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Science News About Depression

August 21, 2024 • Research Highlight

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

June 5, 2024 • Research Highlight

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

May 23, 2024 • Press Release

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

May 14, 2024 • Feature Story • 75th Anniversary

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

February 27, 2024 • Press Release

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

December 18, 2023 • Research Highlight

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

October 27, 2023 • Feature Story • 75th Anniversary

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

June 16, 2023 • Research Highlight

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

May 15, 2023 • Research Highlight

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

January 9, 2023 • Research Highlight

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

September 29, 2022 • Research Highlight

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

May 9, 2022 • Research Highlight

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

March 25, 2022 • Research Highlight

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

February 28, 2022 • Research Highlight

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

May 26, 2021 • Research Highlight

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

April 15, 2021 • Research Highlight

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

February 9, 2021 • Press Release

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

October 29, 2020 • Research Highlight

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

October 22, 2020 • Institute Update

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

April 20, 2020 • Press Release

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

March 30, 2020 • Press Release

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

February 25, 2020 • Research Highlight

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

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

February 10, 2020 • Press Release

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

November 18, 2019 • Press Release

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

October 2, 2019 • Press Release

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

September 3, 2019 • Institute Update

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

April 29, 2019 • Press Release

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

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

April 11, 2019 • Press Release

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

March 19, 2019 • Media Advisory

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

March 13, 2019 • Press Release

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

March 11, 2019 • Press Release

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

December 13, 2018 • Science Update

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

June 20, 2018 • Press Release

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

April 16, 2018 • Institute Update

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

March 1, 2018 • Science Update

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

February 13, 2018 • Science Update

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

November 2, 2017 • Press Release

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

August 28, 2017 • Science Update

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

July 20, 2017 • Institute Update

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

May 31, 2017 • Science Update

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

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

April 19, 2017 • Science Update

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

August 1, 2016 • Press Release

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

July 18, 2016 • Science Update

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

June 16, 2016 • Live Chat

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

May 4, 2016 • Press Release

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

March 17, 2016 • Science Update

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

February 19, 2016 • Science Update

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

August 12, 2015 • Science Update

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

July 16, 2015 • Science Update

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

July 14, 2015 • Live Chat

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

January 29, 2015 • Science Update

Risk genes for different mental disorders work through same pathways

November 5, 2014 • Live Chat

NIMH Twitter Chat on Men and Depression

October 17, 2014 • Press Release

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

October 2, 2014 • Science Update

NIMH Twitter Chat on Depression and the Development of Novel Medications

July 29, 2014 • Science Update

NIMH Twitter Chat on Premenstrual Dysphoric Disorder

June 10, 2014 • Science Update

May 5, 2014 • Science Update

NIMH Twitter Chat on Postpartum Depression

April 17, 2014 • Press Release

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

March 11, 2014 • Science Update

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

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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

Peer-review report’s scientific quality classification

Grade A (Excellent): 0

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Grade D (Fair): D

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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] .

• Depression in Children
• Depression in Teens
• Depression in College
• Depression in Women
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• How Is Depression Diagnosed?
• Related Conditions
• What Are the Different Types of Depression?
• Mild Depression
• Major Depressive Disorder
• Overview of Treatment
• Psychotherapy
• Complementary & Alternative Therapy
• Overview of Antidepressants
• Selective Serotonin Reuptake Inhibitors (SSRIs)
• Tricyclic and Tetracyclic Antidepressants (TCAs)
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Depression: The Latest Research

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

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

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

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

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

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

Fast-Acting Antidepressants

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

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

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

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

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

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

More Exact Antidepressant Selection

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

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

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

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

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

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

Causes of Depression

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

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

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

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

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

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

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

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

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Effect of exercise for depression: systematic review and network meta-analysis of randomised controlled trials

Linked editorial.

Exercise for the treatment of depression

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• Effect of exercise for depression: systematic review and network meta-analysis of randomised controlled trials - May 28, 2024
• 1 School of Psychology, University of Queensland, St Lucia, QLD 4072, Australia
• 2 Institute for Positive Psychology and Education, Australian Catholic University, North Sydney, NSW, Australia
• 3 Department of Physical Education and Sport, University of Seville, Seville, Spain
• 4 School of Health and Behavioural Sciences, Australian Catholic University, Strathfield, NSW, Australia
• 5 Department of Clinical Biomechanics and Sports Science, University of Southern Denmark, Odense, Denmark
• 6 Biomedical Research and Innovation Institute of Cádiz (INiBICA) Research Unit, University of Cádiz, Spain
• 7 School of Health and Behavioural Sciences, University of the Sunshine Coast, Petrie, QLD, Australia
• 8 School of Education, University of Newcastle, Callaghan, NSW, Australia
• 9 School of Health and Behavioural Sciences, Australian Catholic University, Banyo, QLD, Australia
• 10 School of Education, Australian Catholic University, Strathfield, NSW, Australia
• 11 Australian Institute of Health Innovation, Macquarie University, Macquarie Park, NSW, Australia
• 12 Children’s Hospital Westmead Clinical School, University of Sydney, Westmead, NSW, Australia
• 13 Australian Catholic University, North Sydney, NSW, Australia
• 14 Centre for Health Research, University of Southern Queensland, Springfield, QLD, Australia
• 15 Faculty of Sport and Health Science, University of Jyvaskyla, Jyvaskyla, Finland
• Correspondence to: M Noetel m.noetel{at}uq.edu.au (or @mnoetel on Twitter)
• Accepted 15 January 2024

Objective To identify the optimal dose and modality of exercise for treating major depressive disorder, compared with psychotherapy, antidepressants, and control conditions.

Design Systematic review and network meta-analysis.

Methods Screening, data extraction, coding, and risk of bias assessment were performed independently and in duplicate. Bayesian arm based, multilevel network meta-analyses were performed for the primary analyses. Quality of the evidence for each arm was graded using the confidence in network meta-analysis (CINeMA) online tool.

Data sources Cochrane Library, Medline, Embase, SPORTDiscus, and PsycINFO databases.

Eligibility criteria for selecting studies Any randomised trial with exercise arms for participants meeting clinical cut-offs for major depression.

Results 218 unique studies with a total of 495 arms and 14 170 participants were included. Compared with active controls (eg, usual care, placebo tablet), moderate reductions in depression were found for walking or jogging (n=1210, κ=51, Hedges’ g −0.62, 95% credible interval −0.80 to −0.45), yoga (n=1047, κ=33, g −0.55, −0.73 to −0.36), strength training (n=643, κ=22, g −0.49, −0.69 to −0.29), mixed aerobic exercises (n=1286, κ=51, g −0.43, −0.61 to −0.24), and tai chi or qigong (n=343, κ=12, g −0.42, −0.65 to −0.21). The effects of exercise were proportional to the intensity prescribed. Strength training and yoga appeared to be the most acceptable modalities. Results appeared robust to publication bias, but only one study met the Cochrane criteria for low risk of bias. As a result, confidence in accordance with CINeMA was low for walking or jogging and very low for other treatments.

Conclusions Exercise is an effective treatment for depression, with walking or jogging, yoga, and strength training more effective than other exercises, particularly when intense. Yoga and strength training were well tolerated compared with other treatments. Exercise appeared equally effective for people with and without comorbidities and with different baseline levels of depression. To mitigate expectancy effects, future studies could aim to blind participants and staff. These forms of exercise could be considered alongside psychotherapy and antidepressants as core treatments for depression.

Systematic review registration PROSPERO CRD42018118040.

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Introduction

Major depressive disorder is a leading cause of disability worldwide 1 and has been found to lower life satisfaction more than debt, divorce, and diabetes 2 and to exacerbate comorbidities, including heart disease, 3 anxiety, 4 and cancer. 5 Although people with major depressive disorder often respond well to drug treatments and psychotherapy, 6 7 many are resistant to treatment. 8 In addition, access to treatment for many people with depression is limited, with only 51% treatment coverage for high income countries and 20% for low and lower-middle income countries. 9 More evidence based treatments are therefore needed.

Exercise may be an effective complement or alternative to drugs and psychotherapy. 10 11 12 13 14 In addition to mental health benefits, exercise also improves a range of physical and cognitive outcomes. 15 16 17 Clinical practice guidelines in the US, UK, and Australia recommend physical activity as part of treatment for depression. 18 19 20 21 But these guidelines do not provide clear, consistent recommendations about dose or exercise modality. British guidelines recommend group exercise programmes 20 21 and offer general recommendations to increase any form of physical activity, 21 the American Psychiatric Association recommends any dose of aerobic exercise or resistance training, 20 and Australian and New Zealand guidelines suggest a combination of strength and vigorous aerobic exercises, with at least two or three bouts weekly. 19

Authors of guidelines may find it hard to provide consistent recommendations on the basis of existing mainly pairwise meta-analyses—that is, assessing a specific modality versus a specific comparator in a distinct group of participants. 12 13 22 These meta-analyses have come under scrutiny for pooling heterogeneous treatments and heterogenous comparisons leading to ambiguous effect estimates. 23 Reviews also face the opposite problem, excluding exercise treatments such as yoga, tai chi, and qigong because grouping them with strength training might be inappropriate. 23 Overviews of reviews have tried to deal with this problem by combining pairwise meta-analyses on individual treatments. A recent such overview found no differences between exercise modalities. 13 Comparing effect sizes between different pairwise meta-analyses can also lead to confusion because of differences in analytical methods used between meta-analysis, such as choice of a control to use as the referent. Network meta-analyses are a better way to precisely quantify differences between interventions as they simultaneously model the direct and indirect comparisons between interventions. 24

Network meta-analyses have been used to compare different types of psychotherapy and pharmacotherapy for depression. 6 25 26 For exercise, they have shown that dose and modality influence outcomes for cognition, 16 back pain, 15 and blood pressure. 17 Two network meta-analyses explored the effects of exercise on depression: one among older adults 27 and the other for mental health conditions. 28 Because of the inclusion criteria and search strategies used, these reviews might have been under-powered to explore moderators such as dose and modality (κ=15 and κ=71, respectively). To resolve conflicting findings in existing reviews, we comprehensively searched randomised trials on exercise for depression to ensure our review was adequately powered to identify the optimal dose and modality of exercise. For example, a large overview of reviews found effects on depression to be proportional to intensity, with vigorous exercise appearing to be better, 13 but a later meta-analysis found no such effects. 22 We explored whether recommendations differ based on participants’ sex, age, and baseline level of depression.

