Ben Abdellah University, Fez 30070, Morocco.

Roukaya Benjelloun, Department of Psychiatry, Faculty of Medicine, Mohammed VI University of Health Sciences, Casablanca 20000, Morocco.

Yassine Otheman, Department of Psychiatry, Moulay Ismaïl Military Hospital, Faculty of Medicine and Pharmacy, Sidi Mohamed Ben Abdellah University, Fez 30070, Morocco. [email protected] .

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By Jane E. Brody

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

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

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

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

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

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

How common are anxiety and depression?

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

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

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

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

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

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

Treatment can counter emotional tolls

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

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

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

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

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

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

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

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

Jane Brody’s Personal Health Advice

After joining the new york times in 1965, she was its personal health columnist from 1976 to 2022. revisit some of her most memorable writing:.

Brody’s first column, on jogging , ran on Nov. 10, 1976. Her last, on Feb. 21. In it, she highlighted the evolution of health advice  throughout her career.

Personal Health has often offered useful advice and a refreshing perspective. Declutter? This is why you must . Cup of coffee? Yes, please.

As a columnist, she has never been afraid to try out, and write about, new things — from intermittent fasting  to knitting groups .

How do you put into words the pain of losing a spouse of 43 years? It is “nothing like losing a parent,” she wrote of her own experience with grieving .

Need advice on aging? She has explored how to do it gracefully ,  building muscle strength  and knee replacements .

ORIGINAL RESEARCH article

Evolution and emerging trends in depression research from 2004 to 2019: a literature visualization analysis.

• 1 School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, China
• 2 School of Life Sciences, Beijing University of Chinese Medicine, Beijing, China

Depression has become a major threat to human health, and researchers around the world are actively engaged in research on depression. In order to promote closer research, the study of the global depression knowledge map is significant. This study aims to map the knowledge map of depression research and show the current research distribution, hotspots, frontiers, and trends in the field of depression research, providing researchers with worthwhile information and ideas. Based on the Web of Science core collection of depression research from 2004 to 2019, this study systematically analyzed the country, journal, category, author, institution, cited article, and keyword aspects using bibliometric and data visualization methods. A relationship network of depression research was established, highlighting the highly influential countries, journals, categories, authors, institutions, cited articles, and keywords in this research field. The study identifies great research potential in the field of depression, provides scientific guidance for researchers to find potential collaborations through collaboration networks and coexistence networks, and systematically and accurately presents the hotspots, frontiers, and shortcomings of depression research through the knowledge map of global research on depression with the help of information analysis and fusion methods, which provides valuable information for researchers and institutions to determine meaningful research directions.

Introduction

Health issues are becoming more and more important to people due to the continuous development of health care. The social pressures on people are becoming more and more pronounced in a social environment that is developing at an increasing rate. Prolonged exposure to stress can have a negative impact on brain development ( 1 ), and depression is one of the more typical disorders that accompany it. Stress will increase the incidence of depression ( 2 ), depression has become a common disease ( 3 ), endangering people's physical health. Depression is a debilitating mental illness with mood disorders, also known as major depression, clinical depression, or melancholia. In human studies of the disease, it has been found that depression accounts for a large proportion of the affected population. According to the latest data from the World Health Organization (WHO) statistics in 2019, there are more than 350 million people with depression worldwide, with an increase of about 18% in the last decade and an estimated lifetime prevalence of 15% ( 4 ), it is a major cause of global disability and disease burden ( 5 ), and depression has quietly become a disease that threatens hundreds of millions of people worldwide.

Along with the rise of science communication research, the quantification of science is also flourishing. As a combination of “data science” and modern science, bibliometrics takes advantage of the explosive growth of research output in the era of big data, and uses topics, authors, publications, keywords, references, citations, etc. as research targets to reveal the current status and impact of the discipline more accurately and scientifically. Whereas, there is not a wealth of bibliometric studies related to depression. Fusar-Poli et al. ( 6 ) used bibliometrics to systematically evaluate cross-diagnostic psychiatry. Hammarström et al. ( 7 ) used bibliometrics to analyze the scientific quality of gender-related explanatory models of depression in the medical database PubMed. Tran et al. ( 8 ) used the bibliometric analysis of research progress and effective interventions for depression in AIDS patients. Wang et al. ( 9 ) used bibliometric methods to analyze scientific studies on the comorbidity of pain and depression. Shi et al. ( 10 ) performed a bibliometric analysis of the top 100 cited articles on biomarkers in the field of depression. Dongping et al. ( 11 ) used bibliometric analysis of studies on the association between depression and gut flora. An Chunping et al. ( 12 ) analyzed the literature on acupuncture for depression included in PubMed based on bibliometrics. Yi and Xiaoli ( 13 ) used a bibliometric method to analyze the characteristics of the literature on the treatment of depression by Chinese medicine in the last 10 years. Zhou and Yan ( 14 ) used bibliometric method to analyze the distribution of scientific and technological achievements on depression in Peoples R China. Guaijuan ( 15 ) performed a bibliometric analysis of the interrelationship between psoriasis and depression. Econometric analysis of the relationship between vitamin D deficiency and depression was performed by Yunzhi et al. ( 16 ) and Shauni et al. ( 17 ) performed a bibliometric analysis of domestic and international research papers on depression-related genes from 2003 to 2007. A previous review of depression-related bibliometric studies revealed that there is no bibliometric analysis of global studies in the field of depression, including country network analysis, journal network analysis, category network analysis, author network analysis, institutional network analysis, literature co-citation analysis, keyword co-presentation analysis, and cluster analysis.

The aim of this study was to conduct a comprehensive and systematic literature-based data mining and metrics analysis of depression-related research. More specifically, this analysis focuses on cooperative network and co-presentation analysis, based on the 36,477 papers included in the Web of Science Core Collection database from 2004 to 2019, and provides an in-depth analysis of cooperative network, co-presentation network, and co-citation through modern metrics and data visualization methods. Through the mining of key data, the data correlation is further explored, and the results obtained can be used to scientifically and reasonably predict the depression-related information. This study aims to show the spatial and temporal distribution of research countries, journals, authors, and institutions in the field of depression in a more concise manner through a relational network. A deeper understanding of the internal structure of the research community will help researchers and institutions to establish more accurate and effective global collaborations, in line with the trend of human destiny and globalization. In addition, the study will allow for the timely identification of gaps in current research. A more targeted research direction will be established, a more complete picture of the new developments in the field of depression today will be obtained, and the research protocol will be informed for further adjustments. The results of these analyses will help researchers understand the evolution of this field of study. Overall, this paper uses literature data analysis to find research hotspots in the field of depression, analyze the knowledge structure within different studies, and provide a basis for predicting research frontiers. This study analyzed the literature in the field of depression using CiteSpace 5.8.R2 (64-bit) to analyze collaborative networks, including country network analysis, journal network analysis, category network analysis, researcher network analysis, and institutional network analysis using CiteSpace 5.8.R2 (64-bit). In addition, literature co-citation, keyword co-presentation, and cluster analysis of depression research hotspots were also performed. Thus, exploring the knowledge dimensions of the field, quantifying the research patterns in the field, and uncovering emerging trends in the field will help to obtain more accurate and complete information. The large amount of current research results related to depression will be presented more intuitively and accurately with the medium of information technology, and the scientific evaluation of research themes and trend prediction will be provided from a new perspective.

