Elsevier

The Lancet

Volume 401, Issue 10371, 14–20 January 2023, Pages 141-153
The Lancet

Review
Novel and emerging treatments for major depression

https://doi.org/10.1016/S0140-6736(22)02080-3Get rights and content

Summary

Depression is common, costly, debilitating, and associated with increased risk of suicide. It is one of the leading global public health problems. Although existing available pharmacological treatments can be effective, their onset of action can take up to 6 weeks, side-effects are common, and recovery can require treatment with multiple different agents. Although psychosocial interventions might also be recommended, more effective treatments than those currently available are needed for people with moderate or severe depression. In the past 10 years, treatment trials have developed and tested many new targeted interventions. In this Review, we assess novel and emerging biological treatments for major depressive disorder, evaluate their putative brain and body mechanisms, and highlight how close each might be to clinical use.

Introduction

Depression is a major global mental health challenge and the leading cause of mental-health-related disability worldwide.1 It is common and frequently recurrent, with a global prevalence of 4·4%.2 For many people with depression, onset is in mid to late adolescence (eg, age 14 to 25 years); median 12-month prevalence in this age group is 4–5%.3 Major depressive disorder (MDD) negatively affects education, relationships, and employment and is prospectively associated with obesity, cardiac disease, and early death, including suicide.4, 5, 6 The financial costs are substantial and closely linked to working days lost, reduced productivity, and absenteeism. The functional effects of depression can be particularly severe in adults older than 18 years, in whom comorbidity with physical health problems has further effects and leads to complexity in treatment options.

Current biomedical models of depression conceptualise it as a disorder of neural networks incorporating changes in widely distributed brain areas,7 with effective antidepressants improving synaptic plasticity8 and acting as modulators of monoamines (eg, serotonin, noradrenaline, and dopamine). Although guidelines, such as those from the National Insitute for Health and Care Excellence in the UK,9 recommend a comprehensive biopsychosocial approach to treating depression and evidence suggests psychological interventions, social support, and exercise are important, treatment with medication is often essential in moderate or severe depression. Although antidepressants are effective, a third to half of people with MDD do not respond to multiple antidepressants,10, 11 and more might only obtain a partial response. People with depression who do not respond to two trials of antidepressants are often categorised as having treatment-resistant depression (TRD). Typically, individuals have to wait at least 4 weeks before a potential response to current antidepressants occurs and side-effects, such as sexual dysfunction, loss of libido, headache, gastrointestinal symptoms, anxiety, and agitation, are common.

Therefore, there is a need to develop, test, and understand the effectiveness of new agents or treatment modalities, ideally with a more rapid onset of action, better tolerability, and with the potential for greater effectiveness than existing antidepressants in people for whom current antidepressants have failed. In this Review, we aim to provide an evaluation of novel biological treatments using a systematic approach to highlight the best evidence currently available, with a particular emphasis on mechanism of effect, and provide an outline through which new treatments might be clinically useful. Although not a formal systematic review, we outline search terms and strategy.

Section snippets

N-methyl-D-aspartate modulators

Glutamate functioning is known to be disturbed in areas of the brain that are associated with depression.12 It is the most common brain excitatory neurotransmitter, and levels of glutamate are increased by chronic stress. This glutamatergic upsurge can decrease synapse connectivity and result in deficits in γ-aminobutyric acid (GABA) functioning, the most abundant inhibitory brain neurotransmitter. Both glutamate and GABA, or the balance between them in different areas of the brain, are thought

Repetitive transcranial magnetic stimulation

Transcranial magnetic stimulation (TMS) is a form of non-invasive brain stimulation that does not require an anaesthetic; the TMS machine generates a magnetic field that stimulates particular brain areas. This process can lead to changes in neuronal excitability, triggering effects between cortical and subcortical structures. Areas that are particularly relevant to TMS treatment are the left dorsolateral prefrontal cortex, which is known to be underactive in depression and linked to treatment

γ-amino butyric acid modulators

Cognitive distortions, including in episodic memory, impaired learning, impaired attention, negative bias, and poor problem solving, are all common features of depression. Evidence has highlighted the potential of GABA inhibition in these cognitive distortions.59 In a magnetic resonance spectroscopy imaging study, reduced GABA was apparent in MDD patients with anhedonia.60

Brexanolone, a progesterone metabolite, is a positive modulator of the GABA receptor that exerts effects at both synaptic

Anti-inflammatory agents

The proposal that immune dysfunction, or more specifically, non-resolving low-level inflammation, could be relevant in depression and a target for treatment was first proposed in the early 1900s, with vaccine therapy and the potential for typus to improve symptoms in patients in German asylums.64 Associative evidence is strong, with increased levels of inflammatory cytokines, including interleukin 6 (IL-6), tumour necrosis factor α (TNFα), and C-reactive protein (CRP), consistently reported to

