Intended for healthcare professionals

Clinical Review State of the Art Review

New and emerging treatments for major depressive disorder

BMJ 2024; 386 doi: (Published 08 July 2024) Cite this as: BMJ 2024;386:e073823
  1. Cecilia Njenga, physician associate1,
  2. Parashar Pravin Ramanuj, consultant liaison psychiatrist1,
  3. Frederico Jose Coelho de Magalhães, consultant psychiatrist2,
  4. Harold Alan Pincus, professor, vice chair, co-director, senior scientist3 4 5
  1. 1Royal National Orthopaedic Hospital, London, UK
  2. 2Centre for Psychedelic Research, Department of Brain Sciences, Imperial College London, London, UK
  3. 3Department of Psychiatry, Columbia University, New York State Psychiatric Institute, New York, NY, USA
  4. 4Irving Institute for Clinical and Translational Research, Columbia University, New York, NY, USA
  5. 5RAND Corporation, Pittsburgh, PA, USA
  1. Correspondence to: P P Ramanuji p.ramanuj{at}, p.ramanuj{at}


Major depressive disorder (MDD) affects a substantial portion of the population; however, much is still unknown about the pathophysiology of this disorder. Treatment resistance highlights the heterogeneous nature of MDD and the need for treatments to target more than monoamine neurotransmission. This review summarizes research into the new and emerging targets of MDD. These include drugs such as psychedelics, antibiotics, opioid modulators, neuropeptides, and onabotulinumtoxin. Neuromodulatory treatments such as light based therapies and neuromodulation involving either magnetic or electrical stimulation are also discussed. Almost all interventions, pharmacological and neuromodulation, were trialed as adjunctive treatments to an antidepressant. Most research has been conducted on psychedelics, with trials suggesting rapid antidepressant and anti-suicidal effects. Trial findings, tolerability, study design limitations and quality of research have been considered throughout this review. There remains challenges in forming recommendations with the current research at present. With there being considerable interest into the research of new and emerging treatments—in particular, psychedelics—there may be scope in the future to form more robust recommendations.


Major depressive disorder (MDD) has a substantial personal and socioeconomic impact worldwide. It is a leading cause of disability, affecting 322 million people worldwide and contributes 7.5% of all years lived with disability globally.12 Depression cost the UK about £27.1 billion in 2019, with most costs being attributed to lost productivity.3 Lifetime prevalence of MDD ranges from 2% to 21% across different countries, with the highest prevalence being in European countries.4 Effective management of MDD is therefore essential to improve the quality of life of people living with the condition. The cause of MDD remains unclear, and MDD is likely not a singular phenotype but a broad and heterogeneous constellation of conditions spanning physiologic reactions and pathologic states.5 Consequently biologic, psychologic, and psychosocial factors all play an important and intertwined role.6

Agents that act on monoamine neurotransmission are the mainstay of drug treatment for MDD. The Sequenced Treatment to Relieve Depression (STAR*D) trial conducted almost 20 years ago established response rates of 40-60% after a six to eight week trial of antidepressants that act on monoamines.7 Up to 30% of people with a diagnosis of MDD are resistant to traditional drug treatments and considered treatment resistant.8 No set definition for treatment-resistant depression exists, although it is largely viewed as a lack of response to two antidepressants at an adequate dose and duration.9 One explanation for treatment resistance is that MDD has multiple causes, which has led to the search for novel intervention targets.

This narrative review will focus on novel and emerging treatments for MDD (at any stage of the treatment cycle, from initial episode through to failure to respond to treatment) and their effectiveness, safety, and applicability in real world settings. We did not limit the search strategy to particular types of therapy (for example, biologic or psychologic), but we did not consider established treatments or combinations of treatments repurposed for the treatment of MDD as being either novel or emerging. Hence, treatments including established psychologic therapies (such as eye movement desensitization and reprocessing therapy or therapies rooted in cognitive behavioral therapy paradigms), exercise based activities, nutrition, and forms of social care input are not included in this review. We included only interventional data and not theoretical or observational evidence to improve applicability to actual clinical practice.

Sources and selection criteria

We searched PsycINFO, Medline, EMBASE and Web of Science using the following search terms: “depression*” AND “novel treatment*” OR “emerging treatment*” OR “innovative treatment*” OR “psychedelics” OR “neuromodulation.” Box 1 lists the inclusion and exclusion criteria. Two searches were undertaken; both searches covered a period between January 2017 and June 2023 (fig 1).