Data Sources

The data in this paper comes from the Web of Science (WoS) core collection. The time years were selected as 2004–2019. First, the literature was retrieved after entering “depression” using the title search method. A total of 73,829 articles, excluding “depression” as “suppression,” “decline,” “sunken,” “pothole,” “slump,” “low pressure,” “frustration.” The total number of articles with other meanings such as “depression” was 5,606, and the total number of valid articles related to depression was 68,223. Next, the title search method was used to search for studies related to “major depressive disorder” not “depression,” and a total of 8,070 articles were retrieved. For the two search strategies, a total of 76,293 records were collected. The relevant literature retrieved under the two methods were combined and exported in “plain text” file format. The exported records included: “full records and references cited.” CiteSpace processed the data to obtain 41,408 valid records, covering all depression-related research articles for the period 2004–2019, and used this as the basis for analysis.

Processing Tools

CiteSpace ( 18 ), developed by Chao-Mei Chen, a professor in the School of Information Science and Technology at Drexel University, is a Java-based program with powerful data visualization capabilities and is one of the most widely used knowledge mapping tools. The software version used in this study is CiteSpace 5.8.R2 (64-bit).

Methods of Analysis

This study uses bibliometrics and data visualization as analytical methods. First, the application of bibliometrics to the field of depression helped to identify established and emerging research clusters, demonstrating the value of research in this area. Second, data visualization provides multiple perspectives on the data, presenting correlations in a clearer “knowledge graph” that can reveal underestimated and overlooked trends, patterns, and differences ( 19 ). CiteSpace is mainly based on the “co-occurrence clustering idea,” which extracts the information units (keywords, authors, institutions, countries, journals, etc.) in the data by classification, and then further reconstructs the data in the information units to form networks based on different types and strengths of connections (e.g., keyword co-occurrence, author collaboration, etc.). The resulting networks include nodes and links, where the nodes represent the information units of the literature and the links represent the existence of connections (co-occurrence) between the nodes. Finally, the network is measured, statistically analyzed, and presented in a visual way. The analysis needs to focus on: the overall structure of the network, key nodes and paths. The key evaluation indicators in this study are: betweenness centrality, year, keyword frequency, and burst strength. Betweenness centrality (BC) is the number of times a node acts as the shortest bridge between two other nodes. The higher the number of times a node acts as an “intermediary,” the greater its betweenness centrality. Betweenness centrality is a measure of the importance of articles found and measured by nodes in the network by labeling the category (or authors, journals, institutions, etc.) with purple circles. There may be many shortest paths between two nodes in the network, and by counting all the shortest paths of any two nodes in the network, if many of the shortest paths pass through a node, then the node is considered to have high betweenness centrality. In CiteSpace, nodes with betweenness centrality over 0.1 are called critical nodes. Year, which represents the publication time of the article. Frequency, which represents the number of occurrences. Burst strength, an indicator used to measure articles with sudden rise or sudden decline in citations. Nodes with high burst strength usually represent a shift in a certain research area and need to be focused on, and the burst article points are indicated in red. The nodes and their sizes and colors are first analyzed initially, and further analyzed by betweenness centrality indicators for evaluation. Each node represents an article, and the larger the node, the greater the frequency of the keyword word and the greater the relevance to the topic. Similarly, the color of the node represents time: the warmer the color, the more recent the time; the colder the color, the older the era; the node with a purple outer ring is a node with high betweenness centrality; the color of each annual ring can determine the time distribution: the color of the annual ring represents the corresponding time, and the thickness of one annual ring is proportional to the number of articles within the corresponding time division; the dominant color can reflect the relative concentration of the emergence time; the node The appearance of red annual rings in the annual rings means hot spots, and the frequency of citations has been or is still increasing rapidly.

Large-Scale Assessment

Country analysis.

During the period 2004–2019, a total of 157 countries/territories have conducted research on depression, which is about 67.38% of 233 countries/territories worldwide. This shows that depression is receiving attention from many countries/regions around the world. Figure 1 shows the geographical distribution of published articles for 157 countries. The top 15 countries are ranked according to the number of articles published. Table 1 lists the top 15 countries with the highest number of publications in the field of depression worldwide from 2004 to 2019. These 15 countries include 4 Asian countries (Peoples R China, Japan, South Korea, Turkey), 2 North American countries (USA, Canada), 1 South American country (Brazil), 7 European countries (UK, Germany, Netherlands, Italy, France, Spain, Sweden), and 1 Oceania country (Australia).

Figure 1 . Geographical distributions of publications, 2004–2019.

Table 1 . The top 15 productive countries.

Overall, the main distribution of these articles is in USA and some European countries, such as UK, Germany, Netherlands, Italy, France, Spain, and Sweden. This means that these countries are more interested and focused on research on depression compared to others. The total number of publications across all research areas in the Web of Science core collection is similar to the distribution of depression research areas, with the trend toward USA, UK, and Peoples R China as leading countries being unmistakable, and USA has been a leader in the field of depression, with far more articles published than any other country. It can also be seen that USA is the country with the highest betweenness centrality in the network of national collaborations analyzed in this paper. USA research in the field of depression is closely linked to global research, and is an important part of the global collaborative network for depression research. As of 2019, the total number of articles published in depression performance research in USA represents 27.13% of the total number of articles published in depression worldwide, which is ~4 times more than the second-place country, UK, which is far ahead of other countries. Peoples R China, as the third most published country, has a dominant number of articles, but its betweenness centrality is 0.01, reflecting the fact that Peoples R China has less collaborative research with other countries, so Peoples R China should strengthen its foreign collaborative research and actively establish global scientific research partnerships to seek development and generate breakthroughs in cooperation. The average percentage of scientific research on depression in each country is about 0.19%, also highlighting the urgent need to address depression as one of the global human health problems. The four Asian countries included in the top 15 countries are Peoples R China, Japan, South Korea, and Turkey, with Peoples R China ranking third with 6.72% of the total number of all articles counted. The distribution may be explained by the fact that Peoples R China is the largest developing country with a rapid development rate as the largest. Along with the steady rise in the country's economic power, people are creating economic benefits and their health is becoming a consumable commodity. The lifetime prevalence and duration of depression varies by country and region ( 2 ), but the high prevalence and persistence of depression worldwide confirms the increasing severity of the disease worldwide. The WHO estimates that more than 300 million people, or 4.4% of the world's population, suffer from depression ( 20 ), with the number of people suffering from depression increasing at a patient rate of 18.4% between 2005 and 2015. Depression, one of the most prevalent mental illnesses of our time, has caused both physical and psychological harm to many people, and it has become the leading cause of disability worldwide today, and in this context, there is increased interest and focus on research into depression. It is expected that a more comprehensive understanding of depression and finding ways to prevent and cope with the occurrence of this disease can help people get rid of the pain and shadow brought by depression, obtain a healthy and comfortable physical and mental environment and physical health, and make Chinese contributions to the cause of human health. Undoubtedly, the occurrence of depressive illnesses in the context of irreversible human social development has stimulated a vigorous scientific research environment on depression in Peoples R China and other developing countries and contributed to the improvement of research capacity in these countries. Moreover, from a different perspective, the geographical distribution of articles in this field also represents the fundamental position of the country in the overall scientific and academic research field.

Growth Trend Analysis

Figure 2 depicts the distribution of 38,433 articles from the top 10 countries in terms of the number of publications and the trend of growth during 2004–2019.

Figure 2 . The distribution of publications in top 10 productive countries, 2004–2019. Source: author's calculation. National development classification criteria refer to “Human Development Report 2020” ( 21 ).