Psychedelics

Clinical and research interest in psychedelics was sparked by lysergide, which was used widely in clinical practice throughout the 1950s and early 1960s.71 Despite intense interest in the clinical effects of psychedelics (eg, lysergide, psilocybin, dimethyltryptamine, and mescaline), in 1967 they were classified under Schedule 1 of the UN convention on drugs, meaning they were deemed to have no accepted medical use and substantial potential for harm and dependence.72 The important component of

Other agents

Photobiomodulation is a novel device treatment based on non-retinal exposure to light. It is based on the idea that near infrared radiation and red light can be absorbed through the scalp skin and by mitochondrion chromophores that are known to be biologically active. A review suggested some positive results in improving depressive symptoms both in animal models and in humans, but nearly all studies lacked a control group.83

Pimavanserin has been licenced in the USA for the treatment of

Precision medicine in the treatment of major depression

Replicability in large controlled trials is required for clinical use of any new treatment. However, substantial heterogeneity exists in current evidence. One issue that could have an effect on clinical utility is the heterogeneity of MDD itself. Because of the breadth of the diagnostic criteria, two individuals could have a diagnosis of MDD but share no common symptoms. Thus, strategies to develop improved treatments for MDD include stratification of subgroups and prediction of pharmacological

Challenges

Fundamental challenges remain to be addressed to ensure effective treatments become widely used in clinical practice. First, the durability of effect of several interventions requires further investigation, including improved characterisation of factors that predict it or that might prevent it. The effect, for example, of intravenous ketamine appears to be rapid, and thus potentially lifesaving. However, whether the model for ketamine in various forms of administration is continuous treatment

Conclusion

The scientific and clinical community has made major progress in using and advancing mechanistic knowledge, developing new agents and testing them to improve the biological treatment of MDD (table 2). Important developments are that many agents have a rapid onset of action that will be clinically invaluable in various situations, and they might have improved tolerability. Many novel and emerging agents might be able to target people with depression that is difficult to treat, but there is a

Search strategy and selection criteria

We searched the Cochrane Central Register of Controlled Trials, PubMed, Embase, and PsycINFO for literature published between Jan 1, 2015, and Nov 17, 2021, that focused on depression and novel treatments. We also searched for unpublished and ongoing studies in ClinicalTrials.gov. All included papers had to have at least an abstract published in English. The search terms used were “depress*” OR “dysthymi*” OR “mood disorder” OR “affective disorder”. These terms were then combined with multiple

Declaration of interests

SM attended an educational event sponsored by Janssen in 2019. He is an unpaid council member of the British Association of Psychopharmacology. He has grants funded by the National Institute for Health and Care Research, UK Research and Innovation, the Medical Research Council, and the Wellcome Trust. RU receives speaker fees from Sunovion, Springer Heathcare, and Vitaris. She receives grant funding from the Medical Research Council (MR/S037675/1), the National Institute for Health and Care

References (92)

  • CP Taylor et al.

    Pharmacology of dextromethorphan: relevance to dextromethorphan/quinidine (nuedexta) clinical use

    Pharmacol Ther

    (2016)
  • C O'gorman et al.

    601 AXS-05 (dextromethorphan/bupropion), a novel, oral, investigational agent for major depressive disorder: results of a randomized, double-blind, active-controlled, multi-center trial (ASCEND)

    Eur Neuropsychopharmacol

    (2019)
  • LB Razza et al.

    A systematic review and meta-analysis on placebo response to repetitive transcranial magnetic stimulation for depression trials

    Prog Neuropsychopharmacol Biol Psychiatry

    (2018)
  • L Chen et al.

    Efficacy, efficiency and safety of high-frequency repetitive transcranial magnetic stimulation applied more than once a day in depression: a systematic review

    J Affect Disord

    (2020)
  • AI Sonmez et al.

    Accelerated TMS for depression: a systematic review and meta-analysis

    Psychiatry Res

    (2019)
  • H-T Chu et al.

    Efficacy and tolerability of theta-burst stimulation for major depression: a systematic review and meta-analysis

    Prog Neuropsychopharmacol Biol Psychiatry

    (2021)
  • S Senova et al.

    Durability of antidepressant response to repetitive transcranial magnetic stimulation: systematic review and meta-analysis

    Brain Stimul

    (2019)
  • A Miljevic et al.

    Potential predictors of depressive relapse following repetitive transcranial magnetic stimulation: a systematic review

    J Affect Disord

    (2019)
  • D Cappon et al.