Box 1

Inclusion and exclusion criteria of data search

Inclusion criteria

  • Adults (≥18 years old)

  • Written in English

  • Published in the past five years

  • Reviewing novel interventions

  • Focusing on major depressive disorder (MDD)

  • Randomised controlled trial, systematic review, or meta-analysis

Exclusion criteria

  • Not written in English

  • Article not accessible

  • Duplicate article

  • Reviewing interventions that are well established or widely used in clinical practice

Fig 1
Fig 1

Flow diagram of article selection

With regards to pharmacotherapy, papers focused on psychedelics (n=20), anti-inflammatory agents (n=4), onabotulinumtoxin A (n=2), neuropeptide Y (n=1), and buprenorphine-samidorphan combination (n=1). With regards to neuromodulation, the papers covered newer forms of transcranial magnetic stimulation (n=8), transcranial direct current stimulation (n=2), light therapies (n=3), magnetic seizure therapy (n=1) and deep brain stimulation (n=1). Two articles involving the use of psychological interventions alongside novel and emerging interventions were identified in the search: cognitive behavioral therapy with transcranial direct current stimulation (n=1) and cognitive behavioral therapy alongside esketamine (n=1).

Novel treatments

From our search, psychedelics and newer forms of repetitive transcranial magnetic stimulation emerged as the principal novel treatments being trialed for MDD. We considered these interventions to be novel in this review because of the increased academic interest and increased consideration for larger scale clinical use, though their theoretical and practical application to MDD may have been first described many years ago. Tables 1 and 2 summarize the design, sample size, treatment duration, and primary outcomes of the studies of novel treatments.

Table 1

Novel and emerging pharmacological treatments for major depressive disorder

View this table:
Table 2

Novel and emerging neuromodulatory treatments for major depressive disorder

View this table:

Esketamine and ketamine

Ketamine is an N-methyl-D-aspartate (NMDA) receptor antagonist and widely used dissociative anesthetic that is being increasingly repurposed for use in psychiatry. It is hypothesized that, at sub-anesthetic doses, ketamine causes an antidepressant effect through glutamatergic modulation.52 Ketamine has been proposed to facilitate the neuroplasticity involved in new memory formation, fear extinction, and the restructuring of traumatic memories.53 It is suggested that the psychoactive properties of sub-anesthetic ketamine doses may facilitate psychotherapeutic processes.54 Several trials have assessed ketamine administered orally, intramuscularly, and intravenously, as well as a proprietary intranasal esketamine (Spravato).


A single dose of intravenous (IV) ketamine appears to reduce suicidal ideation in people with MDD and suicidality1055 with effects on suicidality lasting up to five days after dose administration. Trials comparing IV ketamine with midazolam (as an active placebo) have found significant effects on depression outcomes ranging from less than three days21 to up to 14 days.10 Similarly, a Cochrane review of glutamate receptor modulators in the treatment of depression found ketamine to be more effective than placebo, and midazolam specifically, at 24 hours.11

Reports of patients developing meaningful insights during dosing sessions, and evidence of possible acute neuroplastic effects, have inspired interest in the possibility of combining ketamine with a psychotherapeutic approach. One trial studied the effectiveness of offering cognitive behavioral therapy (CBT) to participants with treatment-resistant depression who had responded positively to intravenous ketamine infusions,12 but found no significant difference depression scores at 14 weeks after infusion compared with treatment as usual.

Two recent meta-analyses included studies compared IV ketamine with electroconvulsive therapy (ECT) for treatment of depression, and both suggested that that ECT may be superior to ketamine in improving depression severity.2122 A subsequent large randomised controlled trial (RCT) compared thrice weekly ECT with twice weekly ketamine infusion (0.5 mg/kg) over three weeks and found that ketamine was not inferior to ECT in terms of response to treatment at three days after the last treatment session, with fewer patient reports of cognitive symptoms in the ketamine group than in the ECT group.38

Intranasal esketamine (the S enantiomer of ketamine) produces a significant and rapid effect within two hours of administration131415 with a dose-response relationship.16 The most common treatment paradigm in trials is of two applications per week over four weeks. Conclusions vary on the long term effectiveness of esketamine, with some trials reporting no significant effect compared with placebo at day 28,141718 while others have found that the antidepressant effect can last from four to eight weeks after withdrawal of esketamine.13141516 One trial found that optimising esketamine doses over 16 weeks until remission or response was achieved and then maintaining this dose prolonged the time taken for patients to relapse.19