First, the number of articles published per year for the top 10 countries in terms of productivity was counted and then the white bar chart in Figure 2 was plotted, with the year as the horizontal coordinate and total publications as the vertical coordinate, showing the distribution of the productivity of articles in the field of depression per year. The total number of publications for the period 2004–2019 is 38,433. Based on the white bars and line graphs in Figure 2 , we can divide this time period into three growth periods. The number of publications in each growth period is calculated based on the number of publications per year. As can be seen from the figure, the period 2004–2019 can be divided into three main growth periods, namely 2004–2009, 2010–2012, and 2013–2019, the first growth period being from 2004 to 2009, the number of publications totaled 6,749, accounting for 23.97% of all publications; from 2010 to 2012, the number of publications totaled 8,236, accounting for 17.56% of all publications; and from 2013 to 2019, the number of publications totaled 22,473, accounting for 58.47% of all publications. Of these, 2006 was the first year of sharp growth with an annual growth rate of 19.97%, 2009 was the second year of sharp growth with an annual growth rate of 17.64%, and 2008 was the third year of sharp growth with an annual growth rate of 16.09%. In the last 5 years, 2019 has also shown a sharp growth trend with a growth rate of 14.34%. Notably, in 2010 and 2013, there was negative growth with the growth rate of −3.39 and −1.45%. In the last 10 years, depression research has become one of the most valuable areas of human research. It can also be noted that the number of publications in the field of depression in these 10 countries has been increasing year after year.

Second, the analysis is conducted from the perspective of national development, divided into developed and developing countries, as shown in the orange bar chart in Figure 2 , where the horizontal coordinate is year and the vertical coordinate is total publications, comparing the article productivity variability between developed and developing countries. The top 10 most productive countries in the field of depression globally include nine developed countries and one developing country, respectively. During the period 2004–2019, 34,631 papers were published in developed countries and 3,802 papers were published in developing countries, with developed countries accounting for 90.11% of the 38,433 articles and developing countries accounting for 9.89%, and the total number of publications in developed countries was about 9 times higher than that in developing countries. During the period 2004–2019, the number of publications in developed countries showed negative growth in 2 years (2010 and 2013) with growth rates of −3.39 and −1.45%, respectively. The rest of the years showed positive growth with growth rates of 1.52% (2005), 19.97 (2006), 8.11 (2007), 12.70 (2008), 17.64 (2009), 13.22 (2011), 10.17 (2012), 16.09 (2014), 10.46 (2015), 4.10 (2016), 1.59 (2017), 3.91 (2018), and 14.34 (2019), showing three periods of positive growth: 2004–2009, 2011–2012, and 2014–2019, with the highest growth rate of 19.97% in 2006. Recent years have also shown a higher growth trend, with a growth rate of 14.34% in 2019. It is worth noting that developing countries have been showing positive growth in the number of articles in the period 2004–2019, with annual growth rates of 81.25 (2005), 17.24 (2006), 35.29 (2007), 19.57 (2008), 65.45 (2009), 13.19 (2010), 29.13 (2011), 54.89 (2012), 12.14 (2013), 36.36 (2014), 14.92 (2015), 16.02 (2016), 10.24 (2017), 21.17 (2018), and 31.37 (2019), with the highest growth rate of 81.25% in 2005. In the field of depression research, developed countries are still the main force and occupy an important position.

Further, 10 countries with the highest productivity in the field of depression are compared, total publications in the vertical coordinate, and the colored scatter plot contains 10 colored dots, representing 10 different countries. On the one hand, the variability of the contributions of different countries in the same time frame can be compared horizontally. On the other hand, it is possible to compare vertically the variability of the growth of different countries over time. Among them, USA, with about 40.29% of the world's publications in the field of depression, has always been a leader in the field of depression with its rich research results. Peoples R China, as the only developing country, ranks 3rd in the top 10 countries with high production of research papers in the field of depression, and Peoples R China's research in the field of depression has shown a rapid growth trend, and by 2016, it has jumped to become the 2nd largest country in the world, with the number of published papers increasing year by year, which has a broad prospect and great potential for development.

Distribution of Periodicals

Table 2 lists the top 15 journals in order of number of journal co-citations. In the field of depression, the top 15 cited journals accounted for 19.06% of the total number of co-citations, nearly one in five of the total number of journal co-citations. In particular, the top 3 journals were ARCH GEN PSYCHIAT (ARCHIVES OF GENERAL PSYCHIATRY), J AFFECT DISORDERS (JOURNAL OF AFFECTIVE DISORDERS), and AM J PSYCHIAT (AMERICAN JOURNAL OF PSYCHIATRY), with co-citation counts of 20,499, 20,302, and 20,143, with co-citation rates of 2.09, 2.07, and 2.06%, respectively. The main research area of ARCH GEN PSYCHIAT is Psychiatry; the main research area of the journal J AFFECT DISORDERS is Neurosciences and Neurology, Psychiatry; AM J PSYCHIAT is the main research area of Psychiatry, and the three journals have “psychiatry” in common, making them the most frequently co-cited journals in the field of depression.

Table 2 . The top 15 co-cited journals.

Figure 3 shows the network relationship graph of the cited journals from 2004 to 2019. The figure takes g-index as the selection criteria, the scale factor k = 25 to include more nodes. Each node of the graph represents each journal, the node size represents the number of citation frequencies, the label size represents the size of the betweenness centrality of the journal in the network, and the links between journals represent the co-citation relationships. The journal co-citation map reflects the structure of the journals, indicating that there are links between journals and that the journals include similar research topics. These journals included research topics related to neuroscience, psychiatry, neurology, and psychology. The journal with betweenness centrality size in the top 1 was ARCH GEN PSYCHIAT, with betweenness centrality size of 0.07, and impact shadows of 14.48. ARCH GEN PSYCHIAT, has research themes of Psychiatry. In all, these journals in Figure 3 occupy an important position in the journal's co-citation network and have strong links with other journals.

Figure 3 . Prominent journals involved in depression. The betweenness centrality of a node in the network measures the importance of the position of the node in the network. Two types of nodes may have high betweenness centrality scores: (1) Nodes that are highly connected to other nodes, (2) Nodes are positioned between different groups of nodes. The lines represent the link between two different nodes.

Distribution of Categories

Table 3 lists the 15 most popular categories in the field of depression research during the period 2004–2019. In general, the main disciplines involved are neuroscience, psychology, pharmacy, medicine, and health care, which are closely related to human life and health issues. Of these, psychiatry accounted for 20.78%, or about one-five, making it the most researched category. The study of depression focuses on neuroscience, reflecting the essential characteristics of depression as a category of mental illness and better reflecting the fact that depression is an important link in the human public health care. In addition, Table 3 shows that the category with the highest betweenness centrality is Neuroscience, followed by Public, Environment & Occupational Health, and then Pharmacology & Pharmacy, with betweenness centrality of 0.16, 0.13, and 0.11, respectively. It is found that the research categories of depression are also centered on disciplines such as neuroscience, public health and pharmacology, indicating that research on depression requires a high degree of integration of multidisciplinary knowledge and integration of information from various disciplines in order to have a more comprehensive and in-depth understanding of the depression.

Table 3 . The top 15 productive categories, 2004–2019.