Given the challenges presented by behaviour change in people with depression, 29 we also identified autonomy support or behaviour change techniques that might improve the effects of intervention. 30 Behaviour change techniques such as self-monitoring and action planning have been shown to influence the effects of physical activity interventions in adults (>18 years) 31 and older adults (>60 years) 32 with differing effectiveness of techniques in different populations. We therefore tested whether any intervention components from the behaviour change technique taxonomy were associated with higher or lower intervention effects. 30 Other meta-analyses found that physical activity interventions work better when they provide people with autonomy (eg, choices, invitational language). 33 Autonomy is not well captured in the taxonomy for behaviour change technique. We therefore tested whether effects were stronger in studies that provided more autonomy support to patients. Finally, to understand the mechanism of intervention effects, such as self-confidence, affect, and physical fitness, we collated all studies that conducted formal mediation analyses.

Our findings are presented according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses-Network Meta-analyses (PRISMA-NMA) guidelines (see supplementary file, section S0; all supplementary files, data, and code are also available at https://osf.io/nzw6u/ ). 34 We amended our analysis strategy after registering our review; these changes were to better align with new norms established by the Cochrane Comparing Multiple Interventions Methods Group. 35 These norms were introduced between the publication of our protocol and the preparation of this manuscript. The largest change was using the confidence in network meta-analysis (CINeMA) 35 online tool instead of the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) guidelines and adopting methods to facilitate assessments—for example, instead of using an omnibus test for all treatments, we assessed publication bias for each treatment compared with active controls. We also modelled acceptability (through dropout rate), which was not predefined but was adopted in response to a reviewer’s comment.

Eligibility criteria

To be eligible for inclusion, studies had to be randomised controlled trials that included exercise as a treatment for depression and included participants who met the criteria for major depressive disorder, either clinician diagnosed or identified through participant self-report as exceeding established clinical thresholds (eg, scored >13 on the Beck depression inventory-II). 36 Studies could meet these criteria when all the participants had depression or when the study reported depression outcomes for a subgroup of participants with depression at the start of the study.

We defined exercise as “planned, structured and repetitive bodily movement done to improve or maintain one or more components of physical fitness.” 37 Unlike recent reviews, 12 22 we included studies with more than one exercise arm and multifaceted interventions (eg, health and exercise counselling) as long as they contained a substantial exercise component. These trials could be included because network meta-analysis methods allows for the grouping of those interventions into homogenous nodes. Unlike the most recent Cochrane review, 12 we also included participants with physical comorbidities such as arthritis and participants with postpartum depression because the Diagnostic Statistical Manual of Mental Health Disorders , fifth edition, removed the postpartum onset specifier after that analysis was completed. 23 Studies were excluded if interventions were shorter than one week, depression was not reported as an outcome, and data were insufficient to calculate an effect size for each arm. Any comparison condition was included, allowing us to quantify the effects against established treatments (eg, selective serotonin reuptake inhibitors (SSRIs), cognitive behavioural therapy), active control conditions (usual care, placebo tablet, stretching, educational control, and social support), or waitlist control conditions. Published and unpublished studies were included, with no restrictions on language applied.

Information sources

We adapted the search strategy from the most recent Cochrane review, 12 adding keywords for yoga, tai chi, and qigong, as they met our definition for exercise. We conducted database searches, without filters or date limits, in The Cochrane Library via CENTRAL, SPORTDiscus via Embase, and Medline, Embase, and PsycINFO via Ovid. Searches of the databases were conducted on 17 December 2018 and 7 August 2020 and last updated on 3 June 2023 (see supplementary file section S1 for full search strategies). We assessed full texts of all included studies from two systematic reviews of exercise for depression. 12 22

Study selection and data collection

To select studies, we removed duplicate records in Covidence 38 and then screened each title and abstract independently and in duplicate. Conflicts were resolved through discussion or consultation with a third reviewer. The same methods were used for full text screening.

We used the Extraction 1.0 randomised controlled trial data extraction forms in Covidence. 38 Data were extracted independently and in duplicate, with conflicts resolved through discussion with a third reviewer.

For each study, we extracted a description of the interventions, including frequency, intensity, and type and time of each exercise intervention. Using the Compendium of Physical Activities, 39 we calculated the energy expenditure dose of exercise for each arm as metabolic equivalents of task (METs) min/week. Two authors evaluated each exercise intervention using the Behaviour Change Taxonomy version 1 30 for behaviour change techniques explicitly described in each exercise arm. They also rated the level of autonomy offered to participants, on a scale from 1 (no choice) to 10 (full autonomy). We also extracted descriptions of the other arms within the randomised trials, including other treatment or control conditions; participants’ age, sex, comorbidities, and baseline severity of depressive symptoms; and each trial’s location and whether or not the trial was funded.

Risk of bias in individual studies

We used Cochrane’s risk of bias tool for randomised controlled trials. 40 Risk of bias was rated independently and in duplicate, with conflicts resolved through discussion with a third reviewer.

Summary measures and synthesis

For main and moderation analyses, we used bayesian arm based multilevel network meta-analysis models. 41 All network meta-analytical approaches allow users to assess the effects of treatments against a range of comparisons. The bayesian arm based models allowed us to also assess the influence of hypothesised moderators, such as intensity, dose, age, and sex. Many network meta-analyses use contrast based methods, comparing post-test scores between study arms. 41 Arm based meta-analyses instead describe the population-averaged absolute effect size for each treatment arm (ie, each arm’s change score). 41 As a result, the summary measure we used was the standardised mean change from baseline, calculated as standardised mean differences with correction for small studies (Hedges’ g). In keeping with the norms from the included studies, effect sizes describe treatment effects on depression, such that larger negative numbers represent stronger effects on symptoms. Using National Institute for Health and Care Excellence guidelines, 42 we standardised change scores for different depression scales (eg, Beck depression inventory, Hamilton depression rating scale) using an internal reference standard for each scale (for each scale, the average of pooled standard deviations at baseline) reported in our meta-analysis. Because depression scores generally show regression to the mean, even in control conditions, we present effect sizes as improvements beyond active control conditions. This convention makes our results comparable to existing, contrast based meta-analyses.

Active control conditions (usual care, placebo tablet, stretching, educational control, and social support) were grouped to increase power for moderation analyses, for parsimony in the network graph, and because they all showed similar arm based pooled effect sizes (Hedges’ g between −0.93 and −1.00 for all, with no statistically significant differences). We separated waitlist control from these active control conditions because it typically shows poorer effects in treatment for depression. 43

Bayesian meta-analyses were conducted in R 44 using the brms package. 45 We preregistered informative priors based on the distributional parameters of our meta-analytical model. 46 We nested effects within arms to manage dependency between multiple effect sizes from the same participants. 46 For example, if one study reported two self-reported measures of depression, or reported both self-report and clinician rated depression, we nested these effect sizes within the arm to account for both pieces of information while controlling for dependency between effects. 46 Finally, we compared absolute effect sizes against a standardised minimum clinically important difference, 0.5 standard deviations of the change score. 47 From our data, this corresponded to a large change in before and after scores (Hedges’ g −1.16), a moderate change compared with waitlist control (g −0.55), or a small benefit when compared with active controls (g −0.20). For credibility assessments comparing exercise modalities, we used the netmeta package 48 and CINeMA. 49 We also used netmeta to model acceptability, comparing the odds ratio for drop-out rate in each arm.

Additional analyses

All prespecified moderation and sensitivity analyses were performed. We moderated for participant characteristics, including participants’ sex, age, baseline symptom severity, and presence or absence of comorbidities; duration of the intervention (weeks); weekly dose of the intervention; duration between completion of treatment and measurement, to test robustness to remission (in response to a reviewer’s suggestion); amount of autonomy provided in the exercise prescription; and presence of each behaviour change technique. As preregistered, we moderated for behaviour change techniques in three ways: through meta-regression, including all behaviour change techniques simultaneously for primary analysis; including one behaviour change technique at a time (using 99% credible intervals to somewhat control for multiple comparisons) in exploratory analyses; and through meta-analytical classification and regression trees (metaCART), which allowed for interactions between moderating variables (eg, if goal setting combined with feedback had synergistic effects). 50 We conducted sensitivity analyses for risk of bias, assessing whether studies with low versus unclear or high risk of bias on each domain showed statistically significant differences in effect sizes.

Credibility assessment

To assess the credibility of each comparison against active control, we used CINeMA. 35 49 This online tool was designed by the Cochrane Comparing Multiple Interventions Methods Group as an adaptation of GRADE for network meta-analyses. 35 In line with recommended guidelines, for each comparison we made judgements for within study bias, reporting bias, indirectness, imprecision, heterogeneity, and incoherence. Similar to GRADE, we considered the evidence for comparisons to show high confidence then downgraded on the basis of concerns in each domain, as follows:

Within study bias —Comparisons were downgraded when most of the studies providing direct evidence for comparisons were unclear or high risk.

Reporting bias —Publication bias was assessed in three ways. For each comparison with at least 10 studies 51 we created funnel plots, including estimates of effect sizes after removing studies with statistically significant findings (ie, worst case estimates) 52 ; calculated an s value, representing how strong publication bias would need to be to nullify meta-analytical effects 52 ; and conducted a multilevel Egger’s regression test, indicative of small study bias. Given these tests are not recommended for comparisons with fewer than 10 studies, 51 those comparisons were considered to show “some concerns.”

Indirectness — Our primary population of interest was adults with major depression. Studies were considered to be indirect if they focused on one sex only (>90% male or female), participants with comorbidities (eg, heart disease), adolescents and young adults (14-20 years), or older adults (>60 years). We flagged these studies as showing some concerns if one of these factors was present, and as “major concerns” if two of these factors were present. Evidence from comparisons was classified as some concerns or major concerns using majority rating for studies directly informing the comparison.

Imprecision — As per CINeMA, we used the clinically important difference of Hedges’ g=0.2 to ascribe a zone of equivalence, where differences were not considered clinically significant (−0.2<g<0.2). Studies were flagged as some concerns for imprecision if the bounds of the 95% credible interval extended across that zone, and they were flagged as major concerns if the bounds extended to the other side of the zone of equivalence (such that effects could be harmful).