Side effects and tolerability

In esketamine and ketamine studies common side effects reported include headache (11-27%), nausea (10-16%), vertigo (25%), vomiting (5-18%), dysgeusia (11-27%), somnolence (13-21%), and dissociative symptoms (23-59%).131619202122 Some articles reported increases in blood pressure with esketamine treatment, but this increase was not found to be persistent.17 Intravenous ketamine may be more tolerable than ECT: one review noted that more side effects are reported with ECT, whereas another reported no significant difference between the interventions.2122

Clinical application of esketamine and ketamine

Ketamine and its enantiomers seem to show some promise in the treatment of MDD. Intravenous ketamine, most often delivered as one or two 40-minute infusions per week over several weeks, is already in use many healthcare systems, including the NHS, as an off-license alternative to ECT for treatment of severe or difficult to treat depression. Oral ketamine and intranasal esketamine are easier to administer, but the evidence for an effect beyond the course of treatment is still unclear, and there are concerns about habituation and dependence.5657

Esketamine is licensed in the UK for treatment of MDD, but is not approved by the National Institute for Health and Care Excellence (NICE) as it does not meet NICE criteria for cost-effectiveness.58 The US Food and Drug Administration (FDA) approved intranasal esketamine for use as an adjunct to an oral antidepressant in the treatment of MDD in 2019 and suicidal ideation in 2020.15

Ketamine-assisted psychotherapy, increasingly offered by select providers in the UK and US as a putative treatment for depression, will often include psychologically-oriented preparation and follow-up “integration” sessions as well as psychological support during doses. However, there is little evidence at present for this approach.1254


Psilocybin is a commonly occurring hallucinogenic compound found in certain fungi species. Following intense academic and clinical inquiry in the 1950s and 1960s, further research with psychedelics such as psilocybin was severely restricted by drug scheduling laws.59 Renewed interest has occurred since the mid-2000s, with growing evidence for their use in psychedelic-assisted therapy for MDD.


Clinical trials with psilocybin have implemented a model of drug-facilitated psychotherapy, in which the drug is administered to support a process of psychological change within a therapeutic relationship and setting (fig 2). The type of psychological intervention provided in trials is often not clearly stated in trial designs. The emphasis, in most cases, is on preparing and supporting the participant through the experience rather than applying any specific therapeutic framework. Psilocybin is administered orally and given either as a single dose or in two doses at least one week apart.232425 Doses trialed range from 10 mg up to 30 mg per 70 kg body weight, with 25 mg being the most used.

Fig 2
Fig 2

Photo of a clinical room adapted into a more comfortable environment for psilocybin treatment. (Reproduced from Gandy et al 202060)

In one RCT, participants were given doses of 20 mg/70 kg body weight and 30 mg/70 kg one to two weeks apart, in the context of supportive psychotherapy. Participants were randomized to receive the doses either immediately or after an eight week delay. The immediate treatment group showed rapid decrease in depression scores, with a large effect size that maintained statistical significance during the four week follow-up. Of note, 54% of participants in the immediate treatment group met the criteria for remission of depression at week 4.24

However, the first RCT to compare psilocybin (plus psychological support) with an alternative first-line treatment randomized participants to receive either two 25 mg doses of psilocybin, three weeks apart, with six weeks of daily placebo or two doses of 1 mg psilocybin with six weeks of daily oral escitalopram. The trial did not show a significant difference in antidepressant effects between psilocybin and escitalopram at week 6. Although secondary outcomes generally favored psilocybin over escitalopram, these outcomes lacked correction for multiple comparisons.26

In a subsequent phase 2 trial with 233 participants with treatment-resistant depression, a significant antidepressant effect was noted at the primary endpoint three weeks after a single dose of 25 mg of psilocybin with psychological support, but not for 10 mg, when compared with 1 mg of psilocybin.25 However, the response was not sustained at 12 weeks.

Side effects and tolerability

The most reported adverse event is headache of mild to moderate severity.2425 Challenging intense emotions such as fear, anxiety, and sadness—a common side effect of psychedelic therapy, especially in the acute phase—are widely hypothesized to be an important part of the therapeutic experience, often as part of an “emotional breakthrough.”61 However, there are concerns over increased suicidality. One RCT comparing 25 mg, 10 mg, and 1 mg psilocybin (the last being a control group) found the number of participants showing increased suicidal ideation was 14%, 17%, and 9% respectively.25 No statistical analysis was conducted on the incidence of suicidal ideation, but the authors recommended “clinical vigilance” in future trials of psilocybin due to the dose-response relationship.