Figure 4 shows the nine categories with the betweenness centrality in the category research network, with Neuroscience being the node with the highest betweenness centrality in this network, meaning that Neuroscience is most strongly linked to all research categories in the field of depression research. Depression is a debilitating psychiatric disorder with mood disorders. It is worth noting that the development of depression not only has psychological effects on humans, but also triggers many somatic symptoms that have a bad impact on their daily work and life, giving rise to the second major mediating central point of research with public health as its theme. The somatization symptoms of depression often manifest as abnormalities in the cardiovascular system, and many studies have looked at the pathology of the cardiovascular system in the hope of finding factors that influence the onset of depression, mechanisms that trigger it or new ways to treat it. Thus, depression involves not only the nervous system, but also interacts with the human cardiovascular system, for example, and the complexity of depression dictates that the study of depression is an in-depth study based on complex systems.

Figure 4 . Prominent categories involved in depression, 2004–2019. The betweenness centrality of a node in the network measures the importance of the position of the node in the network. Two types of nodes may have high betweenness centrality scores: (1) Nodes that are highly connected to other nodes, (2) Nodes are positioned between different groups of nodes. The lines represent the link between two different nodes.

Author Statistics

The results of the analysis showed that there were many researchers working in the field of depression over the past 16 years, and 63 of the authors published at least 30 articles related to depression. Table 4 lists the 15 authors with the highest number of articles published. It includes the rank of the number of articles published, author, country, number of articles published in depression-related studies, total number of articles included in Web of Science, total number of citations, average number of citations, and H-index. According to the statistics, seven of the top 15 authors are from USA, three from the Netherlands, one from Canada, one from Australia, one from New Zealand, one from Italy, and one from Germany. From this, it can be seen that these productive authors are from developed countries, thus it can be inferred that developed countries have a better research environment, more advanced research technology and more abundant research funding. The evaluation indicators in the author co-occurrence network are frequency, betweenness centrality and time of first appearance. The higher the frequency, i.e., the higher the number of collaborative publications, the more collaboration, the higher the information dissemination rate, the three authors with the highest frequency in this author co-occurrence network are MAURIZIO FAVA, BRENDA W. J. H. PENNINX, MADHUKAR H. TRIVEDI; the higher the betweenness centrality, i.e., the closer the relationship with other authors, the more collaboration, the higher the information dissemination rate, the three authors with the highest betweenness centrality are the three authors with the highest betweenness centrality are MICHAEL E. THASE, A. JOHN RUSH; the time of first appearance, i.e., the longer the influence generated by the author's research, the higher the information dissemination rate; in addition, the impact factor and citations can also reflect the information dissemination efficiency of the authors.

Table 4 . The top 15 authors in network of co-authorship, 2004–2019.

The timezone view ( Figure 5 ) in the author co-occurrence network clearly shows the updates and interactions of author collaborations, for example. All nodes are positioned in a two-dimensional coordinate with the horizontal axis of time, and according to the time of first posting, the nodes are set in different time zones, and their positions are sequentially upward with the time axis, showing a left-to-right, bottom-up knowledge evolution diagram. The time period 2004–2019 is divided into 16 time zones, one for each year, and each circle in the figure represents an author, and the time zone in which the circle appears is the year when the author first published an article in the data set of this study. The closer the color, the warmer the color, the closer the time, the colder the color, the older the era, the thickness of an annual circle, and the number of articles within the corresponding time division is proportional, the dominant color can reflect the relative concentration of the emergence time, the nodes appear in the annual circle of the red annual circle, that is, on behalf of the hot spot, the frequency of being cited was or is still increasing sharply. Nodes with purple outer circles are nodes with high betweenness centrality. The time zone view demonstrates the growth of author collaboration in the field, and it can be found from the graph that the number of author collaborations increases over time, and the frequency of publications in the author collaboration network is high; observe that the thickness of the warm annual rings in the graph is much greater than the thickness of the cold annual rings, which represents the increase of collaboration in time; there are many authors in all time zones, which indicates that there are many research collaborations and achievements in the field, and the field is in a period of collaborative prosperity. The linkage relationship between the sub-time-periods can be seen by the linkage relationship between the time periods, and it can be found from the figure that there are many linkages in the field in all time periods, which indicates that the author collaboration in the field of depression research is strong.

Figure 5 . Timezone view of the author's co-existing network in depression, 2004–2019. The circle represents the author, the time zone in which the circle appears is the year in which the author first published in this study dataset, the radius of the circle represents the frequency of appearance, the color represents the different posting times, the lines represent the connections between authors, and the time zone diagram shows the evolution of author collaboration.

Institutional Statistics

Table 5 lists the top 15 research institutions in network of co-authors' institutions. These include 10 American research institutions, two Netherlands research institutions, one UK research institution, one Canadian research institution and one Australian research institution, all of which, according to the statistics, are from developed countries. Of these influential research institutions, 66.7% are from USA. Figure 6 shows the collaborative network with these influential research institutions as nodes. Kings Coll London (0.2), Univ Michigan (0.17), Univ Toronto (0.15), Stanford Univ (0.14), Univ Penn (0.14), Univ Pittsburgh (0.14), Univ Melbourne (0.12), Virginia Commonwealth Univ (0.12), Columbia Univ (0.1), Duke Univ (0.1), Massachusetts Gen Hosp (0.1), Vrije Univ Amsterdam (0.1), with betweenness centrality >0.1. Kings Coll London has a central place in this collaborative network and is influential in the field of depression research. Table 6 lists the 15 institutions with the strong burst strength. The top 3 institutions are all from USA. Univ Copenhagen, Univ Illinois, Harvard Med Sch, Boston Univ, Univ Adelaide, Heidelberg Univ, Univ New South Wales, and Icahn Sch Med Mt Sinai have had strong burst strength in recent years. It suggests that these institutions may have made a greater contribution to the field of depression over the course of this year and more attention could be paid to their research.

Table 5 . The top 15 institutions in network of co-authors' institutions, 2004–2019.

Figure 6 . Prominent institutions involved in depression, 2004–2019. The betweenness centrality of a node in the network measures the importance of the position of the node in the network. Two types of nodes may have high betweenness centrality scores: (1) Nodes that are highly connected to other nodes, (2) Nodes are positioned between different groups of nodes. The lines represent the link between two different nodes.

Table 6 . The top 15 institutions with the strongest citation bursts, 2004–2019.

Summing up the above analysis, it can be seen that the research institutions in USA are at the center of the depression research field, are at the top of the world in terms of quantity and quality of research, and are showing continuous growth in vitality. Research institutions in USA, as pioneers among all research institutions, lead and drive the development of depression research and play an important role in cutting-edge research in the field of depression.

Article Citations

Table 7 lists the 16 articles that have been cited more than 1,000 times within the statistical range of this paper from 2004 to 2019. As can be seen from the table, the most cited article was written by Dowlati et al. from Canada and published in BIOLOGICAL PSYCHIATRY 2010, which was cited 2,556 times. In addition, 11 of these 16 highly cited articles were from the USA. Notably, two articles by Kroenke, K as first author appear in this list, ranked 7th and 11th, respectively. In addition, there are three articles from Canada, one article from Switzerland, and one article from the UK. And interestingly, all of these countries are developed countries. It can be reflected that developed countries have ample research experience and high quality of research in the field of depression research. On the other hand, it also reflects that depression is a key concern in developed countries. These highly cited articles provide useful information to many researchers and are of high academic and exploratory value.

Table 7 . The top 15 frequency cited articles, 2004–2019.

Research Hotspots Ang Frontiers

Keyword analysis.