Heterogeneity — Prediction intervals account for heterogeneity differently from credible intervals. 35 As a result, CINeMA accounts for heterogeneity by assessing whether the prediction intervals and the credible intervals lead to different conclusions about clinical significance (using the same zone of equivalence from imprecision). Comparisons are flagged as some concerns if the prediction interval crosses into, or out of, the zone of equivalence once (eg, from helpful to no meaningful effect), and as major concerns if the prediction interval crosses the zone twice (eg, from helpful and harmful).

Incoherence — Incoherence assesses whether the network meta-analysis provides similar estimates when using direct evidence (eg, randomised controlled trials on strength training versus SSRI) compared with indirect evidence (eg, randomised controlled trials where either strength training or SSRI uses waitlist control). Incoherence provides some evidence the network may violate the assumption of transitivity: that the only systematic difference between arms is the treatment, not other confounders. We assessed incoherence using two methods: Firstly, a global design-by-treatment interaction to assess for incoherence across the whole network, 35 49 and, secondly, separating indirect and direct evidence (SIDE method) for each comparison through netsplitting to see whether differences between those effect estimates were statistically significant. We flagged comparisons as some concerns if either no direct comparisons were available or direct and indirect evidence gave different conclusions about clinical significance (eg, from helpful to no meaningful effect, as per imprecision and heterogeneity). Again, we classified comparisons as major concerns if the direct and indirect evidence changed the sign of the effect or changed both limits of the credible interval. 35 49

Patient and public involvement

We discussed the aims and design of this study with members of the public, including those who had experienced depression. Several of our authors have experienced major depressive episodes, but beyond that we did not include patients in the conduct of this review.

Study selection

The PRISMA flow diagram outlines the study selection process ( fig 1 ). We used two previous reviews to identify potentially eligible studies for inclusion. 12 22 Database searches identified 18 658 possible studies. After 5505 duplicates had been removed, two reviewers independently screened 13 115 titles and abstracts. After screening, two reviewers independently reviewed 1738 full text articles. Supplementary file section S2 shows the consensus reasons for exclusion. A total of 218 unique studies described in 246 reports were included, totalling 495 arms and 14 170 participants. Supplementary file section S3 lists the references and characteristics of the included studies.

Flow of studies through review

Network geometry

As preregistered, we removed nodes with fewer than 100 participants. Using this filter, most interventions contained comparisons with at least four other nodes in the network geometry ( fig 2 ). The results of the global test design-by-treatment interaction model were not statistically significant, supporting the assumption of transitivity (χ 2 =94.92, df=75, P=0.06). When net-splitting was used on all possible combinations in the network, for two out of the 120 comparisons we found statistically significant incoherence between direct and indirect evidence (SSRI v waitlist control; cognitive behavioural therapy v tai chi or qigong). Overall, we found little statistical evidence that the model violated the assumption of transitivity. Qualitative differences were, however, found for participant characteristics between different arms (see supplementary file, section S4). For example, some interventions appeared to be prescribed more frequently among people with severe depression (eg, 7/16 studies using SSRIs) compared with other interventions (eg, 1/15 studies using aerobic exercise combined with therapy). Similarly, some interventions appeared more likely to be prescribed for older adults (eg, mean age, tai chi=59 v dance=31) or women (eg, per cent female: dance=88% v cycling=53%). Given that plausible mechanisms exist for these systematic differences (eg, the popularity of tai chi among older adults), 53 there are reasons to believe that allocation to treatment arms would be less than perfectly random. We have factored these biases in our certainty estimates through indirectness ratings.

Network geometry indicating number of participants in each arm (size of points) and number of comparisons between arms (thickness of lines). SSRI=selective serotonin reuptake inhibitor

Risk of bias within studies

Supplementary file section S5 provides the risk of bias ratings for each study. Few studies explicitly blinded participants and staff ( fig 3 ). As a result, overall risk of bias for most studies was unclear or high, and effect sizes could include expectancy effects, among other biases. However, sensitivity analyses suggested that effect sizes were not influenced by any risk of bias criteria owing to wide credible intervals (see supplementary file, section S6). Nevertheless, certainty ratings for all treatments arms were downgraded owing to high risk of bias in the studies informing the comparison.

Risk of bias summary plot showing percentage of included studies judged to be low, unclear, or high risk across Cochrane criteria for randomised trials

Synthesis of results

Supplementary file section S7 presents a forest plot of Hedges’ g values for each study. Figure 4 shows the predicted effects of each treatment compared with active controls. Compared with active controls, large reductions in depression were found for dance (n=107, κ=5, Hedges’ g −0.96, 95% credible interval −1.36 to −0.56) and moderate reductions for walking or jogging (n=1210, κ=51, g −0.63, −0.80 to −0.46), yoga (n=1047, κ=33, g=−0.55, −0.73 to −0.36), strength training (n=643, κ=22, g=−0.49, −0.69 to −0.29), mixed aerobic exercises (n=1286, κ=51, g=−0.43, −0.61 to −0.25), and tai chi or qigong (n=343, κ=12, g=−0.42, −0.65 to −0.21). Moderate, clinically meaningful effects were also present when exercise was combined with SSRIs (n=268, κ=11, g=−0.55, −0.86 to −0.23) or aerobic exercise was combined with psychotherapy (n=404, κ=15, g=−0.54, −0.76 to −0.32). All these treatments were significantly stronger than the standardised minimum clinically important difference compared with active control (g=−0.20), equating to an absolute g value of −1.16. Dance, exercise combined with SSRIs, and walking or jogging were the treatments most likely to perform best when modelling the surface under the cumulative ranking curve ( fig 4 ). For acceptability, the odds of participants dropping out of the study were lower for strength training (n=247, direct evidence κ=6, odds ratio 0.55, 95% credible interval 0.31 to 0.99) and yoga (n=264, κ=5, 0.57, 0.35 to 0.94) than for active control. The rate of dropouts was not significantly different from active control in any other arms (see supplementary file, section S8).

Predicted effects of different exercise modalities on major depression compared with active controls (eg, usual care), with 95% credible intervals. The estimate of effects for the active control condition was a before and after change of Hedges’ g of −0.95 (95% credible interval −1.10 to −0.79), n=3554, κ =113. Colour represents SUCRA from most likely to be helpful (dark purple) to least likely to be helpful (light purple). SSRI=selective serotonin reuptake inhibitor; SUCRA=surface under the cumulative ranking curve

Consistent with other meta-analyses, effects were moderate for cognitive behaviour therapy alone (n=712, κ=20, g=−0.55, −0.75 to −0.37) and small for SSRIs (n=432, κ=16, g=−0.26, −0.50 to −0.01) compared with active controls ( fig 4 ). These estimates are comparable to those of reviews that focused directly on psychotherapy (g=−0.67, −0.79 to −0.56) 7 or pharmacotherapy (g=−0.30, –0.34 to −0.26). 25 However, our review was not designed to find all studies of these treatments, so these estimates should not usurp these directly focused systematic reviews.

Despite the large number of studies in the network, confidence in the effects were low ( fig 5 ). This was largely due to the high within study bias described in the risk of bias summary plot. Reporting bias was also difficult to robustly assess because direct comparison with active control was often only provided in fewer than 10 studies. Many studies focused on one sex only, older adults, or those with comorbidities, so most arms had some concerns about indirect comparisons. Credible intervals were seldom wide enough to change decision making, so concerns about imprecision were few. Heterogeneity did plausibly change some conclusions around clinical significance. Few studies showed problematic incoherence, meaning direct and indirect evidence usually agreed. Overall, walking or jogging had low confidence, with other modalities being very low.

Summary table for credibility assessment using confidence in network meta-analysis (CINeMA). SSRI=selective serotonin reuptake inhibitor

Moderation by participant characteristics

The optimal modality appeared to be moderated by age and sex. Compared with models that only included exercise modality (R 2 =0.65), R 2 was higher for models that included interactions with sex (R 2 =0.71) and age (R 2 =0.69). R 2 showed no substantial increase for models including baseline depression (R 2 =0.67) or comorbidities (R 2 =0.66; see supplementary file, section S9).

Effects appeared larger for women than men for strength training and cycling ( fig 6 ). Effects appeared to be larger for men than women when prescribing yoga, tai chi, and aerobic exercise alongside psychotherapy. Yoga and aerobic exercise alongside psychotherapy appeared more effective for older participants than younger people ( fig 7 ). Strength training appeared more effective when prescribed to younger participants than older participants. Some estimates were associated with substantial uncertainty because some modalities were not well studied in some groups (eg, tai chi for younger adults), and mean age of the sample was only available for 71% of the studies.

Effects of interventions versus active control on depression (lower is better) by sex. Shading represents 95% credible intervals

Effects of interventions versus active control on depression (lower is better) by age. Shading represents 95% credible intervals

Moderation by intervention and design characteristics

Across modalities, a clear dose-response curve was observed for intensity of exercise prescribed ( fig 8 ). Although light physical activity (eg, walking, hatha yoga) still provided clinically meaningful effects (g=−0.58, −0.82 to −0.33), expected effects were stronger for vigorous exercise (eg, running, interval training; g=−0.74, −1.10 to −0.38). This finding did not appear to be due to increased weekly energy expenditure: credible intervals were wide, which meant that the dose-response curve for METs/min prescribed per week was unclear (see supplementary file, section S10). Weak evidence suggested that shorter interventions (eg, 10 weeks: g=−0.53, −0.71 to −0.35) worked somewhat better than longer ones (eg, 30 weeks: g=−0.37, −0.79 to 0.03), with wide credible intervals again indicating high uncertainty (see supplementary file, section S11). We also moderated for the lag between the end of treatment and the measurement of the outcome. We found no indication that participants were likely to relapse within the measurement period (see supplementary file, section S12); effects remained steady when measured either directly after the intervention (g=−0.59, −0.80 to −0.39) or up to six months later (g=−0.63, −0.87 to −0.40).