Clinical application of psilocybin

Recent trials show some promise for psilocybin with psychological support in the treatment of depression, building on evidence from previous trials, although follow-up periods have been limited.6263 Considering that participants in most trials have two therapists supporting with preparation, follow-up, and dosing sessions, which can last up to 10 hours each, the amount of therapist time would be higher than most current healthcare interventions. Scalability, with the necessary amount of care, may prove an important barrier to widespread use. Emerging evidence of an increase in suicidality may limit treatment to carefully selected and well supported patient groups. Of note, before full regulatory approval, psilocybin has been afforded special status in some healthcare settings such as Switzerland and Australia, where health authorities have approved its prescription for treatment-resistant depression by specifically authorised psychiatrists. Within the US, psilocybin-facilitated psychotherapy for depression has been given “breakthrough therapy” designation from the FDA.59

Ayahuasca and dimethyltryptamine

Ayahuasca is a traditional plant medicine, a psychoactive brew that has been used for centuries by indigenous cultures in the Amazon rainforest.64 It is made from the Banisteriopsis caapi vine, which contains β-carboline harmala alkaloids, and leaves of the Psychotria viridis bush, which contain the hallucinogen dimethyltryptamine (DMT).64 The harmala alkaloids are monoamine oxidase inhibitors that prevent monoamine oxidase from inactivating DMT.64 DMT is a serotonin and sigma-1 receptor agonist. The function of sigma-1 receptor is not well understood, but it is hypothesized that the receptors may be involved in the pathophysiology of MDD by acting on dopamine neurotransmission.64 Observational evidence suggests that ayahuasca may reduce symptoms of depression,65 but few RCTs have been conducted to date.


Building on a prior open label study, which showed rapid antidepressant effects for ayahuasca in treatment-resistant depression,65 in one RCT with participants with MDD ayahuasca was found to have a significant antidepressant effect compared with placebo, with effect sizes increasing between day 1 and the final follow-up at day 7.27

Side effects and tolerability

Ayahuasca is associated with a high incidence of gastrointestinal side effects, and in traditional settings vomiting after a dose is often framed as “purging” and considered to be of therapeutic value.66 One RCT reported that most participants experienced nausea and 57% vomited.27 Despite this, only one participant in the ayahuasca group withdrew from this RCT.27 The other two studies did not report the frequency of adverse effects experienced, but both studies reported that the placebo used was chosen to induce gastrointestinal side effects like that with ayahuasca.2829

Clinical application of ayahuasca and DMT

The RCT protocols reviewed involve ayahuasca being ingested once during a study visit in which participants remained on their own in a quiet environment with their eyes closed and the option of a pre-defined music playlist.272829 Contrary to psilocybin studies, there is no emphasis on close psychological support in the room, but support was available from assistants when needed. While initial results appear promising, with some interesting neurobiological correlates, there is insufficient high quality evidence to recommend the use of ayahuasca for depression. There are no RCT data for the persistence of antidepressant effects beyond one week, and there is a need for further research and high quality evidence to establish the safety, efficacy, and long term effects of ayahuasca as a treatment for depression. The issue of frequent gastrointestinal side effects, which would be viewed as undesirable in most medical contexts, is an interesting example of the ongoing discussion about the proper translation of traditional ceremonial medicine to international contexts.67 At present, dosing schedules and persistence of effect are not known. In conclusion, current data does not support wider use of ayahuasca.


Transcranial magnetic stimulation (TMS) has been described since 1874, so it is questionable whether it could be considered a novel or emerging treatment.68 We included it in our review because interest in its applicability has grown in recent years from being considered a fringe treatment to one with wider potential.68 TMS is a form of neuromodulation that involves the targeted use of magnetic fields to primarily stimulate the dorsolateral prefrontal cortex (DLPFC).39 Traditionally, the DLPFC is important for executive functioning, particularly task shifting, regulation of attention, planning, and working memory.69 Latterly, its role in the processing of emotions, particularly in integrating emotion and cognition, has been explored.70 The DLPFC is thought to attribute valence to emotions (that is, the pleasantness or unpleasantness of an emotion). Reduced activity within this region has been noted in patients with depression.3940414243447172

A repetitive form of TMS (repetitive TMS or rTMS), has gained clinical interest since its original development in the 1980s. The standard protocol for rTMS involves magnetic stimulation at 10 Hz being applied 75 times during a session lasting 37.5 minutes, and sessions are undertaken daily for five days over a four to six week period.73 The repeated stimulation is thought to produce a longer term change in neuronal activity and synaptic spasticity.68

Repetitive TMS is recommended by NICE in England for the management of severe MDD.74 Newer forms of TMS identified by our search strategy included accelerated TMS, theta burst stimulation, Stanford neuromodulation therapy, and low field magnetic stimulation. The dorsolateral prefrontal cortex remains the primary target for all these forms of neuromodulation, and many of the trials identified in our search investigate different protocols for TMS administration. Optimal standardized protocols for TMS have not yet been established for targeted use in particular patient populations or along the treatment pathway for people with MDD.