The keyword analysis of depression yielded the 25 most frequent keywords in Table 8 and the keyword co-occurrence network in Figure 7 . Also, the data from this study were detected by burst, the 25 keywords with the strongest burst strength were obtained in Table 9 . These results bring out the popular and cutting-edge research directions in the field clearly.

Table 8 . Top 25 frequent keywords in the period of 2004–2019.

Figure 7 . Keyword co-occurrence network in depression, 2004–2019.

Table 9 . Top 25 keywords with strongest citation bursts in the period of 2004–2019.

The articles on depression during 2004–2019 were analyzed in 1-year time slices, and the top 25 keywords with the highest frequency of occurrence were selected from each slice to obtain the keyword network shown in Table 8 . The top 25 keywords with the highest frequencies were: symptom, disorder, major depression, prevalence, meta-analysis, anxiety, risk, scale, association, quality of life, health, risk factor, stress, validity, validation, mental health, women, double blind, brain, population, disease, impact, primary care, mood, and efficacy. High-frequency nodes respond to popular keywords and are an important basis for the field of depression research.

Figure 7 shows the co-occurrence network mapping of keywords regarding depression research. Each circle in the figure is a node representing a keyword, and the greater the betweenness centrality, the more critical the position of the node in the network. The top 10 keywords in terms of betweenness centrality are: symptom (0.6), major depression (0.28), prevalence (0.27), disorder (0.25), double blind (0.18), risk factor (0.12), stress (0.11), children (0.1), schizophrenia (0.1), and expression (0.1). Nodes with high betweenness centrality reflect that the keyword forms a co-occurrence relationship with multiple other keywords in the domain. A higher betweenness centrality indicates that it is more related to other keywords, and therefore, the node plays an important role in the study. Relatively speaking, these nodes represent the main research directions in the field of depression; they are also the key research directions in this period, and to a certain extent, represent the research hotspots in this period.

Burst detection was performed on the keywords, and the 25 keywords with the strongest strength were extracted, as shown in Table 9 . These keywords contain: fluoxetine, community, follow up, illness, psychiatric disorder, dementia, trial, placebo, disability, serotonin reuptake inhibitor, myocardial infarction, hospital anxiety, antidepressant treatment, late life depression, United States, epidemiology, major depression, model, severity, adolescent, people, prefrontal cortex, management, meta-analysis, and expression. The keywords that burst earlier include fluoxetine (2004), community (2004), follow up (2004), illness (2004), and psychiatric disorder (2004), are keywords that imply that researchers focused on themes early in the field of depression. As researchers continue to explore, the study of depression is changing day by day, and the keywords that have burst in recent years are people (2015), prefrontal cortex (2016), management (2016), meta-analysis (2017), and expression (2017). Reflecting the fact that depression research in recent years has mainly focused on human subjects, the focus has been on the characterization of populations with depression onset. The relationship between depression and the brain has aroused the curiosity of researchers, what exactly are the causes that trigger depression and what are the effects of depression for the manifestation of depression have caused a wide range of discussions in the research community, and the topics related to it have become the most popular studies and have been the focus of research in recent years. All of these research areas showed considerable growth, indicating that research into this area is gaining traction, suggesting that it is becoming a future research priority. The keywords with the strongest burst strength are fluoxetine (111.2), community (110.08), antidepressant treatment (94.28), severity (88.35), meta-analysis (86.42), people (85.33), and follow up (84.46). The rapid growth of research based on these keywords indicates that these topics are the most promising and interesting. The keywords that has been around the longest burst are follow up (2004–2013), model (2013–2019), hospital anxiety (2008–2013), severity (2014–2019), and psychiatric disorder (2004–2008), researchers have invested a lot of research time in these research directions, making many research results, and responding to the exploratory value and significance of research on these topics. At the same time, the longer duration of burst also proves that these research directions have research potential and important value.

Research Hotspots

Hotspots must mainly have the characteristics of high frequency, high betweenness centrality, strong burst, and time of emergence can be used as secondary evaluation indicators. The higher the number of occurrences, the higher the degree of popularity and attention. The higher betweenness centrality means the greater the influence and the higher the importance. Nodes with strong burst usually represent key shift nodes and need to be focused on. The time can be dynamically adjusted according to the target time horizon of the analysis. Thus, based on the results of statistical analysis, it is clear that the research hotspots in the field of depression can be divided into four main areas: etiology (external factors, internal factors), impact (quality of life, disease symptoms, co-morbid symptoms), treatment (interventions, drug development, care modalities), and assessment (population, size, symptoms, duration of disease, morbidity, mortality, effectiveness).

Risk factors for depression include a family history of depression, early life abuse and neglect, and female sexuality and recent life stressors. Physical illnesses also increase the risk of depression, particularly increasing the prevalence associated with metabolic (e.g., cardiovascular disease) and autoimmune disorders.

Research on the etiology of depression can be divided into internal and external factors. In recent years, researchers have increasingly focused on the impact of external factors on depression. Depression is influenced by environmental factors related to social issues, such as childhood experiences, social interactions, and lifestyles. Adverse childhood experiences are risk factors for depression and anxiety in adolescence ( 37 ) and are a common pathway to depression in adults ( 38 ). Poor interpersonal relationships with classmates, family, teachers, and friends increase the prevalence of depression in adolescents ( 39 ). Related studies assessed three important, specific indicators of the self-esteem domain: social confidence, academic ability, and appearance ( 40 ). The results suggest that these three dimensions of self-esteem are key risk factors for increased depressive symptoms in Chinese adolescents. The vulnerability model ( 41 ) suggests that low self-esteem is a causal risk factor for depression, and low self-esteem is thought to be one of the main causes of the onset and progression of depression, with individuals who exhibit low self-esteem being more likely to develop social anxiety and social withdrawal, and thus having a sense of isolation ( 42 ), which in turn leads to subsequent depression. Loneliness predicts depression in adolescents. Individuals with high levels of loneliness experience more stress and tension from psychological and physical sources in their daily lives, which, combined with insufficient care from society, can lead to depression ( 43 ). A mechanism of association exists between life events and mood disorders, with negative life events being directly associated with depressive symptoms ( 44 ). In a cross-sectional study conducted in Shanghai, the prevalence of depression was higher among people who worked longer hours, and daily lifestyle greatly influenced the prevalence of depression ( 45 ). A number of studies in recent years have presented a number of interesting ideas, and they suggest that depression is related to different environmental factors, such as temperature, sunlight hours, and air pollution. Environmental factors have been associated with suicidal behavior. Traffic noise is a variable that triggers depression and is associated with personality disorders such as depression ( 46 ). The harmful effects of air pollution on mental health, inhalation of air pollutants can trigger neuroinflammation and oxidative stress and induce dopaminergic neurotoxicity. A study showed that depression was associated with an increase in ambient fine particulate matter (PM2.5) ( 47 ).