Dose-response curve for intensity (METs) across exercise modalities compared with active control. METs=metabolic equivalents of task

Supplementary file section S13 provides coding for the behaviour change techniques and autonomy for each exercise arm. None of the behaviour change techniques significantly moderated overall effects. Contrary to expectations, studies describing a level of participant autonomy (ie, choice over frequency, intensity, type, or time) tended to show weaker effects (g=−0.28, −0.78 to 0.23) than those that did not (g=−0.75, −1.17 to −0.33; see supplementary file, section S14). This effect was consistent whether or not we included studies that used physical activity counselling (usually high autonomy).

Use of group exercise appeared to moderate the effects: although the overall effects were similar for individual (g=−1.10, −1.57 to −0.64) and group exercise (g=−1.16, −1.61 to −0.73), some interventions were better delivered in groups (yoga) and some were better delivered individually (strength training, mixed aerobic exercise; see supplementary file, section S15).

As preregistered, we tested whether study funding moderated effects. Models that included whether a study was funded did explain more variance (R 2 =0.70) compared with models that included treatment alone (R 2 =0.65). Funded studies showed stronger effects (g=−1.01, −1.19 to −0.82) than unfunded studies (g=−0.77, −1.09 to −0.46). We also moderated for the type of measure (self-report v clinician report). This did not explain a substantial amount of variance in the outcome (R 2 =0.66).

Sensitivity analyses

Evidence of publication bias was found for overall estimates of exercise on depression compared with active controls, although not enough to nullify effects. The multilevel Egger’s test showed significance (F 1,98 =23.93, P<0.001). Funnel plots showed asymmetry, but the result of pooled effects remained statistically significant when only including non-significant studies (see supplementary file, section S16). No amount of publication bias would be sufficient to shrink effects to zero (s value=not possible). To reduce effects below clinical significance thresholds, studies with statistically significant results would need to be reported 58 times more frequently than studies with non-significant results.

Qualitative synthesis of mediation effects

Only a few of the studies used explicit mediation analyses to test hypothesised mechanisms of action. 54 55 56 57 58 59 One study found that both aerobic exercise and yoga led to decreased depression because participants ruminated less. 54 The study found that the effects of aerobic exercise (but not yoga) were mediated by increased acceptance. 54 “Perceived hassles” and awareness were not statistically significant mediators. 54 Another study found that the effects of yoga were mediated by increased self-compassion, but not rumination, self-criticism, tolerance of uncertainty, body awareness, body trust, mindfulness, and attentional biases. 55 One study found that the effects from an aerobic exercise intervention were not mediated by long term physical activity, but instead were mediated by exercise specific affect regulation (eg, self-control for exercise). 57 Another study found that neither exercise self-efficacy nor depression coping self-efficacy mediated effects of aerobic exercise. 56 Effects of aerobic exercise were not mediated by the N2 amplitude from electroencephalography, hypothesised as a neuro-correlate of cognitive control deficits. 58 Increased physical activity did not appear to mediate the effects of physical activity counselling on depression. 59 It is difficult to infer strong conclusions about mechanisms on the basis of this small number of studies with low power.

Summary of evidence

In this systematic review and meta-analysis of randomised controlled trials, exercise showed moderate effects on depression compared with active controls, either alone or in combination with other established treatments such as cognitive behaviour therapy. In isolation, the most effective exercise modalities were walking or jogging, yoga, strength training, and dancing. Although walking or jogging were effective for both men and women, strength training was more effective for women, and yoga or qigong was more effective for men. Yoga was somewhat more effective among older adults, and strength training was more effective among younger people. The benefits from exercise tended to be proportional to the intensity prescribed, with vigorous activity being better. Benefits were equally effective for different weekly doses, for people with different comorbidities, or for different baseline levels of depression. Although confidence in many of the results was low, treatment guidelines may be overly conservative by conditionally recommending exercise as complementary or alternative treatment for patients in whom psychotherapy or pharmacotherapy is either ineffective or unacceptable. 60 Instead, guidelines for depression ought to include prescriptions for exercise and consider adapting the modality to participants’ characteristics and recommending more vigorous intensity exercises.

Our review did not uncover clear causal mechanisms, but the trends in the data are useful for generating hypotheses. It is unlikely that any single causal mechanism explains all the findings in the review. Instead, we hypothesise that a combination of social interaction, 61 mindfulness or experiential acceptance, 62 increased self-efficacy, 33 immersion in green spaces, 63 neurobiological mechanisms, 64 and acute positive affect 65 combine to generate outcomes. Meta-analyses have found each of these factors to be associated with decreases in depressive symptoms, but no single treatment covers all mechanisms. Some may more directly promote mindfulness (eg, yoga), be more social (eg, group exercise), be conducted in green spaces (eg, walking), provide a more positive affect (eg, “runner’s high”’), or be more conducive to acute adaptations that may increase self-efficacy (eg, strength). 66 Exercise modalities such as running may satisfy many of the mechanisms, but they are unlikely to directly promote the mindful self-awareness provided by yoga and qigong. Both these forms of exercise are often practised in groups with explicit mindfulness but seldom have fast and objective feedback loops that improve self-efficacy. Adequately powered studies testing multiple mediators may help to focus more on understanding why exercise helps depression and less on whether exercise helps. We argue that understanding these mechanisms of action is important for personalising prescriptions and better understanding effective treatments.

Our review included more studies than many existing reviews on exercise for depression. 13 22 27 28 As a result, we were able to combine the strengths of various approaches to exercise and to make more nuanced and precise conclusions. For example, even taking conservative estimates (ie, the least favourable end of the credible interval), practitioners can expect patients to experience clinically significant effects from walking, running, yoga, qigong, strength training, and mixed aerobic exercise. Because we simultaneously assessed more than 200 studies, credible intervals were narrower than those in most existing meta-analyses. 13 We were also able to explore non-linear relationships between outcomes and moderators, such as frequency, intensity, and time. These analyses supported some existing findings—for example, our study and the study by Heissel et al 22 found that shorter interventions had stronger effects, at least for six months; our study and the study by Singh et al 13 both found that effects were stronger with vigorous intensity exercise compared with light and moderate exercise. However, most existing reviews found various treatment modalities to be equally effective. 13 27 In our review, some types of exercise had stronger effect sizes than others. We attribute this to the study level data available in a network meta-analysis compared with an overview of reviews 24 and higher power compared with meta-analyses with smaller numbers of included studies. 22 28 Overviews of reviews have the ability to more easily cover a wider range of participants, interventions, and outcomes, but also risk double counting randomised trials that are included in separate meta-analyses. They often include heterogeneous studies without having as much control over moderation analyses (eg, Singh et al included studies covering both prevention and treatment 13 ). Some of those reviews grouped interventions such as yoga with heterogeneous interventions such as stretching and qigong. 13 This practise of combining different interventions makes it harder to interpret meta-analytical estimates. We used methods that enabled us to separately analyse the effects of these treatment modalities. In so doing, we found that these interventions do have different effects, with yoga being an intervention with strong effects and stretching being better described as an active control condition. Network meta-analyses revealed the same phenomenon with psychotherapy: researchers once concluded there was a dodo bird verdict, whereby “everybody has won, and all must have prizes,” 67 until network meta-analyses showed some interventions were robustly more effective than others. 6 26

Predictors of acceptability and outcomes

We found evidence to suggest good acceptability of yoga and strength training; although the measurement of study drop-out is an imperfect proxy of adherence. Participants may complete the study without doing any exercise or may continue exercising and drop out of the study for other reasons. Nevertheless, these are useful data when considering adherence.

Behaviour change techniques, which are designed to increase adherence, did not meaningfully moderate the effect sizes from exercise. This may be due to several factors. It may be that the modality explains most of the variance between effects, such that behaviour change techniques (eg, presence or absence of feedback) did not provide a meaningful contribution. Many forms of exercise potentially contain therapeutic benefits beyond just energy expenditure. These characteristics of a modality may be more influential than coexisting behaviour change techniques. Alternatively, researchers may have used behaviour change techniques such as feedback or goal setting without explicitly reporting them in the study methods. Given the inherent challenges of behaviour change among people with depression, 29 and the difficulty in forecasting which strategies are likely to be effective, 68 we see the identification of effective techniques as important.

We did find that autonomy, as provided in the methods of included studies, predicted effects, but in the opposite direction to our hypotheses: more autonomy was associated with weaker effects. Physical activity counselling, which usually provides a great deal of patient autonomy, was among the lowest effect sizes in our meta-analysis. Higher autonomy judgements were associated with weaker outcomes regardless of whether physical activity counselling was included in the model. One explanation for these data is that people with depression benefit from the clear direction and accountability of a standardised prescription. When provided with more freedom, the low self-efficacy that is symptomatic of depression may stop patients from setting an appropriate level of challenge (eg, they may be less likely to choose vigorous exercise). Alternatively, participants were likely autonomous when self-selecting into trials with exercise modalities they enjoyed, or those that fit their social circumstances. After choosing something value aligned, autonomy within the trial may not have helpful. Either way, data should be interpreted with caution. Our judgement of the autonomy provided in the methods may not reflect how much autonomy support patients actually felt. The patient’s perceived autonomy is likely determined by a range of factors not described in the methods (eg, the social environment created by those delivering the programme, or their social identity), so other studies that rely on patient reports of the motivational climate are likely to be more reliable. 33 Our findings reiterate the importance of considering these patient reports in future research of exercise for depression.

Our findings suggest that practitioners could advocate for most patients to engage in exercise. Those patients may benefit from guidance on intensity (ie, vigorous) and types of exercise that appear to work well (eg, walking, running, mixed aerobic exercise, strength training, yoga, tai chi, qigong) and be well tolerated (eg, strength training and yoga). If social determinants permit, 66 engaging in group exercise or structured programmes could provide support and guidance to achieve better outcomes. Health services may consider offering these programmes as an alternative or adjuvant treatment for major depression. Specifically, although the confidence in the evidence for exercise is less strong than for cognitive behavioural therapy, the effect sizes seem comparable, so it may be an alternative for patients who prefer not to engage in psychotherapy. Previous reviews on those with mild-moderate depression have found similar effects for exercise or SSRIs, or the two combined. 13 14 In contrast, we found some forms of exercise to have stronger effects than SSRIs alone. Our findings are likely related to the larger power in our review (n=14 170) compared with previous reviews (eg, n=2551), 14 and our ability to better account for heterogeneity in exercise prescriptions. Exercise may therefore be considered a viable alternative to drug treatment. We also found evidence that exercise increases the effects of SSRIs, so offering exercise may act as an adjuvant for those already taking drugs. We agree with consensus statements that professionals should still account for patients’ values, preferences, and constraints, ensuring there is shared decision making around what best suits the patient. 66 Our review provides data to help inform that decision.