Accelerated TMS (aTMS) is a form of rTMS in which treatment sessions are delivered multiple times a day, thus shortening the treatment period from a few months to a few weeks.3943 Total aTMS sessions delivered in RCTs and open label trials ranged between four to 20 sessions. A review of three RCTs found aTMS to be more effective in reducing MDD symptom severity than sham therapy; with a reported cumulative effect size of 0.39 (95% CI 0.005 to 0.779).43 Of note, only one RCT compared aTMS with rTMS; in which aTMS was not significantly more effective than rTMS after four weeks.39

Theta burst stimulation (TBS) involves stimulation being applied at a higher frequency than rTMS for up to 3 minutes per treatment session, which is significantly shorter than the duration of rTMS (fig 3).4471 Stimulation at 50 Hz is applied in three bursts followed by stimulation at 5 Hz. This pattern is thought to impact more on gamma-aminobutyric acid (GABA) receptor activity, which is implicated in treatment-resistant depression, although the exact mechanism by which GABA dysfunction may underlie this condition is not well understood.7176 TBS has been trialed as a monotherapy and as an adjunct to traditional antidepressant therapy. Two forms have been studied: continuous TBS (cTBS) involves uninterrupted stimulation while intermittent TBS (iTBS) involves stimulation being applied every few seconds.4271 Both unilateral and bilateral coil placements have been considered for TBS,42 but most commonly TBS is applied unilaterally to the left DLPFC.

Fig 3
Fig 3

Protocols of newer forms of transcranial magnetic stimulation (TMS)75

A review of five studies trialing different forms of TBS undertaken in 10 to 30 sessions, found TBS to be more effective than sham therapy,42 although studies found that the difference achieves clinical significance only after two weeks compared.45 A separate study noted unilateral TBS to be as effective as high frequency rTMS over 4-6 weeks.44 Over longer periods of follow-up (3 months) there was a greater response and remission rate with iTBS compared with rTMS.45

Stanford neuromodulation therapy (SNT) is an accelerated form of iTBS involving multiple iTBS sessions within a day, and trialed as an adjunctive treatment.41 Mean reduction in depression score among participants who underwent SNT was greatest at week 1 and remained clinically significant at week 4.41

A systematic review which compared forms of TMS against the established treatment ECT highlighted that ECT’s adverse effects limit its application.46 The authors stated that bilateral TBS has the potential to be the most efficacious of the 16 neuromodulation procedures assessed for treatment-resistant depression; however, as the comparison was through a network meta-analysis, further direct comparisons are needed.46

Low field magnetic stimulation (LFMS) is a form of TMS that uses lower magnetic field strength which does not generate action potentials and is administered over a shorter treatment duration. Stimulation is delivered every 2 seconds over a 20 minute treatment session.4072 An RCT found that LFMS was no more effective in reducing symptoms of MDD than sham therapy within 48 hours and 4 weeks.40

Side effects and tolerability

Very few serious adverse effects have been reported for any forms of neuromodulation. Headache is most reported, occurring in 64% of participants who underwent rTMS in one study. In the same study, headache was reported by 65% of participants who underwent iTBS, but rates of dropout were 1.6 times higher in the rTMS arm.44 Headache is also the commonest adverse effect reported by people undergoing SNT (57%) and in those having aTMS, although at roughly half the incidence as other forms of TMS.41 However, people undergoing aTMS also reported local discomfort (29 out of 224 participants), nausea (4 out of 224 participants), and dizziness (4 out of 224 participants).43 The number of adverse effects reported by those who underwent LFMS, sham therapy, or a combination of both do not greatly differ.40 TBS and aTMS produce mainly mild adverse effects.424344

Clinical application of newer forms of TMS

rTMS and its newer protocols appear to be more effective than sham therapy with few adverse effects. However, we found very few studies that compared forms of TMS against other treatments, and effect sizes may be small to moderate. Although TBS or aTMS may not be more effective than rTMS, both can be administered in a significantly shorter timeframe than rTMS and are well tolerated, so they may have greater clinical utility. It is at yet difficult to know where along the treatment pathway TBS may be recommended, especially compared with more established treatments (including ECT); however, neuromodulation appears to have applicability as monotherapy as well as adjunct to antidepressants.