Increased inflammation is a feature of many diseases and even systemic disorders, such as some autoimmune diseases [e.g., type 1 diabetes ( 48 ) or rheumatoid arthritis ( 49 )] and infectious diseases [e.g., hepatitis and sepsis ( 50 )], are associated with an inflammatory response and have been found to increase the risk of depression. A growing body of evidence supports a bidirectional association between depression and inflammatory processes, with stressors and pathogens leading to excessive or prolonged inflammatory responses when combined with predisposing factors (e.g., childhood adversity and modifying factors such as obesity). The resulting illnesses (e.g., pain, sleep disorders), depressive symptoms, and negative health (e.g., poor diet, sedentary lifestyle) may act as mediating pathways leading to inflammation and depression. In terms of mechanistic pathways, cytokines induce depression by affecting different mood-related processes. Elevated inflammatory signals can dysregulate the metabolism of neurotransmitters, damaging neurons, and thus altering neural activity in the brain. In addition cytokines can modulate depression by regulating hormone levels. Inflammation can have different effects on different populations depending on individual physiology, and even lower levels of inflammation may have a depressive effect on vulnerable individuals. This may be due to lower parasympathetic activity, poorer sensitivity to glucocorticoid inhibitory feedback, a greater response to social threat in the anterior oral cortex or amygdala and a smaller hippocampus. Indeed, these are all factors associated with major depression that can affect the sensitivity to the inhibitory consequences of inflammatory stimuli.

Depression triggers many somatization symptoms, which can manifest as insomnia, menopausal syndrome, cardiovascular problems, pain, and other somatic symptoms. There is a link between sleep deprivation and depression, with insomnia being a trigger and maintenance of depression, and more severe insomnia and chronic symptoms predicting more severe depression. Major depression is considered to be an independent risk factor for the development of coronary heart disease and a predictor of cardiovascular events ( 51 ). Patients with depression are extremely sensitive to pain and have increased pain perception ( 52 ) and is associated with an increased risk of suicide ( 53 , 54 ), and generally the symptoms of these pains are not relieved by medication.

Studies have shown that depression triggers an inflammatory response, promoting an increase in cytokines in response to stressors vs. pathogens. For example, mild depressive symptoms have been associated with an amplified and prolonged inflammatory response ( 55 , 56 ) following influenza vaccination in older adults and pregnant women. Among women who have recently given birth, those with a lifetime history of major depression have greater increases in both serum IL-6 and soluble IL-6 receptors after delivery than women without a history of depression ( 57 ). Pro-inflammatory agents, such as interferon-alpha (IFN-alpha), for specific somatization disorders [e.g., hepatitis C or malignant melanoma ( 58 , 59 )], although effective for somatic disorders, pro-inflammatory therapy often leads to psychiatric side effects. Up to 80% of patients treated with IFN-α have been reported to suffer from mild to moderate depressive symptoms.

Clinical trials have shown better antidepressant treatment with anti-inflammatory drugs compared to placebo, either as monotherapy ( 60 , 61 ) or as an add-on treatment ( 62 – 65 ) to antidepressants ( 66 , 67 ). However, findings like whether NSAIDs can be safely used in combination with antidepressants are controversial. Patients with depression often suffer from somatic co-morbidities, which must be included in the benefit/risk assessment. It is important to consider the type of medication, duration of treatment, and dose, and always balance the potential treatment effect with the risk of adverse events in individual patients. Depression, childhood adversity, stressors, and diet all affect the gut microbiota and promote gut permeability, another pathway that enhances the inflammatory response, and effective depression treatment may have profound effects on mood, inflammation, and health. Early in life gut flora colonization is associated with hypothalamic-pituitary-adrenal (HPA) axis activation and affects the enteric nervous system, which is associated with the risk of major depression, gut flora dysbiosis leads to the onset of TLR4-mediated inflammatory responses, and pro-inflammatory factors are closely associated with depression. Clinical studies have shown that in the gut flora of depressed patients, pro-inflammatory bacteria such as Enterobacteriaceae and Desulfovibrio are enriched, while short-chain fatty acid producing bacteria are reduced, and some of these bacterial taxa may transmit peripheral inflammation into the brain via the brain-gut axis ( 68 ). In addition, gut flora can affect the immune system by modulating neurotransmitters (5-hydroxytryptamine, gamma-aminobutyric acid, norepinephrine, etc.), which in turn can influence the development of depression ( 69 ). Therefore, antidepressant drugs targeting gut flora are a future research direction, and diet can have a significant impact on mood by regulating gut flora.

As the molecular basis of clinical depression remains unclear, and treatments and therapeutic effects are limited and associated with side effects, researchers have worked to discover new treatment modalities for depression. High-amplitude low-frequency musical impulse stimulation as an additional treatment modality seems to produce beneficial effects ( 70 ). Studies have found electroconvulsive therapy to be one of the most effective antidepressant treatment therapies ( 71 ). Physical exercise can promote molecular changes that lead to a shift from a chronic pro-inflammatory to an anti-inflammatory state in the peripheral and central nervous system ( 72 ). Aromatherapy is widely used in the treatment of central nervous system disorders ( 73 ). By activating the parasympathetic nervous system, qigong can be effective in reducing depression ( 74 ). The exploration of these new treatment modalities provides more reference options for the treatment of depression.

Large-scale assessments of depression have found that the probability of developing depression varies across populations. Depression affects some specific populations more significantly, for example: adolescents, mothers, and older adults. Depression is one of the disorders that predispose to adolescence, and depression is associated with an increased risk of suicide among college students ( 75 ). Many women develop depression after childbirth. Depression that develops after childbirth is one of the most common complications for women in the postpartum period ( 76 ). The health of children born to mothers who suffer from postpartum depression can also be adversely affected ( 77 ). Depression can cause many symptoms within the central nervous system, especially in the elderly population ( 78 ).

Furthermore, one of the most consistent findings of the association between inflammation and depression is the elevated levels of peripheral pro-inflammatory markers in depressed individuals, and peripheral pro-inflammatory marker levels can also be used as a basis for the assessment of depressed patients. Studies have shown that the following pro-inflammatory markers have been found to be at increased levels in depressed individuals: CRP ( 79 , 80 ), IL-6 ( 22 , 79 , 81 , 82 ), TNF–α, and interleukin-1 receptor antagonist (IL-1ra) ( 79 , 82 ), however, this association is not unidirectional and the subsequent development of depression also increases pro-inflammatory markers ( 82 , 83 ). These biomarkers are of great interest, and depressed patients with increased inflammatory markers may represent a relatively drug-resistant population.

Frontier Analysis

The exploration and analysis of frontier areas of depression were based on the results of the analysis of the previous section on keywords. According to the evaluation index and analysis idea of this study, the frontier research topics need to have the following four characteristics: low to medium frequency, strong burst, high betweenness centrality, and the research direction in recent years. Therefore, combining the results of keyword analysis and these characteristics, it can be found that the frontier research on depression also becomes clear.

Research on Depression Characterized by Psychosexual Disorders

Exploration of biological mechanisms based on depression-associated neurological disorders and analysis of depression from a neurological perspective have always been the focus of research. Activation of neuroinflammatory pathways may contribute to the development of depression ( 84 ). A research model based on the microbial-gut-brain axis facilitates the neurobiology of depression ( 85 ). Some probiotics positively affect the central nervous system due to modulation of neuroinflammation and thus may be able to modulate depression ( 86 ). The combination of environmental issues and the neurobiological study of depression opens new research directions ( 46 ).

Research on Relevant Models of Depression

How to develop a model that meets the purpose of the study determines the outcome of the study and has become the direction that researchers have been exploring in recent years. Martínez et al. ( 87 ) developed a predictive model to assess factors that modify the treatment pathway for postpartum depression. Nie et al. ( 88 ) extended the work on predictive modeling of treatment-resistant depression to establish a predictive model for treatment-resistant depression. Rational modeling methods and behavioral testing facilitate a more comprehensive exploration of depression, with richer studies and more scientifically valid findings.