Strengths, limitations, and future directions

Based on our findings, dance appears to be a promising treatment for depression, with large effects found compared with other interventions in our review. But the small number of studies, low number of participants, and biases in the study designs prohibits us from recommending dance more strongly. Given most research for the intervention has been in young women (88% female participants, mean age 31 years), it is also important for future research to assess the generalisability of the effects to different populations, using robust experimental designs.

The studies we found may be subject to a range of experimental biases. In particular, researchers seldom blinded participants or staff delivering the intervention to the study’s hypotheses. Blinding for exercise interventions may be harder than for drugs 23 ; however, future studies could attempt to blind participants and staff to the study’s hypotheses to avoid expectancy effects. 69 Some of our ratings are for studies published before the proliferation of reporting checklists, so the ratings might be too critical. 23 For example, before CONSORT, few authors explicitly described how they generated a random sequence. 23 Therefore, our risk of bias judgements may be too conservative. Similarly, we planned to use the Cochrane risk of bias (RoB) 1 tool 40 so we could use the most recent Cochrane review of exercise and depression 12 to calibrate our raters, and because RoB 2 had not yet been published. 70 Although assessments of bias between the two tools are generally comparable, 71 the RoB 1 tool can be more conservative when assessing open label studies with subjective assessments (eg, unblinded studies with self-reported measures for depression). 71 As a result, future reviews should consider using the latest risk of bias tool, which may lead to different assessments of bias in included studies.

Most of the main findings in this review appear robust to risks from publication bias. Specifically, pooled effect sizes decreased when accounting for risk of publication bias, but no degree of publication bias could nullify effects. We did not exclude grey literature, but our search strategy was not designed to systematically search grey literature or trial registries. Doing so can detect additional eligible studies 72 and reveal the numbers of completed studies that remain unpublished. 73 Future reviews should consider more systematic searches for this kind of literature to better quantify and mitigate risk of publication bias.

Similarly, our review was able to integrate evidence that directly compared exercise with other treatment modalities such as SSRIs or psychotherapy, while also informing estimates using indirect evidence (eg, comparing the relative effects of strength training and SSRIs when tested against a waitlist control). Our review did not, however, include all possible sources of indirect evidence. Network meta-analyses exist that directly focus on psychotherapy 7 and pharmacotherapy, 25 and these combined for treating depression. 6 Those reviews include more than 500 studies comparing psychological or drug interventions with controls. Harmonising the findings of those reviews with ours would provide stronger data on indirect effects.

Our review found some interesting moderators by age and sex, but these were at the study level rather than individual level—that is, rather than being able to determine whether women engaging in a strength intervention benefit more than men, we could only conclude that studies with more women showed larger effects than studies with fewer women. These studies may have been tailored towards women, so effects may be subject to confounding, as both sex and intervention may have changed. The same finding applied to age, where studies on older adults were likely adapted specifically to this age group. These between study differences may explain the heterogeneity in the effects of interventions, and confounding means our moderators for age and sex should be interpreted cautiously. Future reviews should consider individual patient meta-analyses to allow for more detailed assessments of participant level moderators.

Finally, for many modalities, the evidence is derived from small trials (eg, the median number of walking or jogging arms was 17). In addition to reducing risks from bias, primary research may benefit from deconstruction designs or from larger, head-to-head analyses of exercise modalities to better identify what works best for each candidate.

Clinical and policy implications

Our findings support the inclusion of exercise as part of clinical practice guidelines for depression, particularly vigorous intensity exercise. Doing so may help bridge the gap in treatment coverage by increasing the range of first line options for patients and health systems. 9 Globally there has been an attempt to reduce stigma associated with seeking treatment for depression. 74 Exercise may support this effort by providing patients with treatment options that carry less stigma. In low resource or funding constrained settings, group exercise interventions may provide relatively low cost alternatives for patients with depression and for health systems. When possible, ideal treatment may involve individualised care with a multidisciplinary team, where exercise professionals could take responsibility for ensuring the prescription is safe, personalised, challenging, and supported. In addition, those delivering psychotherapy may want to direct some time towards tackling cognitive and behavioural barriers to exercise. Exercise professionals might need to be trained in the management of depression (eg, managing risk) and to be mindful of the scope of their practice while providing support to deal with this major cause of disability.

Conclusions

Depression imposes a considerable global burden. Many exercise modalities appear to be effective treatments, particularly walking or jogging, strength training, and yoga, but confidence in many of the findings was low. We found preliminary data that may help practitioners tailor interventions to individuals (eg, yoga for older men, strength training for younger women). The World Health Organization recommends physical activity for everyone, including those with chronic conditions and disabilities, 75 but not everyone can access treatment easily. Many patients may have physical, psychological, or social barriers to participation. Still, some interventions with few costs, side effects, or pragmatic barriers, such as walking and jogging, are effective across people with different personal characteristics, severity of depression, and comorbidities. Those who are able may want to choose more intense exercise in a structured environment to further decrease depression symptoms. Health systems may want to provide these treatments as alternatives or adjuvants to other established interventions (cognitive behaviour therapy, SSRIs), while also attenuating risks to physical health associated with depression. 3 Therefore, effective exercise modalities could be considered alongside those intervention as core treatments for depression.

What is already known on this topic

Depression is a leading cause of disability, and exercise is often recommended alongside first line treatments such as pharmacotherapy and psychotherapy

Treatment guidelines and previous reviews disagree on how to prescribe exercise to best treat depression

What this study adds

Various exercise modalities are effective (walking, jogging, mixed aerobic exercise, strength training, yoga, tai chi, qigong) and well tolerated (especially strength training and yoga)

Effects appeared proportional to the intensity of exercise prescribed and were stronger for group exercise and interventions with clear prescriptions

Preliminary evidence suggests interactions between types of exercise and patients’ personal characteristics

Ethics statements

Ethical approval.

Not required.

Acknowledgments

We thank Lachlan McKee for his assistance with data extraction. We also thank Juliette Grosvenor and another librarian (anonymous) for their review of our search strategy.

Contributors: MN led the project, drafted the manuscript, and is the guarantor. MN, TS, PT, MM, BdPC, PP, SB, and CL drafted the initial study protocol. MN, TS, PT, BdPC, DvdH, JS, MM, RP, LP, RV, HA, and BV conducted screening, extraction, and risk of bias assessment. MN, JS, and JM coded methods for behaviour change techniques. MN and DGG conducted statistical analyses. PP, SB, and CL provided supervision and mentorship. All authors reviewed and approved the final manuscript. The corresponding author attests that all listed authors meet authorship criteria and that no others meeting the criteria have been omitted.

Funding: None received.

Competing interests: All authors have completed the ICMJE uniform disclosure form at www.icmje.org/disclosure-of-interest/ and declare: no support from any organisation for the submitted work; no financial relationships with any organisations that might have an interest in the submitted work in the previous three years; no other relationships or activities that could appear to have influenced the submitted work.

Data sharing Data and code for reproducing analyses are available on the Open Science Framework ( https://osf.io/nzw6u/ ).

The lead author (MN) affirms that the manuscript is an honest, accurate, and transparent account of the study being reported; that no important aspects of the study have been omitted; and that any discrepancies from the study as planned (and, if relevant, registered) have been explained.

Dissemination to participants and related patient and public communities: We plan to disseminate the findings of this study to lay audiences through mainstream and social media.

Provenance and peer review: Not commissioned; externally peer reviewed.

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

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FDA Approves Rapid-Acting Oral Antidepressant

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September Issues of APA Journals Cover Depression Risk Factors and Treatments, Noninvasive Brain Stimulation Treatments and the Evidence for School-Based Services

• September 06, 2024

WASHINGTON, D.C. — The latest issues of two American Psychiatric Association journals, The American Journal of Psychiatry and Psychiatric Services, are now available online.

The September issue of The American Journal of Psychiatry brings together research on depression, both therapeutic insights and contributing risk factors, and an overview and look at the promise of noninvasive brain stimulation. Highlights include:

• Entactogen Effects of Ketamine: A Reverse-Translational Study.
•   
• Peer Social Genetic Effects and the Etiology of Substance Use Disorders, Major Depression, and Anxiety Disorder in a Swedish National Sample. (Lead author Jessica Salvatore, Ph.D., is the featured guest in the AJP Audio podcast and AJP Deputy Editor Danny Pine, M.D., highlights the study in this video .)
• rTMS as a Next Step in Antidepressant Nonresponders: A Randomized Comparison With Current Antidepressant Treatment Approaches. (AJP Deputy Editor Danny Pine highlights the study in this video .)
• Association Between Intrauterine System Hormone Dosage and Depression Risk. Toward Precision Noninvasive Brain Stimulation.
• Closed-Loop Transcranial Alternating Current Stimulation for the Treatment of Major Depressive Disorder: An Open-Label Pilot Study.

The September issue of Psychiatric Services features :

• Effects of Recreational Cannabis Legalization on Mental Health: Scoping Review.
• The Need to Adapt the Psychiatric Clinical Assessment to the Digital Age: A Practical Approach.
• Reimbursement for a Broader Array of Services in Coordinated Specialty Care for Early Psychosis.
• Comparative Effectiveness of Clinician- Versus Peer-Supported Problem-Solving Therapy for Rural Older Adults With Depression.
• Self-Pay Outpatient Mental Health Care for Children and Adolescents, by Socioeconomic Status.
• Assessing the Evidence Base for School-Based Promotion and Prevention Interventions.

Journalists who wish to access the publications should email [email protected] .

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The American Psychiatric Association, founded in 1844, is the oldest medical association in the country. The APA is also the largest psychiatric association in the world with more than 38,900 physician members specializing in the diagnosis, treatment, prevention and research of mental illnesses. APA’s vision is to ensure access to quality psychiatric diagnosis and treatment. For more information, please visit www.psychiatry.org.