Administration of novel treatments

Protocols have laid out the way in which novel treatments are administered and considerations that need to be made in their application. We have summarized these considerations in table 3.

Table 3

Clinical application suggestions for novel treatments

View this table:

Emerging treatments


Anti-inflammatory agents

Neuropeptide Y is involved in the regulation of inflammation and noted to be reduced in people with MDD and other psychiatric disorders.3077 An RCT administered neuropeptide Y intranasally as an adjunct to an antidepressant. There was a significant antidepressant effect compared with placebo within 24 hours of administration, but this did not persist at 48 hours. The treatment was well tolerated with no adverse effects noted in the RCT. Strong conclusions cannot be made at present due to the limited research; its effect with repeated administration also needs to be studied further.

Minocycline is a tetracycline and is typically administered in capsule form.78 It has been trialed as a monotherapy and as an adjunct to an antidepressant.31 In two systematic reviews, minocycline significantly reduced depressive symptoms when compared with a placebo or treatment as usual. Minocycline is well tolerated,323334 and it is currently available for treatment of acne so there is a well established side effect profile. Early studies may signal its use as an adjunct over monotherapy but further research is needed.

Non-steroidal anti-inflammatory drugs (NSAIDs)—Celecoxib has been trialed as an adjunct to an antidepressant.31 Meta-analysis of four trials found there to be a significant reduction in depressive symptoms compared with an antidepressant alone. The safety profile of NSAIDs is well defined.

Statins—RCTs have compared the use of statins as an adjunct to an antidepressant with the antidepressant alone.31 The addition of a statin is more effective at reducing depressive symptoms than antidepressants alone. The safety profile of statins is well defined.

Omega-3 fatty acid has been trialed as a monotherapy or adjunctive to treatment as usual.31 A significant reduction in depressive symptoms has been found.


We found two RCTs trialing a combination of buprenorphine and samidorphan, a weak opioid antagonist. It is administered daily in the form of a sublingual tablet as an adjunct to an antidepressant.35 Higher doses of the buprenorphine-samidorphan drug caused a greater reduction in depressive symptoms compared with the placebo group in both trials. The combination of buprenorphine and samidorphan was well tolerated, with no reported incidences of opioid dependence or withdrawal during the trials.35 Buprenorphine-samidorphan as an adjunct to established treatments appears to show promise, but conclusions regarding its effect with long term use cannot be made from the current research.

Onabotulinumtoxin A

We identified two articles in which a single injection of onabotulinumtoxin A into the glabellar region was used as either a monotherapy or as an adjunctive treatment to antidepressants.3637 A significant antidepressant effect was found compared with placebo, whether as an adjunct or monotherapy. Strong conclusions cannot be made using current research. Onabotulinumtoxin A was trialed as a single dose intervention, and, although the trials were well designed, there is high heterogeneity across studies and it was difficult to maintain blinding due to the aesthetic effect of onabotulinumtoxin A.36 Further research is required on its proposed mechanism of action as there is a risk of medicalising people unhappy with their appearance.


Transcranial direct current stimulation

Transcranial direct current stimulation (tDCS) involves weak electrical signals being delivered to a patient’s scalp to target the dorsolateral prefrontal cortex.4647 Little is known about the effectiveness of tDCS in forms of depression other than vascular depression (a subtype of late-life depression characterized by executive dysfunction in association with cerebrovascular damage). In vascular depression tDCS appears to be more effective than sham therapy and shows a dose-response relationship in that people who received twice daily doses achieved greater and quicker responses than those who received once daily doses or sham. A systematic review found it to be non-inferior to sham therapy in more common forms of depression, but there was little other evidence.46 A combination of tDCS and cognitive behavioral therapy (CBT) does not have a significant antidepressant effect over either CBT alone or CBT with sham tDCS.48 Other conclusions cannot be drawn at this stage, especially regarding its use in lieu of established treatments.

Light therapies

The search identified bright light therapy and both transcranial and systemic forms of photobiomodulation.