Research and Characterization of the Depressed Patient Population

Current research on special groups and depression has received much attention. In a study of a group of children, 4% were found to suffer from depression ( 89 ). The diagnosis and treatment of mental health disorders is an important component of pediatric care. Second, some studies of populations with distinct characteristics have been based primarily on female populations. Maternal perinatal depression is also a common mental disorder with a prevalence of over 10% ( 90 ). In addition, geriatric depression is a chronic and specific disorder ( 91 ). Studies based on these populations highlight the characteristics of the disorder more directly than large-scale population explorations and are useful for conducting extended explorations from specific to generalized.

Somatic Comorbidities Associated With Depression

Depression often accompanies the onset and development of many other disorders, making the study of physical comorbidities associated with depression a new landing place for depression research. Depression is a complication of many neurological or psychopathological disorders. Depression is a common co-morbidity of glioblastoma multiforme ( 92 ). Depression is an important disorder associated with stroke ( 93 ). Chronic liver disease is associated with depression ( 94 ). The link between depressive and anxiety states and cancer has been well-documented ( 95 ). In conclusion, depression is associated with an increased risk of lung, oral, prostate, and skin cancers, an increased risk of cancer-specific death from lung, bladder, breast, colorectal, hematopoietic system, kidney, and prostate cancers, and an increased risk of all-cause mortality in lung cancer patients. The early detection and effective intervention of depression and its complications has public health and clinical implications.

Research on Mechanisms of Depression

Research based on the mechanisms of depression includes the study of disease pathogenesis, the study of drug action mechanisms, and the study of disease treatment mechanisms. Research on the pathogenesis of depression has focused more on the study of the hypothalamic-pituitary-adrenal axis. Social pressure can change the hypothalamic-pituitary-adrenal axis ( 96 ). Studies on the mechanism of action of drugs are mostly based on their effects on the central nervous system. The antidepressant effects of Tanshinone IIA are mediated by the ERK-CREB-BDNF pathway in the hippocampus of mice ( 97 ). Research on the mechanisms of depression treatment has also centered on the central nervous system. It has been shown that the vagus nerve can transmit signals to the brain that can lead to a reduction in depressive behavior ( 98 ).

In this study, based on the 2004–2019 time period, this wealth of data is effectively integrated through data analysis and processing to reproduce the research process in a particular field and to co-present global trends in homogenous fields while organizing past research.

Journals that have made outstanding contributions in this field include ARCH GEN PSYCHIAT, J AFFECT DISORDERS and AM J PSYCHIAT. PSYCHIATRY, NEUROSCIENCES & NEUROLOGY and CLINICAL NEUROLOGY are the three most popular categories. The three researchers with the highest number of articles were MAURIZIO FAVA (USA), BRENDA W. J. H. PENNINX (NETHERLANDS) and MADHUKAR H TRIVEDI (USA). Univ Pittsburgh (USA), Kings Coll London (UK) and Harvard Univ (USA) are three of the most productive and influential research institutions. A Meta-Analysis of Cytokines in Major Depression, Evaluation of outcomes with citalopram for depression using measurement-based care in STAR*D: Implications for clinical practice and Deep brain stimulation for treatment-resistant depression are key articles. Through keyword analysis, a distribution network centered on depression was formed. Although there are good trends in the research on depression, there are still many directions to be explored in depth. Some recommendations regarding depression are as follows.

(1) The prevention of depression can be considered by focusing on treating external factors and guiding the individual.

Faced with the rising incidence of depression worldwide and the difficulty of treating depression, researchers can think more about how to prevent the occurrence of depression. Depressed moods are often the result of stress, not only social pressures on the individual, but also environmental pressures in the developmental process, which in turn have an unhealthy relationship with the body and increase the likelihood of depression. The correlation between external factors and depression is less well-studied, but the control of external factors may be more effective in the short term than in the long term, and may be guided by self-adjustment to avoid major depressive disorder.

(2) The measurement and evaluation of the degree of depression should be developed in the direction of precision.

In the course of research, it has been found that the Depression Rating Scale is mostly used for the detection and evaluation of depression. This kind of assessment is more objective, but it still lacks accuracy, and the research on measurement techniques and methods is less, which is still at a low stage. Patients with depression usually have a variety of causes, conditions, and duration of illness that determine the degree of depression. Therefore, whether these scales can truly accurately measure depression in depressed patients needs further consideration. Accurate measurement is an important basis for evidence-based treatment of depression, and thus how to achieve accurate measurement of depression is a research direction that researchers can move toward.

Therefore, there is an urgent need for further research to address these issues.

A systematic analysis of research in the field of depression in this study concludes that the distribution of countries, journals, categories, authors, institutions, and citations may help researchers and research institutions to establish closer collaboration, develop appropriate publication plans, grasp research hotspots, identify valuable research ideas, understand current emerging research, and determine research directions. In addition, there are still some limitations that can be overcome in future work. First, due to the lack of author and address information in older published articles, it may not be possible to accurately calculate their collaboration; second, although the data scope of this paper is limited to the Web of Science, it can adequately meet our objectives.

Data Availability Statement

The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author/s.

Author Contributions

HW conceived and designed the analysis, collected the data, performed the analysis, and wrote the paper. XT, XW, and YW conceived and designed the analysis. All authors contributed to the article and approved the submitted version.

This work was supported by the National Natural Science Foundation of China under Grant No. 81973495.

Conflict of Interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Publisher's Note

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.

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Keywords: depression, major depressive disorder, bibliometrics, visual analysis, knowledge graphs, CiteSpace

Citation: Wang H, Tian X, Wang X and Wang Y (2021) Evolution and Emerging Trends in Depression Research From 2004 to 2019: A Literature Visualization Analysis. Front. Psychiatry 12:705749. doi: 10.3389/fpsyt.2021.705749

Received: 06 May 2021; Accepted: 05 October 2021; Published: 29 October 2021.

Reviewed by:

Copyright © 2021 Wang, Tian, Wang and Wang. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY) . The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

*Correspondence: Yun Wang, wangyun@bucm.edu.cn

Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.

Research could unlock more precise prognoses and targeted treatments for children with cancer

Neuroblastoma study identifies new subgroups with distinct prognoses and potential vulnerabilities to therapies

Researchers have identified new variations in neuroblastoma that could lead to a more accurate prognosis and better-targeted treatments for this devastating childhood cancer.

A study published in the  British Journal of Cancer reveals three new subgroups of the most common type of neuroblastoma, each with different genetic traits, expected outcomes, and distinguishing features that offer clues as to which treatments may be most effective.

Dr Yihua Wang from the University of Southampton, a senior author on the paper said: “This research represents a pivotal advancement in our understanding of MYCN non-amplified neuroblastomas. The results are striking. These kinds of neuroblastomas can be classified into three distinct subgroups, each demonstrating unique prognostic implications and varying vulnerabilities to investigational therapies.”

Around 100 children are diagnosed with neuroblastoma each year in the UK, representing six to ten per cent of all childhood cancers. Neuroblastoma is a cancer that starts in a type of nerve cell called a neuroblast. It can present in the abdomen, chest neck or pelvis and can spread to other parts of the body.

The overall prognosis of the disease is poor, with just 20 per cent of patients still alive at 5 years after diagnosis, but the likelihood of the cancer being cured varies widely, with some tumours spontaneously regressing and others proving resistant to therapy and progressing.