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Researchers discovered novel and unique neural signature for depression

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A recent study led by  Dr. Sameer Sheth , professor and vice chair of research in the  Department of Neurosurgery  at Baylor College of Medicine, director of the Gordon and Mary Cain Pediatric Neurology Research Foundation Laboratories and investigator at the Jan and Dan Duncan Neurological Research Institute (Duncan NRI) at Texas Children’s Hospital, identified beta frequency neural activity in the anterior cingulate cortex (ACC) of the brain’s frontal lobe as the key neural signature underlying processes associated with recognizing rewards and determining subsequent choices and, thus, shaping future behaviors.

The study is published in Nature Communications .

The authors report that this neural signature is altered in patients with depression, opening an exciting possibility of using these neural signals as a new biomarker and a potential innovative avenue for therapy.

Anhedonia is a cardinal symptom of depression and other psychiatric conditions

Human beings derive pleasure through various physical or mental activities, sensory experiences and interactions with family and friends.

Individuals with depression often experience feelings of hopelessness, sadness or despair for prolonged periods due to disengagement and anhedonia – a medical term meaning loss of the ability to feel joy or contentment in activities and things that they once found pleasurable, all of which has a profound negative impact on their quality of life.

Anhedonia is also associated with other psychiatric and neurological disorders such as schizophrenia and bipolar disorder, substance abuse disorder, anxiety and Parkinson’s disease. Traditional antidepressants and standard treatments often fail to adequately address this symptom in individuals with severe treatment-resistant depression and other conditions. A better understanding of anhedonia can guide the development of targeted and more effective treatments for depression and related conditions.

Reward bias response is regulated by beta activity in the frontal lobe

To identify the underlying neural basis for anhedonia, Sheth and team recorded and analyzed neural activity from four brain regions of 15 patients with medication-resistant epilepsy who were undergoing invasive monitoring to localize the zone from where their seizures originated.

As their brain activity was being monitored, these patients performed a perceptual discrimination task called the probabilistic reward task (PRT), a well-validated behavioral task that objectively measures anhedonia by observing subtle changes in behavior related to reward.

“We found that the unequal assignment of reward between two correct responses in this task produced a response bias toward the more frequently rewarded stimulus,” said lead author Dr. Jiayang Xiao, who conducted this study as a graduate student in the Sheth lab. “We found that based on feedback, most individuals modified their subsequent responses to make choices that were likely to get rewarded, irrespective of the accuracy of their answers.”

Moreover, they found a specific signal – neural oscillations in the beta frequency range – originating from the anterior cingulate cortex (ACC) in the frontal lobe of the brain, showed a consistently strong and positive correlation with the reward bias behavior and tracked closely with the receipt of rewards and their value. Further, they found that this specific brain region was engaged in evaluating both reward stimuli and outcomes, potentially acting as a critical node with a common mechanism for reward assessment.

“Our study has addressed a longstanding fundamental question in neuroscience – which specific brain region and signal regulates the classic reward bias response, a famous example of which is the Pavlovian conditioning where dogs learned to associate the sound of a ringing bell to food,” said co-senior author Dr. Benjamin Hayden , professor of neurosurgery at Baylor.

Reward bias response is altered in patients with treatment-resistant depression 

Next, Sheth and his team conducted the PRT in four individuals with severe treatment-resistant depression. They found that reward processing in the ACC was altered in this group. These individuals did not exhibit the typical behavioral response of favoring choices that are more frequently rewarded. This observation suggests a lack of reward-oriented anticipation and that their choices were less driven by reward feedback. Consistent with this change in reward bias behavior, beta activity in the ACC region was reduced and delayed in these individuals.

“In this study, we identified beta activity in the ACC as a potential biomarker for anhedonia,” said Sheth, also a McNair Scholar and Cullen Foundation Endowed Chair at Baylor.

Studying the beta activity in the ACC could have many potential benefits, including improving diagnosis and monitoring symptoms of patients with severe depression and other anhedonia-related psychiatric conditions.

Moreover, our findings present an exciting possibility that modulation of the ACC beta activity might be effective treatment anhedonia, a hypothesis we plan to test in future clinical trials.”

The neurotechnology improvements of this research have advanced at a pace not previously possible due in part to funding by the National Institutes of Health Brain Research Through Advancing Innovative Neurotechnologies Initiative, or the BRAIN Initiative.

“This study exemplifies how BRAIN-funded research is already having an impact in the clinic today,” said Dr. John Ngai, director of the NIH BRAIN Initiative. “The innovations in data collection and individualized deep brain stimulation demonstrated in this study may enable a new generation of precision treatments.”

Information about other authors involved in the study, their affiliations and their declaration of interest can be found  here . This research was supported by the National Institutes of Health by award numbers UH3 NS103549, K01 MH116364, R21 NS104953, UH3 NS100549 and R01 MH114854; and the McNair Medical Institute at the Robert and Janice McNair Foundation. The researchers would also like to thank the Cullen Foundation, the Jan and Dan Duncan Neurological Research Institute and the Gordon and Mary Cain Pediatric Neurology Research Foundation Labs at Texas Children’s Hospital.

By Graciela Gutierrez

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Study shows cognitive behavioral therapy can lead to brain changes in depression patients

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Cognitive behavioral therapy, one of the most common treatments for depression, can teach skills for coping with everyday troubles, reinforce healthy behaviors and counter negative thoughts. But can altering thoughts and behaviors lead to lasting changes in the brain?

New research led by Stanford Medicine has found that it can -; if a therapy is matched with the right patients. In a study of adults with both depression and obesity -; a difficult-to-treat combination -; cognitive behavioral therapy that focused on problem solving reduced depression in a third of patients. These patients also showed adaptative changes in their brain circuitry.

Moreover, these neural adaptations were apparent after just two months of therapy and could predict which patients would benefit from long-term therapy.

The findings add to evidence that choosing treatments based on the neurological underpinnings of a patient's depression -; which vary among people -; increases the odds of success. 

The same concept is already standard practice in other medical specialties.

"If you had chest pain, your physician would suggest some tests -; an electrocardiogram, a heart scan, maybe a blood test -; to work out the cause and which treatments to consider," said Leanne Williams, PhD, the Vincent V.C. Woo Professor, a professor of psychiatry and behavioral sciences, and the director of Stanford Medicine's Center for Precision Mental Health and Wellness.

"Yet in depression, we have no tests being used. You have this broad sense of emotional pain, but it's a trial-and-error process to choose a treatment, because we have no tests for what is going on in the brain."

Williams and Jun Ma, MD, PhD, professor of academic medicine and geriatrics at the University of Illinois at Chicago, are co-senior authors of the study published Sept. 4 in  Science Translational Medicine.  The work is part of a larger clinical trial called RAINBOW (Research Aimed at Improving Both Mood and Weight).

Problem solving

The form of cognitive behavioral therapy used in the trial, known as problem-solving therapy, is designed to improve cognitive skills used in planning, troubleshooting and tuning out irrelevant information. A therapist guides patients in identifying real-life problems -; a conflict with a roommate, say -; brainstorming solutions and choosing the best one.

These cognitive skills depend on a particular set of neurons that function together, known as the cognitive control circuit.

Previous work from Williams' lab, which identified six biotypes of depression based on patterns of brain activity, estimated that a quarter of people with depression have dysfunction with their cognitive control circuits -; either too much or too little activity.

The participants in the new study were adults diagnosed with both major depression and obesity, a confluence of symptoms that often indicates problems with the cognitive control circuit. Patients with this profile generally do poorly on antidepressants: They have a dismal response rate of 17%.

Of the 108 participants, 59 underwent a year-long program of problem-solving therapy in addition to their usual care, such as medications and visits to a primary care physician. The other 49 received only usual care.

They were given fMRI brain scans at the beginning of the study, then after two months, six months, 12 months and 24 months. During the brain scans, the participants completed a test that involves pressing or not pressing a button according to text on a screen -; a task known to engage the cognitive control circuit. The test allowed the researchers to gauge changes in the activity of that circuit throughout the study.

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"We wanted to see whether this problem-solving therapy in particular could modulate the cognitive control circuit," said Xue Zhang, PhD, a postdoctoral scholar in psychiatry who is the lead author of the study.

With each brain scan, participants also filled out standard questionnaires that assessed their problem-solving ability and depression symptoms. 

Working smarter

As with any other depression treatment, problem-solving therapy didn't work for everyone. But 32% of participants responded to the therapy, meaning their symptom severity decreased by half or more.

"That's a huge improvement over the 17% response rate for antidepressants," Zhang said.

When researchers examined the brain scans, they found that in the group receiving only usual care, a cognitive control circuit that became less active over the course of the study correlated with worsening problem-solving ability.

But in the group receiving therapy, the pattern was reversed: Decreased activity correlated with enhanced problem-solving ability. The researchers think this may be due to their brains learning, through the therapy, to process information more efficiently.

"We believe they have more efficient cognitive processing, meaning now they need fewer resources in the cognitive control circuit to do the same behavior," Zhang said.

Before the therapy, their brains had been working harder; now, they were working smarter.

Both groups, on average, improved in their overall depression severity. But when Zhang dug deeper into the 20-item depression assessment, she found that the depression symptom most relevant to cognitive control -; "feeling everything is an effort" -; benefited from the more efficient cognitive processing gained from the therapy.

"We're seeing that we can pinpoint the improvement specific to the cognitive aspect of depression, which is what drives disability because it has the biggest impact on real-world functioning," Williams said.

Indeed, some participants reported that problem-solving therapy helped them think more clearly, allowing them to return to work, resume hobbies and manage social interactions.

Fast track to recovery

Just two months into the study, brain scans showed changes in cognitive control circuit activity in the therapy group.

"That's important, because it tells us that there is an actual brain change going on early, and it's in the time frame that you'd expect brain plasticity," Williams said. "Real-world problem solving is literally changing the brain in a couple of months."

The idea that thoughts and behaviors can modify brain circuits is not so different from how exercise -; a behavior -; strengthens muscles, she added.

The researchers found that these early changes signaled which patients were responding to the therapy and would likely improve on problem-solving skills and depression symptoms at six months, 12 months and even one year after the therapy ended, at 24 months. That means a brain scan could be used to predict which patients are the best candidates for problem-solving therapy.

It's a step toward Williams' vision of precision psychiatry -; using brain activity to match patients with the therapies most likely to help them, fast-tracking them to recovery.