Bright light therapy entails the use of a light box that patients sit in front of in the morning while it emits light at a controlled wavelength.4950 Bright light therapy has been trialed as a component of a novel intervention called triple chronotherapy and as an adjunct to repetitive TMS (rTMS).50 Triple chronotherapy produced a rapid antidepressant effect noted at week 1 and lasting throughout the 26-week study period.50 Bright light therapy increases the effect of rTMS; an RCT found there was a greater reduction in depressive symptoms following bright light therapy as an adjunct to rTMS compared with rTMS alone.49 Bright light therapy may have some applicability as an adjunct to rTMS. The US Departments of Veterans Affairs and Defense recommend bright light therapy for people with “mild to moderate MDD, regardless of seasonal pattern or component.”79

Photobiomodulation is a type of light therapy administered at low levels of red and near infrared light.51 One trial found a significant decrease in depressive symptoms with photobiomodulation compared with sham therapy.51 Most studies report no adverse effects from either photobiomodulation or bright light therapy; one study within the search reported a few cases of mild headaches associated with bright light therapy.49 The mechanisms by which transcranial photobiomodulation may exert an effect are poorly understood and require more investigation before it can be recommended. Systemic photobiomodulation does not have enough evidence for recommendation for wider use, especially as all forms of photobiomodulation require training and healthcare resources to be administered in a standardised manner.

Deep brain stimulation

Deep brain stimulation (DBS) is an invasive treatment in which electrodes are surgically implanted into the brain and stimulate electrical activity.46 A systematic review comparing multiple forms of non-invasive neuromodulation found that DBS was less effective than rTMS.46 There was a greater discontinuation rate with DBS compared with sham therapy.46 Considering the invasive nature of DBS, it cannot be recommended for wider adoption except in extreme circumstances and only when other interventions for MDD, including rTMS, have failed. Risks would need to be balanced against benefits for individual patients in all cases.

Magnetic seizure therapy

Magnetic seizure therapy (MST) involves the induction of seizures using high-dose magnetic stimulation.46 It is performed under general anesthesia.80 A systematic review found it to be non-inferior to electroconvulsive therapy46 but with a higher discontinuation rate. Current data are limited, so conclusions on wider adoption are difficult to make at present. Much like DBS, the intervention requires a theater room due to the anesthesia requirements and surgical input. Availability of appropriate staff will likely limit how often the procedures can be undertaken.

Clinical application of emerging treatments

A limited number of studies identified emerging pharmacological and neuromodulation interventions. Almost all these interventions, whether pharmacological or neuromodulator, were trialed as adjunctive treatments to an antidepressant, and research is particularly limited on their influence on MDD treatment outcomes. Of the pharmacotherapy agents, minocycline at present appears to hold the most promise. Bright light therapies offer an intriguing mechanism for potentiating effects of other forms of neuromodulation. Beyond this, it is difficult to make even tentative recommendations. Maybe the most important contribution these emerging treatments offer is into possible etiological mechanisms for forms of MDD; for example, minocycline and neuropeptide Y point to the role of inflammatory mediators in the development of MDD and bright light therapy on the importance of sleep and circadian rhythms.


The US Departments of Veterans Affairs and Defense recommends offering ketamine or esketamine to people with MDD who have “not responded to several adequate pharmacologic trials” on the “balance of consistent evidence of benefit weighed against the risks for adverse effects and the limited information on the long term consequences.”79 The guidelines also recommend the use of rTMS in such patients but not TBS, concluding that the strength of the evidence is too low to justify a recommendation. Similarly, they considered but did not include psilocybin in their recommendation. The guideline does recommend bright light therapy for people with “mild to moderate MDD, regardless of seasonal pattern or component.” Similarly, the European Medical Agency approved the use of ketamine for people with treatment-resistant depression in 2019.81 In contrast, the National Institute for Health and Care Excellence (NICE) in England, did not recommend ketamine or esketamine in the same patient population on the basis of uncertain cost-effectiveness82 (which suggests that, were the cost to reduce in the future, it may be approved). NICE has not made specific recommendations on any of the other interventions we identified, though it noted that evidence of the efficacy of rTMS “in the short term is adequate, although the clinical response is variable”; it makes no specific recommendations for its use.


We have presented a synopsis of the novel and emerging treatments for MDD. While our intention was not to limit the search to any intervention, the treatments our search strategy highlighted fell broadly into two categories: pharmacological and neuromodulatory, maybe reflecting the thrust of research activity in recent years. That is not to say that there have not been important advances in psychological and psychosocial treatments also, but these could be considered as iterations on already established treatments (for example, third wave psychological therapies) and so fell outside the remit of our review. We would emphasize, however, that the treatment of MDD requires a holistic, bio-psycho-social approach and so the psychological and social must be considered alongside the treatment of the neurobiological. Indeed, some of the most robust evidence wase for treatments that incorporated psychedelic interventions with psychological support.