    Transcranial magnetic stimulation (TMS) for geriatric depression

    Ageing Res Rev

    (2022)
  • A Ganho-Ávila et al.

    Efficacy of rTMS in decreasing postnatal depression symptoms: a systematic review

    Psychiatry Res

    (2019)
  • D Hett et al.

    Repetitive transcranial magnetic stimulation (rTMS) for the treatment of depression in adolescence: a systematic review

    J Affect Disord

    (2021)
  • S De Smet et al.

    Determinants of sham response in tDCS depression trials: a systematic review and meta-analysis

    Prog Neuropsychopharmacol Biol Psychiatry

    (2021)
  • AH Moffa et al.

    Efficacy and acceptability of transcranial direct current stimulation (tDCS) for major depressive disorder: an individual patient data meta-analysis

    Prog Neuropsychopharmacol Biol Psychiatry

    (2020)
  • YA Berlow et al.

    Transcranial direct current stimulation for depression and risk of treatment emergent mania: an updated meta-analysis

    Brain Stimul

    (2019)
  • C Zhou et al.

    A systematic review and meta-analysis of deep brain stimulation in treatment-resistant depression

    Prog Neuropsychopharmacol Biol Psychiatry

    (2018)
  • DD Dougherty et al.

    A randomized sham-controlled trial of deep brain stimulation of the ventral capsule/ventral striatum for chronic treatment-resistant depression

    Biol Psychiatry

    (2015)
  • A Shaw et al.

    Marked reductions in visual evoked responses but not γ-aminobutyric acid concentrations or γ-band measures in remitted depression

    Biol Psychiatry

    (2013)
  • S Kanes et al.

    Brexanolone (SAGE-547 injection) in post-partum depression: a randomised controlled trial

    Lancet

    (2017)
  • S Meltzer-Brody et al.

    Brexanolone injection in post-partum depression: two multicentre, double-blind, randomised, placebo-controlled, phase 3 trials

    Lancet

    (2018)
  • PNS Kumar et al.

    A pilot, open-label investigation of the efficacy of glucosamine for the treatment of major depression

    Asian J Psychiatr

    (2020)
  • MI Husain et al.

    Minocycline and celecoxib as adjunctive treatments for bipolar depression: a multicentre, factorial design randomised controlled trial

    Lancet Psychiatry

    (2020)
  • B Deakin et al.

    The benefit of minocycline on negative symptoms of schizophrenia in patients with recent-onset psychosis (BeneMin): a randomised, double-blind, placebo-controlled trial

    Lancet Psychiatry

    (2018)
  • MA Nettis

    Minocycline in major depressive disorder: and overview with considerations on treatment-resistance and comparisons with other psychiatric disorders

    Brain Behav Immun Health

    (2021)
  • N-X Li et al.

    Dose effect of psilocybin on primary and secondary depression: a preliminary systematic review and meta-analysis

    J Affect Disord

    (2022)
  • MA Caldieraro et al.

    Transcranial and systemic photobiomodulation for major depressive disorder: a systematic review of efficacy, tolerability and biological mechanisms

    J Affect Disord

    (2019)
  • MS Yatham et al.

    Do statins have an effect on depressive symptoms? A systematic review and meta-analysis

    J Affect Disord

    (2019)
  • Depression and other common mental disorders: global health estimates

    (2017)
  • M Pinquart et al.

    Depression and cancer mortality: a meta-analysis

    Psychol Med

    (2010)
  • G Hasler et al.

    Depressive symptoms during childhood and adult obesity: the Zurich Cohort Study

    Mol Psychiatry

    (2005)
  • A Nicholson et al.

    Depression as an aetiologic and prognostic factor in coronary heart disease: a meta-analysis of 6362 events among 146 538 participants in 54 observational studies

    Eur Heart J

    (2006)
  • JL Price et al.

    Neurocircuitry of mood disorders

    Neuropsychopharmacology

    (2010)
  • RS Duman et al.

    Synaptic plasticity and depression: new insights from stress and rapid-acting antidepressants

    Nat Med

    (2016)
  • Depression in adults: treatment and management

  • AJ Rush et al.

    STAR*D: revising conventional wisdom

    CNS Drugs

    (2009)
  • AA Conley et al.

    Efficacy of ketamine for major depressive episodes at 2, 4, and 6-weeks post-treatment: a meta-analysis

    Psychopharmacology (Berl)

    (2021)
  • TdM Lima et al.

    Use of ketamine and esketamine for depression: an overview of systematic reviews with meta-analyses

    Eur J Clin Pharmacol

    (2022)
  • Cited by (101)

    View all citing articles on Scopus
    View full text