"It's definitely advancing the science," Zhang said. "But it's also going to transform a lot of people's lives."

Researchers from University of Washington, University of Pittsburgh School of Medicine and The Ohio State University also contributed to the work.

The study received funding from the National Institutes of Health (grants UH2 HL132368, UH3 HL132368 and R01 HL119453).

Stanford Medicine

Posted in: Medical Research News | Medical Condition News

Tags: Blood , Blood Test , Brain , Chest Pain , Clinical Trial , Cognitive Behavioral Therapy , Depression , Disability , Exercise , Geriatrics , Heart , Medicine , Mental Health , Neurons , Neuroscience , Obesity , Pain , Primary Care , Psychiatry , Research

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Cognitive behavioral therapy enhances brain circuits to relieve depression

A new study led by Stanford Medicine scientists found that certain changes in neural activity predicted which patients would benefit from a type of cognitive behavioral therapy.

September 6, 2024 - By Nina Bai

Stanford Medicine researchers and their colleagues have found that choosing treatments based on the type of a patient’s depression increases the odds of success. Emily Moskal

Cognitive behavioral therapy, one of the most common treatments for depression, can teach skills for coping with everyday troubles, reinforce healthy behaviors and counter negative thoughts. But can altering thoughts and behaviors lead to lasting changes in the brain?

New research led by Stanford Medicine has found that it can — if a therapy is matched with the right patients. In a study of adults with both depression and obesity — a difficult-to-treat combination — cognitive behavioral therapy that focused on problem solving reduced depression in a third of patients. These patients also showed adaptative changes in their brain circuitry.

Moreover, these neural adaptations were apparent after just two months of therapy and could predict which patients would benefit from long-term therapy.

The findings add to evidence that choosing treatments based on the neurological underpinnings of a patient’s depression — which vary among people — increases the odds of success. 

The same concept is already standard practice in other medical specialties.

“If you had chest pain, your physician would suggest some tests — an electrocardiogram, a heart scan, maybe a blood test — to work out the cause and which treatments to consider,” said Leanne Williams , PhD, the Vincent V.C. Woo Professor, a professor of psychiatry and behavioral sciences, and the director of Stanford Medicine’s  Center for Precision Mental Health and Wellness .

“Yet in depression, we have no tests being used. You have this broad sense of emotional pain, but it’s a trial-and-error process to choose a treatment, because we have no tests for what is going on in the brain.”

Williams and Jun Ma, MD, PhD, professor of academic medicine and geriatrics at the University of Illinois at Chicago, are co-senior authors of the study published Sept. 4 in Science Translational Medicine. The work is part of a larger clinical trial called RAINBOW (Research Aimed at Improving Both Mood and Weight).

Leanne Williams

Problem solving

The form of cognitive behavioral therapy used in the trial, known as problem-solving therapy, is designed to improve cognitive skills used in planning, troubleshooting and tuning out irrelevant information. A therapist guides patients in identifying real-life problems — a conflict with a roommate, say — brainstorming solutions and choosing the best one.

These cognitive skills depend on a particular set of neurons that function together, known as the cognitive control circuit.

Previous work from Williams’ lab, which identified six biotypes of depression based on patterns of brain activity, estimated that a quarter of people with depression have dysfunction with their cognitive control circuits — either too much or too little activity.

The participants in the new study were adults diagnosed with both major depression and obesity, a confluence of symptoms that often indicates problems with the cognitive control circuit. Patients with this profile generally do poorly on antidepressants: They have a dismal response rate of 17%.

Of the 108 participants, 59 underwent a year-long program of problem-solving therapy in addition to their usual care, such as medications and visits to a primary care physician. The other 49 received only usual care.

They were given fMRI brain scans at the beginning of the study, then after two months, six months, 12 months and 24 months. During the brain scans, the participants completed a test that involves pressing or not pressing a button according to text on a screen — a task known to engage the cognitive control circuit. The test allowed the researchers to gauge changes in the activity of that circuit throughout the study.

“We wanted to see whether this problem-solving therapy in particular could modulate the cognitive control circuit,” said Xue Zhang , PhD, a postdoctoral scholar in psychiatry who is the lead author of the study.

With each brain scan, participants also filled out standard questionnaires that assessed their problem-solving ability and depression symptoms.  

Working smarter

As with any other depression treatment, problem-solving therapy didn’t work for everyone. But 32% of participants responded to the therapy, meaning their symptom severity decreased by half or more.

“That’s a huge improvement over the 17% response rate for antidepressants,” Zhang said.

When researchers examined the brain scans, they found that in the group receiving only usual care, a cognitive control circuit that became less active over the course of the study correlated with worsening problem-solving ability.

But in the group receiving therapy, the pattern was reversed: Decreased activity correlated with enhanced problem-solving ability. The researchers think this may be due to their brains learning, through the therapy, to process information more efficiently.

“We believe they have more efficient cognitive processing, meaning now they need fewer resources in the cognitive control circuit to do the same behavior,” Zhang said.

Before the therapy, their brains had been working harder; now, they were working smarter.

Both groups, on average, improved in their overall depression severity. But when Zhang dug deeper into the 20-item depression assessment, she found that the depression symptom most relevant to cognitive control — “feeling everything is an effort” — benefited from the more efficient cognitive processing gained from the therapy.

“We’re seeing that we can pinpoint the improvement specific to the cognitive aspect of depression, which is what drives disability because it has the biggest impact on real-world functioning,” Williams said.

Indeed, some participants reported that problem-solving therapy helped them think more clearly, allowing them to return to work, resume hobbies and manage social interactions.

Fast track to recovery

Just two months into the study, brain scans showed changes in cognitive control circuit activity in the therapy group.

“That’s important, because it tells us that there is an actual brain change going on early, and it’s in the time frame that you’d expect brain plasticity,” Williams said. “Real-world problem solving is literally changing the brain in a couple of months.”

The idea that thoughts and behaviors can modify brain circuits is not so different from how exercise — a behavior — strengthens muscles, she added.

The researchers found that these early changes signaled which patients were responding to the therapy and would likely improve on problem-solving skills and depression symptoms at six months, 12 months and even one year after the therapy ended, at 24 months. That means a brain scan could be used to predict which patients are the best candidates for problem-solving therapy.

It’s a step toward Williams’ vision of precision psychiatry — using brain activity to match patients with the therapies most likely to help them, fast-tracking them to recovery.

“It’s definitely advancing the science,” Zhang said. “But it’s also going to transform a lot of people’s lives.”

Researchers from University of Washington, University of Pittsburgh School of Medicine and The Ohio State University also contributed to the work.

The study received funding from the National Institutes of Health (grants UH2 HL132368, UH3 HL132368 and R01 HL119453).

Listen to a podcast of Leanne Williams discussing depression biotypes.

About Stanford Medicine

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

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New Study Reports High Rates of Anxiety and Depression in 11- to 13-Year-Olds During the COVID-19 Pandemic

Rates of depression in 11- to 13-year-olds increased significantly between the early and middle stages of the COVID-19 pandemic, and rates of anxiety and suicidal ideation stayed consistently high during the same period, according to a new study conducted in three U.S. states. The study, supported by the National Center for Complementary and Integrative Health with co-funding from the National Institute on Drug Abuse, the Office of Disease Prevention, and the Office of Behavioral and Social Sciences Research, and published in the Journal of Adolescence, also showed differences among population subgroups, with the greatest concerns about girls and Hispanic/Latinx youth in the early pandemic and among girls and Medicaid-insured youth at mid-pandemic.

Research conducted before the COVID-19 pandemic showed rates of anxiety, depression, and suicidal ideation among U.S. adolescents ranging from about 4 to 12 percent. Studies conducted during the early stage of the COVID-19 pandemic showed similar or slightly higher rates. This study extended the findings of previous research by analyzing data collected from a group of early adolescents, aged 11 to 13 years, during two time periods within the pandemic: March to September 2020 (early pandemic) and September 2020 to May 2021 (mid-pandemic). 

The 623 participants were recruited from pediatric primary care practices in California, Colorado, and Michigan for a pragmatic trial study testing the feasibility and effectiveness of implementing Guiding Good Choices, a family-focused substance use prevention program for caregivers of younger adolescents in health care systems. They completed a baseline behavioral health survey between March and September 2020, and then, because of a pandemic-related delay in the start of the study, they completed the survey again between September 2020 and May 2021. The survey included measures of anxiety (generalized anxiety disorder scale-7 [GAD-7]) and depression (patient health questionnaire-9 [PHQ-9]). The PHQ-9 item on “thoughts that you would be better off dead or of hurting yourself in some way” was used to assess suicidal ideation. 

During the early stage of the pandemic, 10.5 percent of the youth reported moderate-to-severe depression, with the lowest rate in boys (3.6 percent) and the highest rates in Hispanic/Latinx youth (16.7 percent) and girls (16.0 percent). In the overall sample, the rate of moderate-to-severe depression increased significantly from early to mid-pandemic, from 10.5 to 15.1 percent. The largest increases were seen in boys, black youth, and Medicaid-insured youth. Hispanic/Latinx youth showed a nonsignificant decrease in depression (from 16.7 to 13.9 percent). 

In the early stage of the pandemic, 12.0 percent of the youth reported moderate-to-severe anxiety, with the lowest rates in boys (4.6 percent) and Black youth (7.1 percent), and the highest rates in girls (17.7 percent) and Hispanic/Latinx youth (15.3 percent). The overall sample showed a nonsignificant increase in the prevalence of anxiety between early and mid-pandemic. In contrast, a decrease in the prevalence of anxiety was seen among Hispanic/Latinx youth at mid-pandemic.  

Early in the pandemic, 9.3 percent of the youth reported suicidal ideation, with the lowest rate among boys (4.8 percent) and the highest rates among girls (13.1 percent) and Hispanic/Latinx youth (12.2 percent). Nonsignificant increases were observed in the overall sample and some subgroups from early to mid-pandemic, and a nonsignificant decrease was seen among Hispanic/Latinx youth.