Strong conclusions on wider clinical uses cannot yet be made. Of the novel pharmacological treatments identified, most research has been conducted on the psychedelics, particularly ketamine and its enantiomer and psilocybin, with trials suggesting rapid antidepressant effects and, in the case of ketamine, reductions in suicidal ideation. However, concerns regarding the methodology of these trials, the risks of dependence and habituation with ketamine, and increased suicidality in some people administered psilocybin, may limit their applicability until better established in real-world settings.

For these novel and emerging treatments to acquire wider acceptance, their effectiveness will need to be compared with that of established treatments; far more studies will need to be conducted specifically into adverse consequences of their wider use, and novel research strategies to circumvent the problem of blinding (for example, by using active placebos) would need to be trialed.

Maybe their greatest promise lies in the intriguing ways they offer to incorporate different treatment modalities—for example, combining psychological support and psilocybin administration as one treatment—rather than one being seen as an adjunct to the other. However, researchers must be willing to describe in much more detail the psychological protocols they use in their studies than is currently available. The FDA recently published draft industry guidance on conducting clinical trials on psychedelic agents, in which it highlighted that many drug development programmes involve the provision of psychological support either while the participant is experiencing the acute effect of the drug or in subsequent sessions, but that this provision is inadequately characterized. Comparisons of different psychotherapeutic approaches would help determine which types of support or other contextual factors best augment and sustain the antidepressant effect of psychedelic agents.

The newer etiological mechanisms novel and emerging treatments hint at—for example, the role of inflammatory processes—provide opportunities to explore how external psycho-social factors influence endogenous risk to developing MDD. Even if these treatments do not gain wider adoption, either because of matters of effectiveness or tolerability, they are an important step in our understanding and characterization of MDD.

Questions for future research

  • What psychotherapeutic approaches are most effective in augmenting and sustaining the antidepressant effect of psychedelic agents in people who have major depressive disorder (MDD)?

  • What measures should be implemented for monitoring misuse, abuse, effectiveness, and adverse consequences of novel and emerging treatments for people with MDD?

  • What is the clinical and cost effectiveness of new and emerging treatments for people with MDD compared with established treatments?

  • Are there specific patient subpopulations for whom novel and emerging treatments for MDD are better indicated?

How patients were involved in the creation of this article

We sought feedback from people participating in trials of psychedelic treatments for major depressive disorder on our search strategy, findings, and analysis. One participant provided the following feedback (reproduced with permission): “Having been struggling with depression for over a decade, I have now been through several different types of treatment and therapies without a lasting success. I have been trying to keep up with the latest developments on the subject of novel therapies, but the myriad of clinical trials and papers on the novel therapies is overwhelming. [This article] brings a timely and much needed review on all the latest results and developments. The authors did an exhaustive search for novel treatments and made a very comprehensive summary of the results obtained with each type of treatment. This review highlights which treatments seem to be the most promising and also raises some of the issues that still need addressing in order for those to become mainstream.”


We thank UCL Institute of Orthopedics/RNOH Library for their assistance with the literature search.


  • State of the Art Reviews are commissioned on the basis of their relevance to academics and specialists in the US and internationally. For this reason they are written predominantly by US authors

  • Contributors: CN, PPR, and HAP all provided substantial contributions to the design of the work. All authors provided substantial contributions to the acquisition, analysis, and interpretation of data for this work. The acquisition of data was aided by the UCL Institute of Orthopedics and Royal National Orthopedic Hospital Library services. CN, PPR, and FJCdM drafted the work. All authors reviewed the work critically for important intellectual content. All authors gave final approval of the version to be published and agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved

  • Competing interests: We have read and understood the BMJ policy on declaration of interests and declare the following interests: CN declares no competing interests; PPR received a grant from the Royal National Orthopedic Hospital Charity to conduct a feasibility trial on using a collaborative model of care for people with co-occurring major depressive disorder and musculoskeletal disorders; FJCdM is a member of the Royal College of Psychiatry Working Group on Therapeutic use of Psychedelic and Related Substances; HAP is on the Clinical Advisory Committee for AbleTo and Magellan Studio and is a consultant for the National Committee for Quality Assurance.

  • Provenance and peer review: Commissioned; externally peer reviewed.