One of the key indicators of risk is the amplification of a gene called MYCN, where tumours have too many of this type of gene. This occurs in around 20 per cent of cases and accounts for about 40 per cent of high-risk neuroblastomas.

Researchers from the University of Southampton and China wanted to find out more about cases where the MYCN gene isn’t amplified to better understand the diversity of outcomes within these cases. Using advanced analytical techniques, the research team analysed over 1,500 biopsy samples from 16 different datasets sourced from Gene Expression Omnibus (GEO) and ArrayExpress.

The team were able to identify three distinct subtypes of these MYCN non-amplified cases based on their transcriptional signatures - patterns of gene expression that can provide valuable insights into biological processes.

The first subgroup makes up around half of MYCN non-amplified cases and has the best prognosis, with a long-term survival rate of over 85 per cent, despite some cases being clinically classified as high risk.

Subgroup 2, representing a quarter of MYCN non-amplified cases, had the worst outcomes with a long-term survival rate of 50%. Interestingly, this group had a similar genetic signature to cases where MYCN is amplified. Researchers found a protein called Aurora Kinase A (AURKA) was expressed at significantly higher levels than in the other two subgroups. On further analysis, they found that AURKA mRNA levels alone could predict overall survival. This suggests that patients within the subgroup may benefit from treatment with AURKA inhibitors.

Meanwhile, Subgroup 3, which made up another quarter of MYCN non-amplified cases, is characterised by an ‘inflamed’ gene signature, with significantly higher levels of activity in immune cells. Further analysis indicates that patients in this subgroup were predicted to respond better to immunotherapy.

Dr Wang  added: “This research opens new avenues for personalised medicine in the treatment of neuroblastomas. By leveraging transcriptional subtyping, we are now equipped to offer more precise prognosis and tailor therapies accordingly for patients with MYCN non-amplified neuroblastomas, potentially improving outcomes and quality of life."

Identification of MYCN non-amplified neuroblastoma subgroups points towards molecular signatures for precision prognosis and therapy stratification is published in the British Journal of Cancer and is available online.

The project was supported by the UK Medical Research Council and the Natural Science Foundation of China.

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• 29 March 2024

The great rewiring: is social media really behind an epidemic of teenage mental illness?

• Candice L. Odgers 0

Candice L. Odgers is the associate dean for research and a professor of psychological science and informatics at the University of California, Irvine. She also co-leads international networks on child development for both the Canadian Institute for Advanced Research in Toronto and the Jacobs Foundation based in Zurich, Switzerland.

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Social-media platforms aren’t always social. Credit: Getty

The Anxious Generation: How the Great Rewiring of Childhood is Causing an Epidemic of Mental Illness Jonathan Haidt Allen Lane (2024)

Two things need to be said after reading The Anxious Generation . First, this book is going to sell a lot of copies, because Jonathan Haidt is telling a scary story about children’s development that many parents are primed to believe. Second, the book’s repeated suggestion that digital technologies are rewiring our children’s brains and causing an epidemic of mental illness is not supported by science. Worse, the bold proposal that social media is to blame might distract us from effectively responding to the real causes of the current mental-health crisis in young people.

Haidt asserts that the great rewiring of children’s brains has taken place by “designing a firehose of addictive content that entered through kids’ eyes and ears”. And that “by displacing physical play and in-person socializing, these companies have rewired childhood and changed human development on an almost unimaginable scale”. Such serious claims require serious evidence.

Collection: Promoting youth mental health

Haidt supplies graphs throughout the book showing that digital-technology use and adolescent mental-health problems are rising together. On the first day of the graduate statistics class I teach, I draw similar lines on a board that seem to connect two disparate phenomena, and ask the students what they think is happening. Within minutes, the students usually begin telling elaborate stories about how the two phenomena are related, even describing how one could cause the other. The plots presented throughout this book will be useful in teaching my students the fundamentals of causal inference, and how to avoid making up stories by simply looking at trend lines.

Hundreds of researchers, myself included, have searched for the kind of large effects suggested by Haidt. Our efforts have produced a mix of no, small and mixed associations. Most data are correlative. When associations over time are found, they suggest not that social-media use predicts or causes depression, but that young people who already have mental-health problems use such platforms more often or in different ways from their healthy peers 1 .

These are not just our data or my opinion. Several meta-analyses and systematic reviews converge on the same message 2 – 5 . An analysis done in 72 countries shows no consistent or measurable associations between well-being and the roll-out of social media globally 6 . Moreover, findings from the Adolescent Brain Cognitive Development study, the largest long-term study of adolescent brain development in the United States, has found no evidence of drastic changes associated with digital-technology use 7 . Haidt, a social psychologist at New York University, is a gifted storyteller, but his tale is currently one searching for evidence.

Of course, our current understanding is incomplete, and more research is always needed. As a psychologist who has studied children’s and adolescents’ mental health for the past 20 years and tracked their well-being and digital-technology use, I appreciate the frustration and desire for simple answers. As a parent of adolescents, I would also like to identify a simple source for the sadness and pain that this generation is reporting.

A complex problem

There are, unfortunately, no simple answers. The onset and development of mental disorders, such as anxiety and depression, are driven by a complex set of genetic and environmental factors. Suicide rates among people in most age groups have been increasing steadily for the past 20 years in the United States. Researchers cite access to guns, exposure to violence, structural discrimination and racism, sexism and sexual abuse, the opioid epidemic, economic hardship and social isolation as leading contributors 8 .

How social media affects teen mental health: a missing link

The current generation of adolescents was raised in the aftermath of the great recession of 2008. Haidt suggests that the resulting deprivation cannot be a factor, because unemployment has gone down. But analyses of the differential impacts of economic shocks have shown that families in the bottom 20% of the income distribution continue to experience harm 9 . In the United States, close to one in six children live below the poverty line while also growing up at the time of an opioid crisis, school shootings and increasing unrest because of racial and sexual discrimination and violence.

The good news is that more young people are talking openly about their symptoms and mental-health struggles than ever before. The bad news is that insufficient services are available to address their needs. In the United States, there is, on average, one school psychologist for every 1,119 students 10 .

Haidt’s work on emotion, culture and morality has been influential; and, in fairness, he admits that he is no specialist in clinical psychology, child development or media studies. In previous books, he has used the analogy of an elephant and its rider to argue how our gut reactions (the elephant) can drag along our rational minds (the rider). Subsequent research has shown how easy it is to pick out evidence to support our initial gut reactions to an issue. That we should question assumptions that we think are true carefully is a lesson from Haidt’s own work. Everyone used to ‘know’ that the world was flat. The falsification of previous assumptions by testing them against data can prevent us from being the rider dragged along by the elephant.

A generation in crisis

Two things can be independently true about social media. First, that there is no evidence that using these platforms is rewiring children’s brains or driving an epidemic of mental illness. Second, that considerable reforms to these platforms are required, given how much time young people spend on them. Many of Haidt’s solutions for parents, adolescents, educators and big technology firms are reasonable, including stricter content-moderation policies and requiring companies to take user age into account when designing platforms and algorithms. Others, such as age-based restrictions and bans on mobile devices, are unlikely to be effective in practice — or worse, could backfire given what we know about adolescent behaviour.

A third truth is that we have a generation in crisis and in desperate need of the best of what science and evidence-based solutions can offer. Unfortunately, our time is being spent telling stories that are unsupported by research and that do little to support young people who need, and deserve, more.

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Competing Interests

The author declares no competing interests.

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