The researchers said that the COVID-19 pandemic may have had a persistent negative impact on mental health in early adolescents, as symptoms did not improve despite reductions in restrictions and closures in response to COVID-19 between early and mid-pandemic. The findings underscore the need for continued support for youth who experienced pandemic-related stressors. The researchers suggested that the possible improvements seen among Hispanic/Latinx youth from early to mid-pandemic might reflect the larger prevalence of multigenerational households in this group, which could contribute to a greater sense of community, perceived support, and resiliency. Additionally, most of the Hispanic/Latinx youth lived in Northern California or Colorado, where cities created outdoor space to promote outdoor activities during the pandemic, and these efforts were shown to significantly lower anxiety and depression. 

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• Danzo S, Kuklinski MR, Sterling SA, et al. Anxiety, depression, and suicidal ideation among early adolescents during the COVID-19 pandemic . Journal of Adolescence. 2024;96(6):1379-1387.

Publication Date: April 28, 2024

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Nature vs. nurture: the interplay between a child’s mind and environment

Depression amplified in difficult environments for youth with a larger left hippocampus, study finds

• Link to: Northwestern Now Story

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• Embargo date: September 2, 2024 2:00 PM CT
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Journal: Proceedings of the National Academy of Sciences (PNAS)

• Youth showed greater increases in depressive symptoms when they had experienced greater family conflict, peer victimization and less prosocial school environments
• A larger left hippocampus also enhanced sensitivity to these social contexts
• Research based on the Adolescent Brain Cognitive Development (ABCD) study, largest study of brain development and child health in America

EVANSTON, Ill. --- While the mental health crisis has touched the lives of young people across a broad age spectrum, new Northwestern University research has found that the presence of difficult social environments and the absence of positive social environments predicted greater increases in depressive symptoms in youth, aged 9-11, over a two-year period. In addition to environment, left hippocampal volume amplified the social context effects, suggesting that youth with a larger left hippocampus experience greater increases in Major Depressive Disorder (MDD) symptoms in challenging social spaces.

“Our research has implications not only for future research, but we also hope it increases awareness among parents, educators, mental health professionals and policy makers,” said co-lead author Claudia Haase, associate professor of human development and social policy at Northwestern’s School of Education and Social Policy (SESP). “Over the years, the pendulum has swung back and forth between some researchers and practitioners emphasizing the role of nature and others emphasizing the role of nurture. And we have come to really appreciate that we need to look at both and their interplay together.”

The study , publishing tomorrow (September 3) in Proceedings of the National Academy of Sciences (PNAS), underscores the importance of families, peers and schools in the development of depression during adolescence, and how variation in neural structure can amplify or diminish sensitivity to their environment.

The study was first authored by Matías Martínez, doctoral student at SESP, with senior co-authors Haase and Yang Qu, associate professor of human development and social policy at SESP. Titled “Depressive symptoms during the transition to adolescence: Left hippocampal volume as a marker of social context sensitivity,” additional authors include Tianying Cai; Beiming Yang; Zexi Zhou; Stewart Shankman; and Vijay A. Mittal.

“Our study emphasizes the importance of paying attention to individual differences and how some people are more sensitive to social environments than others,” Qu said. “We should never assume that the same environment will have the same impact for everyone. There is no one size fits all.”

Since neuroscience has seen major developments over the past few years, the researchers focused on brain-based sensitivity in the development of depressive symptoms. “Previous studies have focused on physiological processes or genetic variants, but with the development of neuroscience, now we can look at how the brain can play a role in the sensitivity to environments,” Martinez said. “There's a longstanding debate on whether some individuals are more or less sensitive to environments and in this study, we focused on sensitivity to social experiences, both negative and positive.”

The results concluded that the left hippocampus — a region of the brain that is primarily associated with memory, learning and how humans experience the world around them — plays an important role in whether a person becomes depressed if they find themselves in a challenging social space. A larger hippocampus would result in an individual being better able to remember an experience or recall a memory.

“It is one of the most plastic regions of the brain,” Martinez said. “It's very responsive to the environment, especially in a person’s early years. Our findings show that this brain region is playing a role in making youth more sensitive to difficult environments and to the absence of positivity in their life experiences — leading to depression symptoms.”

That area of the brain being larger in a child could result in that child having more sensitivity to social experiences — family conflicts, primary caregiver’s depressive symptoms, peer victimization, parental warmth and prosocial school environment — into adolescence.

“Some people tend to assume that we are ‘born this way’ when it comes to the human brain. But the more we learn about the brain, the more scientists have come to understand how open and malleable our brains are, not just in infancy but across the life span,” Haase said. “Our brains can change in response to the environments we find ourselves in — and studies show that this is certainly the case for the hippocampus as a brain region.”

The researchers examined two-year longitudinal data from the Adolescent Brain Cognitive Development study. The study — one of the largest studies in the U.S. conducted by 21 research sites across the country — aims to follow a diverse sample of 11,800 kids aged 9-11 over a 10-year period to observe their cognitive, brain, social and emotional development over time.

“The ABCD study is phenomenal, and we are deeply indebted to the National Institutes of Health and all the researchers involved for making this possible, and, of course, to all the youth and their families who are participating,” Qu said. “It’s the largest long-term study of brain development and child health in the United States.”

The data revealed a stronger association between socio-experiential environments and MDD symptoms for youth with a larger left hippocampal volume and no differences in MDD symptoms between individuals with different sizes of left hippocampus at low levels of negative and high levels of positive context exposure.

What’s next

The researchers are hoping the study helps parents, teachers and policymakers better understand and support youth’s mental health during adolescence. Martinez is hoping their expanded research can better explain how children in difficult social environments adapt to their surroundings in the long term.

“The ABCD study is such a comprehensive project that will continue to follow youth development for many more years,” Martinez said. “It will be exciting to examine what the interplay between exposure to different environments, hippocampal volume and depressive symptoms looks like as our youth navigate their teenage years.”

UCF Researchers Develop Rapid Test to Detect Dopamine

The sensor could serve as a low-cost and efficient tool for early detection of neurological disorders and conditions, including Parkinson’s disease, Alzheimer’s disease and depression.

By Eddy Duryea ’13 | September 5, 2024

Dopamine, a neurotransmitter in our brains, not only regulates our emotions but also serves as a biomarker for the screening of certain cancers and other neurological conditions.

UCF researchers, led by UCF NanoScience Technology Center Professor Debashis Chanda, have developed an integrated optical sensor capable of detecting dopamine directly from an unprocessed blood sample. This sensor may serve as a low-cost and efficient screening tool for various neurological conditions and cancers, ultimately providing better outcomes for patients.

The study was funded by the U.S. National Science Foundation and was published this week in Science Advances .

“This plasmonic biosensor is extremely sensitive to low concentrations of biomolecules, which make them promising platform for specialized assays, point of care applications in remote locations,” says Chanda, the study’s principal investigator who also has appointments in UCF’s Department of Physics and CREOL, the College of Optics and Photonics. “In this work, we demonstrated an all-optical, surface-functionalized plasmonic biosensing platform for the detection of low concentrations of neurotransmitter dopamine directly from diverse biological samples which includes protein solutions, artificial cerebrospinal fluid, and unprocessed whole blood.”

Neurotransmitters play a vital role in regulating neural function and overall well-being in humans and animals, necessitating a harmonious balance of neurological hormones for optimal bodily function, Chanda says. Dopamine serves as a crucial transmitter, as it exerts significant influence over cognitive processes such as motor function or emotions like happiness or pleasure.

Disruptions in dopamine levels are closely linked with various neurodegenerative disorders such as Parkinson’s disease and Alzheimer’s disease, neurodevelopmental conditions like attention deficit hyperactivity disorder and Tourette’s Syndrome, and psychological disorders such as bipolar disorder and schizophrenia, Chanda says.

Deviations from normal dopamine levels can also serve as an important diagnostic marker for certain types of cancers. The precise and dependable measurement of dopamine concentrations is of utmost importance for advancing pharmaceutical research and medical therapies, Chanda says.

How It Works

The plasmonic sensor is made of a tiny gold pattern that causes electrons to move together in waves. These waves, called plasmons, become stronger with a special optical setup. When a new molecule enters the sensor’s environment, it changes how the electrons move, which affects how light is reflected from the sensor. This change in reflection helps detect the presence of the molecule.

Unlike traditional biosensors that rely on biological elements like antibodies or enzymes, this UCF-developed device uses a specially designed aptamer—a synthetic DNA strand—to precisely detect dopamine. This approach not only makes the sensor more cost-effective and easier to store, but it also allows the device to detect dopamine directly from unprocessed blood without any preparation. This breakthrough could be particularly valuable in areas with limited medical resources, as it simplifies the detection process and opens the door for diagnosing other conditions using the same technology.

Researchers were able to target specific molecules by coating the sensor’s active area with an aptamer specifically created to latch onto a particular biomarker with great accuracy.

The study’s results highlight the potential of plasmonic “aptasensors” using aptamers to sense for developing rapid and accurate diagnostic tools for disease monitoring, medical diagnostics, and targeted therapies, the researchers say.

“There have been numerous demonstrations of plasmonic biosensors but all of them fall short in detecting the relevant biomarker directly from unprocessed biological fluids, such as blood,” says Aritra Biswas ‘12MS 24PhD , the lead author of the paper.

The new research builds upon the team’s previous work developing a dopamine detector by replacing cerium oxide nanoparticles with DNA-based aptamers, enhancing the sensor’s selectivity and expanding its applicability to detect dopamine directly in diverse biological samples without needing prior sample preparation.

“This concept can be further explored in the detection of different biomolecules directly from unprocessed blood, such as proteins, viruses, DNA,” says Chanda. “There may be great interest in developing countries where access to analytical laboratories is limited.”

The research was performed by students in Chanda’s lab at UCF and are co-authors of the study: Sang Lee ‘22MS , postdoctoral fellows Pablo Cencillo-Abad and Manobina Karmakar, biomedical sciences undergraduate students Jay Patel and Francisco Hernandez Guitierrez and physics doctoral student Mahdi Soudi.

Researcher’s Credentials:

Chanda has joint appointments in UCF’s NanoScience Technology Center, Department of Physics and CREOL, The College of Optics and Photonics. He received his doctorate in photonics from the University of Toronto and worked as a postdoctoral fellow at the University of Illinois at Urbana-Champaign. He joined UCF in fall 2012.

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Pegasus magazine.

For a decade, UCF-based nonprofit Limbitless Solutions has transformed kids’ lives through bionic limbs.